24-27 March 2019 ● Frankfurt, Germany
Copyright: Modified and published with permission from https://www.ebmt.org/annual-meeting
Sponsorship Statement: Publication of this supplement is sponsored by the European Society for Blood and Marrow Transplantation. All content was reviewed and approved by the EBMT Committee, which held full responsibility for the abstract selections.
Presenting author names are bold type in the contributor lists.
P001 Low treatment related mortality and relapse leading to excellent outcomes after allogeneic transplantation for acute lymphoblastic leukaemia using a non-myeloablative conditioning without T CELL depletion
Mary Lynn Savoie1,2, Jeff K Davies3,4, Jamie Cavenagh3,4, Heather Oakervee4, Jonathan Sive4, Matthew Smith4, Deborah Anderson4, John Gribben3,4, Bela Wrench3,4
1 University of Calgary, Calgary, Canada, 2 Tom Baker Cancer Centre, Calgary, Canada, 3 Barts Cancer Institute, Queen Mary University of London, London, United Kingdom, 4 St Bartholomew's Hospital, Barts Health NHS Trust, Barts Cancer Centre, London, United Kingdom
Background: Allogeneic hematopoietic stem cell transplantation is routinely offered to patients with high-risk or advanced ALL in the hopes of improving outcomes. Use of truly non-myeloablative (NMA) conditioning reduces toxicity in other contexts but outcome data for ALL patients after NMA transplants is lacking. We report the outcomes of 31 patients with ALL transplanted using a NMA conditioning without T cell depletion.
Methods: First transplant patients between October 2006 and June 2018 were reviewed. These were consecutive patients until 2015 then only those considered unfit for FMC conditioning as per the UKALL 2014 protocol. All patients were conditioned with fludarabine 25mg/m2/day for 5 days and cyclophosphamide 1g/m2/day for 2 days. Short course MTX and ciclosporin were used for GVHD prophylaxis. Standard supportive care was employed. Thirty-one patients with a median age of 43 (23-67) met the criteria for this case review. 30 had B-ALL and 10 were Philadelphia chromosome positive. 24 patients (77%) had high risk disease by standard diagnostic criteria. 27 (87%) were in first complete remission (CR1). Matched sibling donors were used in 13 instances with the remaining being fully matched unrelated donors. 58% of patients had a HCT-CI score of 0, 32% a score of 1 or 2 with 3 patients having a score of 3 or higher. Median CD34 dose was 5.3 x 106/kg (0.93-34.12) with a median CD3 dose of 2.13 x 108/kg (0.12-7.37)
Results: TRM was low at 7% at 1 year and 11% at 2 and 3 years respectively. No factors included in a univariate analysis (which included age, diagnosis, disease status, HCT-CI, donor type, CMV risk and cell dose) significantly impacted TRM. The incidence of classical acute (a) GVHD grade 2-4 and 3-4 was 18% and 8% by day 100 and 29% and 13% by day 180 if late onset aGVHD is included. 24 out of 30 eligible patients developed chronic GVHD of any stage. Relapse incidence was low (22% at 3 years in all patients, 17% in CR1 patients) and was not impacted by any pre-transplant factors including positive MRD post phase 2 induction (present in 6 patients). Notably, in univariate analysis relapse was significantly lower in patients who developed chronic GvHD.
Event-Free Survival (EFS) and Overall Survival (OS) at 3 years were 70% and 72% respectively for the whole cohort and 73% and 76% respectively for patients transplanted in CR1. Univariate analysis for pre- and post-transplant factors impacting EFS and OS identified only chronic GvHD which was associated with significantly better EFS and OS.
Conclusions: In conclusion, non-myeloablative T-replete conditioning for ALL transplantation is associated with low TRM and relapse resulting in excellent outcomes (Fig 1). Although this approach is associated with a significant incidence of cGvHD, this was protective against disease relapse consistent with a concomitant and sustained immunological Graft-versus-Leukemia effect.
[ [P001 Image] 1 . Figure 1]
Disclosure: Nothing to declare
P002 clinical relevance of in vitro generation of dendritic cells of leukemic origin to predict response to immunotherapy in patients with AML and MDS
Markus Freudenreich1, Johanna Tischer1, Tanja Kroell1, Andreas Kremser1, Julia Dreyssig1, Christine Grabrucker1, Anja Liepert1, Hans Jochem Kolb1, Christoph Schmid2, Helga Schmetzer1,3
1 University Hospital Grosshadern Ludwigs-Maximilians-University, Munich, Germany, 2 Augsburg University Hospital, Augsburg, Germany, 3 Helmholtz Center Munich, German Research Center for Environmental Health/Clinical Cooperative Group Haematopoetic Cell Transplantation (CCG-HCT), Munich, Germany
Background: Allogeneic stem cell transplantation (alloSCT) is the treatment of choice for many patients (pts) suffering from acute myeloid leukemia (AML). The graft vs. leukemia effect (GvL), applied by immunocompetent cells of donor origin, is the most important effector mechanism for the eradication of leukemia, The presentation of leukemic or allospecific antigens by malignant blasts is regarded as a crucial trigger for an effective allogeneic immune response. Conversely, insufficient stimulatory capacity by the leukemic blasts is thought to be a relevant escape mechanism from cellular immunotherapy (alloSCT or donor-lymphocyte infusion (DLI)).
The purpose was to test, whether the ability of malignant blasts to differentiate in vitro towards dendritic cells of leukemic origin (DCleu) is associated with response to alloSCT or outcome after immunotherapy (second alloSCT or DLI) for post-transplant relapse in AML.
Methods: Leukemic blasts were isolated from peripheral blood (PB) or bone marrow (BM) samples of AML patients before alloSCT (n=47) or at relapse after alloSCT (n=22). A panel of 6 different assays was used to generate DCleu in vitro (5 of them containing GM-CSF). Finally, in vitro results were correlated with clinical characteristics and outcome of patients treated with donor lymphocyte infusion and/or alloSCT.
Results: DCleu could be generated in vitro from all 69 samples. When correlating proportions of DC-subtypes generated ex vivo with clinical data, significantly higher mean proportions of DCleu in the DC-fraction were found in responders vs. non-responders to immunotherapy (76.8% vs 58.8%,p=0.006, range:13%-99%). Vice versa, the chance for response to immunotherapy was significantly higher, if a DCleu/DC ratio of >=50% could be reached in vivo (p=0.004). Those patientswere characterized by a longer time to relapse (p=0.04) and by a higher probability for leukemia-free survival (p=0.005).
Similarly, generation of higher amounts (>8%, p=0.04) of DCleu in the MNC-fraction, and generation of more mature DC (>47% CD83+, p=0.03 using the best GM-CSF containing assay) were associated with a longer time to relapse in the respective patients. Moreover, overall survival was improved, if >70% DCleu/DC could be generated with the best GM-CSF containing assay (p=0.048).
Conclusions: In vitro generation of DC/DCleu from leukemic blasts obtained in active stages of AML before alloSCT or at relapse post transplant were associated with clinical outcome. This observation supports a role of antigen presentation by leukemic cells for an allogeneic immune response in AML.
Disclosure: Nothing to declare
Abstract already published.
P004 Impact of consolidation by autologous HCT as compared to chemotherapy on toxicity of subsequent allogeneic HCT in CR2 in patients with AML
Jakob Passweg1, M, Labopin2, M. Christopeit3, J. Cornelissen4, T. Pabst5, G. Socié6, N. Russell7, I. Yakoub-Agha8, D. Blaise9, T. Gedde-Dahl10, H. Labussière-Wallet11, R. Malladi12, E. Forcade13, S. Maury14, E. Polge15, F. Lanza16, N.C. Gorin17, A. Nagler18, M. Mohty17
1 Universitätsspital Basel, Basel, Switzerland, 2 Saint Antoine Hospital, EBMT ALWP Office, Paris, France, 3 University Hospital Eppendorf, Hamburg, Germany, 4 Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands, 5 University Hospital Bern, Clinic of Oncology, Bern, Switzerland, 6 Hopital St. Louis, Paris, France, 7 Nottingham University Hospital NHS Trust, Nottingham, United Kingdom, 8 CHRU de Lille, Lille, France, 9 Institut Paoli Calmettes, Marseille, France, 10 Oslo University Hospital, Rikshospitalet, Oslo, Norway, 11 Centre Hospitalier Lyon Sud, Service Hematologie, Lyon, France, 12 University Hospitals Birmingham, Birmingham, United Kingdom, 13 CHU Bordeaux, Pessac, France, 14 Hôpital Henri Mondor, Creteil, France, 15 Hôpital Saint Antoine, Paris, France, 16 Ospedale Civile, Dipartimento di Ematologia, Medicina Trasfusionale e Biotecnologie, Unità Operativa di Ematologia, Ravenna, Italy, 17 Hospital Saint Antoine, Paris, France, 18 Chaim Sheba Medical Center, Tel Aviv University, Tel Hashomer, Israel
Background: The role of autologous hematopoetic cell transplantation (HCT) in the treatment of AML is not clear. Trials in the past have shown that autologous HCT consolidation lowers the risk of relapse, however the magnitude of this effect is limited . Autologous HCT is advocated in patients with AML with lower genetic risk in CR1.Many of these patients will eventually relapse and will undergo reinduction followed by allogeneic HCT in CR2.
Methods: The aims of this study is to analyze outcome of allogeneic HCT performed in CR2 comparing patients with prior consolidation by autologous HCT vs. patients with chemotherapy consolidation. Primary outcome is Non relapse mortality (NRM) of allogeneic HCT in CR2 in patients with, or without prior autologous HCT in CR1. Secondary outcomes include leukemia free survival (LFS), relapse rate (RI), graft versus host disease free relapse free survival (GRFS), overall survival (OS), and treatment related toxicities.
Results: 2619 adult patients reigstered with the ALWP of the EBMT with de novo AML were included, receiving a first allogeneic HCT in CR2, in 2000-2017 with (n=417) or without (n=2202) prior autologous HCT. Patient and transplant characteristics are shown in the Table. Patient groups were not entirely comparable, patients with prior autologous HCT were younger, had less often a favorable cytogenetic profile, had more commonly donors other than matched siblings and more often received reduced intensity conditioning (RIC) as compared to MAC conditioning.
Univariate outcomes are shown in the Table with slightly higher NRM risks in patients with prior autologous HCT consolidation. In multivariate analysis NRM risks in patients with prior autologous HCT were 1.34 (1.07-1.67), p=0.01 after adjustment for patient age, cytogenetic risk category, year of transplant, donor type, conditioning intensity, sex matching, time from diagnosis to relapse and time from relapse to allogeneic HCT as compared to patients with chemotherapy consolidation. Similarly, risks of events in LFS and GRFS were higher with prior autologous HCT, 1.17 (1.01-1.35), p=0.03 and 1.18 (1.03-1.35) p= 0.02, respectively, risk of death was also higher 1.13 (0.974-1.32) p=0.1 but this was not statistically significant.
Conclusions: We may conclude that some of the advantages of potentially higher anti-leukemic activity of high dose chemotherapy and autologous HCT when given to patients with AML in CR1(as was shown in a randomized trial by Vellenga E et al with lower relapse and higher LFS by approximately 10% but no significant differences in overall survival) may be lost by higher toxicity of allogeneic HCT in CR2 in case of subsequent relapse.
|Chemotherapy consolidation||Autologous HCT consolidation||P|
[ [P004 Table] 1 . Outcome]
Abstract already published.
P006 Extramedullary relapse as a poor predictor of survival even in patients with graft-versus-host disease post allogeneic hematopoietic cell transplantation for acute leukemia
Ioanna Sakellari1, Eleni Gavriilaki1, Ioannis Batsis1, Despina Mallouri1, Maria Gavriilaki2, Chrysa Apostolou1, Michalis Iskas1, Georgia Voutiadou1, Stella Bouziana1, Zoi Bousiou1, Varnavas Constantinou1, Marianna Masmanidou1, Damianos Sotiropoulos1, Evangelia Yannaki1, Chrysavgi Lalayanni1, Maya Pilavaki1, Konstantinos Chatziioannou1, Sotirios Papayannopoulos1, Achilles Anagnostopoulos1
1 G. Papanicolaou Hospital, Thessaloniki, Greece, 2 Aristotle University of Thessaloniki, Postgraduate Course, Medical Research Methodology, Thessaloniki, Greece
Background: Although relapse is a major cause of mortality in patients receiving allogeneic hematopoietic cell transplantation (HCT) for acute leukemia, limited and conflicting data exist on extramedullary relapse (EMR). We aimed to describe the incidence, risk factors, outcomes and prognosis in relapsed HCT recipients.
Methods: We retrospectively reviewed charts of consecutive allogeneic HCT recipients transplanted in our center with the indication of acute leukemia (7/1990-7/2018). We recorded: age, gender, disease, previous extramedullary involvement, phase at transplant, type of transplant, donor, conditioning, graft-versus-host-disease (GVHD), infections, treatment-related mortality and relapse mortality. In patients with extramedullary relapses, additional data on clinical manifestations, imaging, cerebrospinal fluid testing, histopathology and management were additionally documented. Incidence of isolated EMR (iEMR) and bone marrow relapse (BMR) was calculated using cumulative incidence (CI) analysis, with each and treatment-related mortality considered a competing risk.
Results: Among 554 alloHCT recipients followed for 1.8 (0.04-27.75) years, 61 (11%) patients presented with EMR. The majority of EMRs involved the central nervous system (CNS, 56%). Isolated EMR was observed in 38 patients at 9.5 (1.8-67.3) months. 10-year cumulative incidence (CI) of 10.5% for iEMR was associated only with pre-transplant advanced disease phase (p< 0.001). BMR was observed in 149 patients at 9 (0.3-276 months), with a 10-year CI of 34.8%. In the multivariate analysis, BMR CI was independently associated with fungal infections (p< 0.001), pre-transplant disease phase (p< 0.001) and lines of treatment (p=0.042). 10-year TRM of our whole cohort was 33.2%.
The majority of iEMR and BMR (75% and 81%, respectively) patients received systemic treatment combined with local radiation for iEMR (26%) and donor lymphocyte infusions (DLIs, 16% and 28% respectively) when feasible. Extensive chronic GVHD was recorded in 47% of iEMR and 48% of BMR patients. Outcomes were poor in iEMR, with 10-year overall survival (OS) of 18.3%. Favorable OS in iEMR was associated only with sibling donors (p=0.049) and not with other factors, such as treatment with DLIs or presence of chronic GVHD. Similarly poor outcomes (10-year OS of 19.1%) were observed in BMR. Favorable OS was independently associated only with the diagnosis of AML (p=0.050) and absence of bacterial infections (p=0.049). In the whole cohort, both iEMR and BMR were independent unfavorable predictors of OS (p< 0.001) along with extensive chronic GVHD (p=0.012).
Conclusions: In a large population with long-term follow-up, incidence of iEMR was relatively high, developed at the late post-transplant period and associated only with disease phase at transplant. Furthermore, iEMR and BMR conferred similarly poor outcomes despite systemic treatment or extensive chronic GVHD. These independent predictors of survival highlight the unmet clinical need of novel approaches either as maintenance or treatment to reduce extramedullary or systemic relapse post alloHCT for acute leukemia.
Disclosure: No competing financial interest.
P007 Impact of T-cell depletion on outcome in patients undergoing allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia
Sarah Morin1, Yan Beauverd1, Mitja Nabergoj1, Federica Giannotti1, Carole Dantin1, Amandine Pradier1, Thien-An Tran1, Thomas Longval2, Maria Anastasiou1, Laura Bounaix1, Caroline Stephan1, Olga Tsopra1, Carmen de Ramon Ortiz1, Anne-Claire Mamez1, Stavroula Masouridi-Levrat1, Yves Chalandon1
1 Geneva University Hospitals, Geneva, Switzerland, 2 APHP, Paris, France
Background: Allogeneic stem cell transplantation (HSCT) remains the only curative option for most patients with acute myeloid leukemia . However, HSCT is associated with significant morbidity and mortality, mainly related to acute or chronic graft-versus-host disease (aGvHD or cGvHD). At the Geneva University Hospital, we use in vitro partially T-cell depleted grafts in selected patients with < 0.1% Mesurable Residual Disease (MRD) at the time of transplantation. This approach is based on studies that showed reduced incidence of aGvHD and cGVHD with no significant impact on outcome with this procedure. However, this has not been studied specifically in patients with AML.
Methods: We conducted a single-center retrospective analysis to compare outcomes in adult patients who were transplanted with T-cell replete or in vitro partially T-cell depleted grafts (TDEP) for AML in first complete remission between 1998 and 2018, with either HLA-identical or 10/10 matched unrelated donors. In vitro partial T-cell depletion was performed using alemtuzumab.
Results: A total of 145 patients were analyzed. 89 (61%) and 56 (39%) received partially TDEP and T-cell replete grafts, respectively. Patients in the partially TDEP group were significantly younger (median age 50 vs 58.5 years (p< 0.05)). Their EBMT score was significantly lower (EBMT score 1: 11.2% vs 1.8%; score 2: 46.1% vs 25%; score 3: 34.8% vs 60.7%; score 4: 7.9% vs 7.1%; score 5: 0% vs 5.4%; p< 0.05) and their Disease Risk Index was significantly lower (low: 3.4% vs 0%; intermediate: 83.1% vs 69.6%; high: 10.1% vs 30.4%; p< 0.05). RIC regimen was used in 31.5% in the TDEP group in 66.1% in the T-cell replete group (p< 0.05). Stem cell source was PBSC in 98.9% in the partially TDEP and 95.6% in the T cell replete group, respectively. The 3-year overall survival (OS) and progression-free survival (PFS) were 55.9% and 49.2% in the patially TDEP group and 42.2% and 41.6% in the T-cell replete group (p=0.94 for OS and 0.53 for PFS). The 3 year cumulative incidence (CI) of grade II-IV aGVHD was 22% in the TDEP group and 61.7%n the T-cell replete group (p< 0.05) and for cGVHD it was 11.9% and 40.1%, respectively (p < 0.05). The CI of non-relapse mortality at 3 years was 27% in the T-cell replete group and 15.1% in the TDEP group (p = 0.124) and the CI of relapse at 3 years was 35.8% and 31.5% respectively (p = 0.53). Importantly, partial T-cell depletion had no impact on OS (HR 0.99%, p=0.98) in a multivariate analysis.
Conclusions: Partial T-cell depletion significantly reduced the CI of grade II-IV aGVHD and cGVHD in patients with AML with no significant impact on OS and RI. These results support the use of partial T-cell depletion for HSCT in selected AML patients with negative MRD prior to transplantation.
Clinical Trial Registry: Non applicable
Disclosure: Nothing to declare
Abstract already published.
Abstract already published.
P010 Long-term complete remission in CR1-AML patients after transplantation: Rising survivorship awareness
Maria Teresa Lupo-Stanghellini1, Francesca Lorentino1, Matteo Carrabba1, Carlo Messina1, Daniela Clerici1, Simona Piemontese1, Francesca Pavesi1, Fabio Giglio1, Raffaella Greco1, Magda Marcatti1, Sara Mastaglio1, Sarah Marktel1, Andrea Assanelli1, Luca Vago1, Chiara Bonini1,2, Consuelo Corti1, Jacopo Peccatori1, Massimo Bernardi1, Fabio Ciceri1,2
1 San Raffaele Scientific Institute, Milano, Italy, 2 University Vita-Salute San Raffaele, Milano, Italy
Background: After a diagnosis of acute myeloid leukemia (AML) the majority of patients (pts) who achieve complete remission (CR) eventually relapse, with only approximately 30% of pts maintaining CR for 3 years or longer. Late relapses (after 3 years in CR) occur rarely (6-10%) in pts receiving HSCT in CR1 and late effects are followed up by routine surveillance as well as preventative measures.
The purpose of this study was to investigate long-term outcomes in pts with diagnosis of AML undergoing HSCT at our Institution in CR1.
Methods: A standardized follow-up of HSCT-survivors is applied at our center. We analyzed 116 adult pts with AML in CR1 consecutively transplanted between January 2004 and December 2016 at our Institution. A written consent was given for the use of medical records for research. A landmark analysis was adopted for patients in CR at 2-y after HSCT (LTCR - long-term CR).
Results: LTCR was achieved after HSCT in 91/116 patients (male 55, female 36) transplanted in CR1. The median follow-up was 6 years and the median age at transplant 52 years (r 20-72). The selected donor was a family haploidentical relative in 29 cases, an HLA identical relative in 21, a match unrelated donor in 39 and a cord-blood in 2.
In this cohort of LTCR, the 5-year overall survival was 92% (95% CI 83-96). Cumulative incidence of relapse - evaluated in competing risk with transplant related mortality (TRM) - and TRM - evaluated in competing risk with relapse - were respectively 7% (95% CI 1-23) and 2% for the CR1 cohort. The event-free-survival (EFS) was 91% (95% CI 83-95).
The causes of death were relapse (6/10 pts), second cancer (3/10 pts) and sepsis (1/10 pts).
The 5-year incidence of dyslipidemia - defined as cholesterol >/= 200 mg/dl, and/or LDL >/= 115 mg/dl, and/or triglycerides >/= 150 mg/dl or need for specific treatment - was 24%.
The 5-year incidence of osteopenia / osteoporosis - defined as T-score lower than -1 and greater than -2.5 and T-score lower than 2.5 respectively - was 38%.
The 5-year incidence of second cancer was 11%: 10 non-melanoma skin cancer, 2 lung carcinoma, 3 cervical intraepithelial neoplasm, 1 thyroid cancer, 1 gastric cancer and 1 colon cancer.
The 2-year incidence of chronic moderate-severe GvHD was 27% (95% CI 13-38), with the latest diagnosis performed on day 570. Of note, 4/24 pts are still on active treatment at last follow-up.
Conclusions: Relapse incidence is low for patient that reached LTCR: patients in CR1 at transplant can obtain excellent OS and EFS once reached the target of LTCR.
A proactive long-term follow-up and strategy of counseling are essential to keep at best quality the survival advantage offered by HSCT in patients with AML in CR1.
Disclosure: Chiara Bonini has research contract with Intellia Therapeutics. The other authors declare that they have no conflicts of interest.
P011 Results of hematopoietic stem cells transplantation with TCRαβ+/CD19+-depletion from matched unrelated donors in pediatric acute leukemia patients in complete remission
M Ilyushina1, A Livshits1, Larisa Shelikhova1, Z Shekhovtsova1, D Balashov1, I Shipitsina1, D Shasheleva1, R Khismatullina1, S Blagov1, A Bogoyavlenskaya1, S Kovrygin1, S Kozlovskaya1, S Radygina1, Y Skvortsova1, E Kurnikova1, Y Muzalevsky1, A Kazachenok1, D Pershin1, M Fadeeva1, A Popov1, Y Olshanskaya1, I Kalinina1, N Miakova1, D Litvinov1, G Novichkova1, A Maschan1, M Maschan1
1 “Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology”, Moscow, Russian Federation
Background: Relapse, graft-versus-host disease (GvHD) and GvHD-associated mortality are major obstacles to success of transplantation from unrelated (MUD) donors in children with acute leukemia (AL). Negative depletion of αβ T cells and CD19+ B lymphocytes, conserves the mature donor-derived natural killer cells and γδ T cells in the graft, may improve GvHD control, immune reconstitution and prevent the relapse. We present a retrospect analyses of a cohort of pts with AL in CR transplanted from MUD with depletion.
Methods: A total of 59 children with acute leukemia (34 AML, 25 ALL, 21 female, 38 male, median age 8,5y) underwent allo HSCT from matched unrelated donor between June 2012 and July 2017. All pts were in complete remission (CR1=34, CR2=23, CR>2=2).
All pts, except one, received treosulfan-based conditioning. Either melphalan (n=56) or thiophosphamide (n=2) or etoposide (n=1) were added as a second agent. Fludarabine was used in all pts. Two types of GVHD prophylaxis were used: Type 1 (n=35): hATG 50 mg/kg and post-HSCT tacro/mtx (n=30) or without prophylaxis (n=5); type 2 (n=24): thymoglobulin(rATG) 5mg/kg, rituximab 200mg/m2 with either bortezomib on days +2, +5 (n=21) or tacro/mtx (n=3). aβ T cell depletion with CliniMACS was used in all cases. The median dose of CD34+ cells was 9 x106/kg, aβ T cells - 15 x103/kg. Median time of follow-up for survivors was 5,3 years (range, 2,3 - 6,5).
Results: Primary engraftment was achieved in 100% pts., the median time to neutrophil and platelet recovery was 15 and 14 days, respectively. All evaluable pts achieved sustained complete donor chimerism by day +30.
Early (100 day) mortality was 3,4% (1pt - bacterial sepsis, 1pt - ADV fulminant hepatitis), 5-years overall pTRM at 4 years was 13,5% (95%CI:7-26). Six late TRM events were due to: viral infection in 2 pts (CMV=1, ADV+CMV=1), bacterial sepsis in 2 pts and 2 pts had bacterial and viral infection, all late deaths were associated with cGvHD and prolonged corticosteroid therapy.
CI of acute GvHD grades II-IV was 36% (95% CI: 25-50), acute GvHD grades III-IV 3,7% (95% CI:1,5-14,5). CI of cGvHD was 27%(95%CI:18-41).
Regimen 2 was more effective in prevention of aGvHD II-IV in comparison with regimen 1: 8% (95% CI: 2,2-30) vs 45,7%, respectively, p=0,04. All events with acute GvHD grades III-IV had pts with regimen 1. rATG was also effective in prevention of cGvHD: CI at 4 years after HSCT was 12,5% vs. 37%, respectively, p=0,04. Cumulative incidence of relapse was 25% (95%CI: 14-50) without difference between rATG and hATG.
Event-free survival (EFS) (event=death or relapse) at 4 years was 61% (95%CI: 48-73), overall survival 59%(95%CI:47-72), there were no difference between age and diagnosis.
Conclusions: We confirm that the depletion of TCRαβ+/CD19+ T lymphocytes from the graft ensures high engraftment rate. Transplant-related mortality is caused by infections, mostly associated with cases of chronic GVHD. GvHD prophylaxis including rATG/Rituximab/Bortezomib improves GvHD control in recipients of TCRαβ+/CD19+depleted grafts in comparison to hATG/Tacro/MTX apparently without loss of anti-leukemic activity.
Disclosure: No disclosure
P012 Outcome of relapsed or refractory acute lymphoblastic leukemia patients with extramedullary disease or lymphoblastic lymphoma receiving inotuzumab ozogamicin or standard care in the INO-VATE trial
David I. Marks1, Daniel J. DeAngelo2, Matthias Stelljes3, Michaela Liedtke4, Wendy Stock5, Nicola Gökbuget6, Susan O'Brien7, Elias Jabbour8, Akil Merchant9, Tao Wang10, Eric Vandendries11, Alexander Neuhof12, Anjali Advani13, Hagop Kantarjian8
1 University Hospitals Bristol, Bristol, United Kingdom, 2 Dana-Farber Cancer Institute, Boston, MA, United States, 3 Universitätsklinikum Münster, Münster, Germany, 4 Stanford University School of Medicine, Stanford, CA, United States, 5 University of Chicago, Chicago, IL, United States, 6 Goethe University Frankfurt, Frankfurt, Germany, 7 University of California, Chao Family Comprehensive Cancer Center, Irvine, CA, United States, 8 MD Anderson Cancer Center, Houston, TX, United States, 9 University of Southern California, Los Angeles, CA, United States, 10 Pfizer, Groton, CT, United States, 11 Pfizer, Cambridge, MA, United States, 12 Pfizer Pharma GmbH, Berlin, Germany, 13 Cleveland Clinic, Cleveland, OH, United States
Background: Extramedullary relapse is difficult to treat in patients with acute lymphoblastic leukemia (ALL). Inotuzumab ozogamicin (InO) is a humanized anti-CD22 monoclonal antibody conjugated to calicheamicin. In patients with relapsed or refractory B-cell (R/R) ALL, InO showed significant higher response, MRD-negativity rates, and longer progression-free survival (PFS) and overall survival (OS) versus standard of care (SC) chemotherapy. This analysis of the INO-VATE trial investigated the outcomes of R/R ALL patients with extramedullary disease (EMD) or lymphoblastic lymphoma (LBL) at baseline.
Methods: Adult patients with R/R ALL (excluding isolated extramedullary relapse and active central nervous system leukemia) were randomized to InO (n=164) or SC (n=162). InO starting dose was 1.8 mg/m2/cycle (0.8 mg/m2 on Day 1; 0.5 mg/m2 on Days 8 and 15 of a 21-28-day cycle for ≤6 cycles). For patients with complete remission (CR) or CR with incomplete hematologic recover (CRi), InO dose was 1.5 mg/m2/cycle. SC included fludarabine/cytarabine [Ara-C]/granulocyte colony-stimulating factor [FLAG], Ara-C plus mitoxantrone, or high-dose Ara-C. Outcomes were analyzed by baseline EMD and LBL status.
|Response, n (%)||Inotuzumab ozogamicin (N=18)||Standard care (N=11)||Rate difference||P-value|
|Complete remission (CR)||4 (22.2)||0|
|CR with incomplete hematologic recover (CRi)||8 (44.4)||2 (18.2)|
|Partial response (PR)||1 (5.6)||1 (9.1)|
|Resistant disease (RD)||4 (22.2)||8 (72.7)|
|Progressive disease (PD)||1 (5.6)||0|
|CR/CRi, n (%) (95% confidence interval [CI] for rate and 97.5% CI for rate difference)||12 (66.7) (41.0-86.7)||2 (18.2) (2.3-51.8)||48.5 (12.4-84.5)||0.0144|
[ [P012 Table] 1 . Best overall response in patients with extramedullary disease at baseline or lymphoblastic lymphoma]
Results: At baseline, R/R ALL with EMD and LBL were diagnosed in 7 and 11 InO patients and 5 and 6 SC patients. Median (range) age of the InO and SC patients was 55.5 (20-78) and 47.0 (28-64) years, with 8/18 (44.4%) and 8/11 (72.7%) males, respectively. The rate of CR/CRi was significantly higher in the InO group (12/18 [66.7%], 95% confidence interval [CI]: 41.0-86.7) compared with SC (2/11 [18.2%], 95% CI: 2.3-51.8; P=0.0144) (Table). Allogeneic hematopoietic stem cell transplantation was carried out in 6/18 (33.3%) InO and 2/11 (18.2%) SC patients prior to any post-study induction therapy. The PFS hazard ratio [HR] was 0.502 (97.5% CI: 0.203-1.240; P=0.0410), with median PFS of 4.4 (95% CI: 1.9-7.1) months among InO and 1.6 (95% CI: 0.8-3.7) months in SC patients. The OS HR was 0.661 (97.5% CI: 0.269-1.621; P=0.1478), with median OS of 5.9 (95% CI: 3.4-9.4) months in InO versus 5.5 (95% CI: 2.1-6.7) months in SC patients (Figure). All patients had adverse events (AEs). Serious AEs occurred in 10/18 (55.6%) InO and 5/11 (45.5%) SC patients; 4 (22.2%) InO and 0 SC patients had grade 5 AE. One (1/15, 6.7%) patient in the InO group died from veno occlusive disease.
Conclusions: Among R/R ALL patients with EMD and LBL, improvement in remission rates, transplant rates, and progression free survival was shown in the InO group versus the SC group. Although patient numbers were small and limited the ability for a robust comparison, these results support the use of InO in patients in this difficult to treat population with R/R ALL and EMD or LBL.
[ [P012 Image] 1 . PFS and OS in patients with extramedullary disease or lymphoblastic lymphoma]
Clinical Trial Registry: www.clinicaltrials.gov (Identifier: NCT01564784)
Disclosure: DM: Consultancy: Novartis, Pfizer, and Amgen.
DJD: Honoraria: Takeda, Novartis, Shire, Pfizer, Blueprint Medicines, Incyte, Amgen, and BMS. Consultancy: Novartis, Pfizer, Amgen, ARIAD, and BMS. Research funding: Blueprint Medicines, Glycomimetics, and ARIAD.
MS: Honoraria: Novartis, Amgen, Jazz Pharmaceuticals, and Pfizer. Consultancy: MSD and Pfizer. Research funding: Pfizer.
ML: Research funding: Amgen/Onyx, BlueBirdBio, Celgene, Genentech/Roche, Gilead, Pfizer, Prothena, and Takeda. Membership on an entity´s Board of Directors or advisory committees: Caelum, Gilead, Pfizer, Prothena, and Takeda. Honoraria: Pfizer, Prothena, and Amgen/Onyx. Consultancy: Amgen/Onyx.
WS: Consultancy: Jazz Pharmaceuticals.
NG: Honoraria and research funding: Amgen and Pfizer.
SO: Consultancy: Vaniam Group, Pharmacyclics, Aptose Biosciences, GlaxoSmithKline, Amgen, Astellas, TG Therapeutics, Pfizer, Janssen, Gilead, Celgene, Alexion, Sunesis, and Abbvie. Research funding: Pharmacyclics, Kite Pharma, TG Therapeutics, Pfizer, Gilead, Acerta, Regeneron, and Sunesis.
EJ: Consultancy: Takeda, Pfizer and Bristol-Myers Squibb. Research funding: Novartis, Takeda, Pfizer, Abbvie, and Bristol-Myers Squibb.
AM: Nothing to declare.
TW, EV, and AN: Employment and equity ownership: Pfizer.
AA: Consultancy: Novartis and Glycomimetics. Research funding: Amgen and Pfizer. Honoraria: Pfizer.
HK: Honoraria: Pfizer, Orsenix, Immunogen, BMS, ARIAD, Amgen, Actinium and AbbVie. Research funding: Pfizer, Novartis, BMS, Astex, ARIAD, and Amgen.
P013 Stroma-mediated resistance to dasatinib of acute lymphoblastic leukemia (ALL) tumor cells can be abrogated by the histone deacetylase inhibitor panobinostat via calcineurin-dependent CXCR4 downregulation
Katia Beider1, Olga Landes1, Ania Hava Grushchenko-Polaq1, Olga Ostrovsky1, Valeria Voevoda-Dimenshtein1, Ivetta Danylesko1, Avichai Shimoni1, Amnon Peled2, Mohamad Mohty3, Arnon Nagler1
1 Sheba Medical Center, Ramat Gan, Israel, 2 Hadassah Hebrew University Medical Center, Jerusalem, Israel, 3 Hospital Saint-Antoine, Paris, France
Background: BCR-ABL-targeted tyrosine kinase inhibitors (TKI) revolutionized the outcome of patients inflicted with Ph+ B-ALL. Moreover, addition of TKI may be relevant strategy for Ph-like ALL patients.
Methods: We hypothesized that overcoming the BM microenvironment-mediated protection of ALL cells from TKI-mediated apoptosis may further enhance the responsiveness to TKI therapy.
Results: In vitro treatment of BCR-ABL-positive ALL cell lines (BV-173, NALM1 and NALM20) with dasatinib resulted in significant dose-dependent cell growth inhibition, with IC50 of 10-15 nM (p< 0.01). Furthermore, dasatinib exhibited significant growth suppression of BCR-ABL -negative ALL cells (NALM6 and REH), with IC50 of 250 nM and 185 nM, respectively. However, when co-cultured with bone marrow stromal cells (BMSCs), dasatinib-mediated effect was abrogated in both Ph- and Ph+ ALL cells. Furthermore, dasatinib treatment promoted significant upregulation of chemokine receptor CXCR4, on both mRNA and cell surface levels. Elevated CXCR4 expression was accompanied by increased responsiveness of ALL cells to CXCL12 stimulation, resulting in strong and sustained phosphorylation of Erk1/2 and Akt and increased adhesion capacity to BMSCs. Therefore, dasatinib-induced upregulation of CXCR4 promotes stroma-mediated survival advantage of ALL cells upon TKI therapy.
Next, in order to overcome the CXCR4-mediated stromal protection, we choose to combine dasatinib with the histone deacetylase inhibitor panobinostat, for its known ability to deplete CXCR4 in AML cells. Single-agent treatment with panobinostat demonstrated significant inhibition of Ph- and Ph+ ALL cell growth at low nanomolar concentrations (p< 0.01). Importantly, combination of panobinostat with dasatinib synergized (CI< 0.5), effectively overcoming the protection provided by BMSCs and inducing the apoptosis of Ph- and Ph+ ALL cells, as demonstrated by phosphatidylserine externalization, mitochondrial depolarization and DNA fragmentation. Furthermore, combining panobinostat with dasatinib significantly reduced CXCR4 surface levels in Ph- and Ph+ ALL cells. Accordingly, CXCL12-mediated responses, including Erk1/2 and Akt activation and adhesion to BMSCs were significantly reduced upon combined panobinostat/dasatinib treatment. These data indicate that panobinostat effectively suppresses both basal and dasatinib-induced CXCR4 expression and function in ALL cells overcoming stroma-mediated resistance to dasatinib.
To determine the molecular mechanism, we performed gene and protein expression analysis. Panobinostat, alone or in combination with dasatinib, significantly down-regulated the protein levels of calcineurin, a serine-threonine protein phosphatase previously implicated in T-ALL and B-ALL pathogenesis, as well as of NFATc1, a critical effector of the calcineurin signaling cascade, and NFATc1-regulated target genes. It was previously found that calcineurin signaling positively regulates CXCR4 expression in T lymphocytes. Additionally, cyclosporin A (CsA) decreased both basal and dasatinib-induced CXCR4 surface levels in ALL cells, overcoming the protection of the BMSCs which result in potentiation of the cytotoxic effect of dasatininb and panobinostat. Combining CsA with panobinostat resulted in deeper suppression of NFATc1-regulated target genes. We thus link the effect of panobinostat with calcineurin-dependent downregulation of CXCR4, blocking the ability of the leukemic cells to respond to CXCL12-mediated stromal support.
Conclusions: Taken together, our results identify calcineurin signaling pathway as a novel target of panobinostat in ALL cells and indicate that HDAC inhibition with panobinostat may be effective strategy for facilitating the anti-leukemic activity of TKI therapy.
Disclosure: nothing to disclose
P014 Allogeneic stem cell transplantation (allo-SCT) with sequential conditioning in patients with relapsed/refractory acute lymphoblastic leukemia: A report from EBMT acute leukemia working party
Abdul Hamid Bazarbachi1, Rama Al Hamed1, Labopin Myriam1, Boris Afanasyev2, Rose-Marie Hamladji3, Beelen Dietrich4, Ganser Arnold5, Scheid Christof6, Wu Depei7, Bunjes Donald8, Polina Stepensky9, Johanna Tischer10, Nicolaus Kröger11, Zina Peric12, Sebastian Giebel13, Arnon Nagler14, Mohamad Mohty15
1 EBMT Paris Study Office / CEREST-TC, Saint Antoine Hospital, INSERM UMR 938, Université Pierre et Marie Curie, Paris, France, 2 First State Pavlov Medical University of St. Petersburg, Raisa Gorbacheva Memorial Research Institute for Paediatric Oncology, Hematology and Transplantation, St Petersburg, Russian Federation, 3 Centre Pierre et Marie Curie, Service Hématologie Greffe de Moëlle, Alger, Algeria, 4 University Hospital, Essen, Germany, 5 Hannover Medical School, Hannover, Germany, 6 University of Cologne, I. Cologne, Germany, 7 First Affiliated Hospital of Soochow University, Suzhou, China, 8 Klinik fuer Innere Medzin III, Universitätsklinikum Ulm, Ulm, Germany, 9 Hadassah University Hospital, Jerusalem, Israel, 10 Klinikum Grosshadern, Med. Klinik III, Munich, Germany, 11 University Hospital Eppendorf, Bone Marrow Transplantation Centre, Hamburg, Germany, 12 University Hospital Centre, Zagreb, Croatia, 13 Maria Sklodowska-Curie Institute - Oncology Center, Gliwice, Poland, 14 Chaim Sheba Medical Center, Tel Hashomer, Israel, 15 Hopital St. Antoine, Paris, France
Background: The treatment of relapsed/refractory acute lymphoblastic leukemia (RR-ALL) remains a clinical challenge with a generally dismal prognosis. Allo-SCT using a sequential conditioning (“FLAMSA”-like regimen) has shown promising results in relapsed/refractory AML, but little is known about the efficacy of this procedure in RR-ALL.
Methods: We identified 115 adult patients (45% females; median age: 38 y; range, 18-66) with ALL in primary refractory phase (26%) or in relapse (74%), allografted between 2000 and 2017 from a matched sibling (31%), matched unrelated (58%) or haploidentical donor (11%) at EBMT participating centers. Almost half (49%) of the patients had T-ALL and 23% had a positive Philadelphia chromosome. Six patients (5%) underwent a previous auto-transplant. Karnofsky score was above 90 in 52% of patients. Conditioning was myeloablative (MAC) with high dose TBI in 30% of patients, reduced intensity (RIC) including low dose TBI in 22%, or with chemotherapy alone in 48%. In vivo T cell depletion was performed in 77 cases (69%). Most patients (74%) and about half of the donors (47%) were CMV positive. 14% of patients were males who received a graft from a female donor. The median follow-up was 37 (range, 13-111) months.
Results: Overall, 14 patients (13%) failed to engraft, 18 (16%) died within 100 days after allo-SCT without relapse, and 64 (56%) could achieve complete remission. At day 100, the cumulative incidences of grade II-IV and grade III-IV acute GVHD were 30% and 17%, respectively. The 2-year cumulative incidences of chronic and extensive chronic GVHD were 25% and 11%, respectively. The 2-year relapse incidence (RI) and non-relapse mortality (NRM) were 45% and 41%, respectively. The 2-year leukemia free survival (LFS), overall survival (OS) and GVHD relapse-free survival (GRFS) were 14%, 17% and 12%, respectively. In a multivariable Cox analysis, Karnofosky score below 90 negatively affected RI, LFS, OS and GRFS. Also, conditioning with chemotherapy alone, compared to TBI-based conditioning, negatively affected relapse rates (HR=4.13; p=0.0006), LFS (HR=2.32; p=0.004) and OS (HR=2.29; p=0.006).
Conclusions: Allo-SCT using a sequential conditioning regimen is proposed by different teams in RR-ALL, and could be an option, especially when considering a TBI-based regimen. However, the overall 2-year LFS of 14% suggests that these patients still face extremely dismal outcomes, highlighting that other therapies (e.g. BITE antibodies, inotuzumab, CAR T cells) need to be combined prior and/or after allo-SCT in order to further improve outcome.
Disclosure: no conflict of interest, no funding
Abstract already published.
P016 HLA-haploidentical microtransplantation as consolidation therapy in older patients with acute myeloid leukemia
Sergey Bondarenko1, Olesya Smykova1, Elena Darskaya1, Olga Pirogova1, Tatiana Rudakova1, Anna Smirnova2, Elena Babenko1, Ildar Barkhatov1, Tatiana Gindina1, Alexander Alyanskiy2, Ivan Moiseev1, Alexander Kulagin1, Boris Afanasyev2
1 Pavlov First Saint Petersburg State Medical University, R.M. Gorbacheva Memorial Institute of Hematology, Oncology and Transplantation, St. Petersburg, Russian Federation, 2 Pavlov First Saint Petersburg State Medical University, R.M. Gorbacheva Memorial Institute of Hematology, Oncology and Transplantation, St Petersburg, Russian Federation
Background: Clinical outcomes of acute myeloid leukemia (AML) in older patients still remain unsatisfactory. Allogeneic hematopoietic stem cell transplantation significantly improves the prognosis of patients with AML, but it is limited by severe toxicities and high incidence of treatment-related mortality in older patients. Microtransplantation (microHCT) is a promising cellular therapy in this group of patients.
Methods: We analyzed data of 65 patients ≥ 55 y.o. with AML who achieved complete remission (CR). The first group of 44 patients (microHCT group) received 1-3 courses of consolidation therapy, which consisted of cytarabine 0.5-1.0 g/m2 every 12h for 3 days (D-4, -3, -2), followed by an infusion of G-CSF-mobilized PBSC from haploidentical donor, without any GVHD prophylaxis. The median number of CD3+ cells infused per course was 1,4 (range, 1,0-2,5) х 108/kg. Among this group, 15 patients received nivolumab 100 mg/d on D+5. Donor chimerism was detected by short tandem repeat PCR and donor microchimerism was detected by quantitative real-time PCR method based on insertion/deletion polymorphism (D+3, +8, +15, etc.).
The second group of 21 patients (historical control group) received chemotherapy only as consolidation therapy. Age, sex and cytogenetic risk group were comparable between the 2 groups.
Results: The median follow-up time was 14 months (range, 4-46 months). The 2-year OS and DFS were 56% and 42%, respectively, in the microHCT group. The probabilities of 2-year DFS was significantly higher in the microHCT group than in the historical control group (42% vs 14%, respectively, P=.02). Donor microchimerism was detected in 38 (86%) patients with the median period of microchimerism persistence 8 days (range, 3-58 days). And 2 patients developed mixed chimerism (12% and 20%). One patient who had 12% of chimerism developed a cytokine release syndrome, this patient failed to respond to treatment and died on D+12. Another patient with 20% of chimerism developed a skin graft-versus-host-disease (GVHD) grade 3 (histologic confirmation), resolved by therapy with glucocorticosteroids. The regimen was well tolerated with the non-relapse mortality of 2% and low risk of GVHD. The most common adverse events were fever in the first 48 hours, transient rash and hematological toxicity. Given the small group of patients, it is impossible to assess the effectiveness of nivolumab.
Conclusions: Immunotherapy with HLA-haploidentical microHCT demonstrated higher efficacy compared to the historical control and has acceptable toxicity. Additional studies are necessary to further assess the role of microHCT as consolidation treatment for older patients with AML.
Disclosure: Nothing to declare
P017 Relapse of acute leukemia after allogeneic haematopoietic stem cell transplantation (HSCT): Combination of pharmacological and cellular approach
Riccardo Boncompagni1, Ilaria Cutini1, Carlo Nardini1, Stefano Guidi1, Antonella Gozzini1, Chiara Nozzoli1, Riccardo Saccardi1
1 Careggi University Hospital, Florence, Italy
Background: Relapse of Acute Leukemia (AL) after Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) is a dramatic event with a dismal prognosis. The availability of new drugs, such as azacitidine (AZA) and blinatumomab (Bl), either alone or in combination with donor T-Lymphocyte infusion (DLI), might improve the outcome. We report the experience of our centre in AL patients showing an initial relapse after HSCT.
Methods: From January 2012 to January 2017, 103 allogeneic HSCT were performed at our institution. 99 patients (pts) (96%) affected by AL (myeloid non-promyelocitic = 71, lymphoblastic = 27, undifferentiated/mixed phenotype = 5), 4 pts (4%) were second allogeneic procedures due to a previously relapse (3 pts), and 1 pts was an engraftment failure. All patients were regularly monitored for both chimerism and Minimal Residual Disease (MRD); patients showing an overt clinical relapse or a loss of full chimerism and/or detection of MRD received a conventional chemo-based reinduction or repeated DLI infusions, possibly interposed to the administrations of either Aza in Myeloid AL or Bl in Lymphoid AL. The median follow-up from HSCT was 22 months. Post-transplant relapse occurred in 33 pts. Ten pts received DLI based therapy: 4 pts alone, 3 pts in combination with Aza, and 3 pts in combination with Bl. The other 23 pts received chemotherapy courses, only 2 pts were not treated: 1 pts for the worsening of the general status and the other for invasive fungal infection.
Results:Forty-three pts (42%) were in complete remission (CR) and negative minimal residual disease (MRD) at the time of HSCT; 16 pts were in active disease (16%), and 44 (42%) showed a morphological CR with positive MRD. 41pts (40%) developed chronic Graft Versus-Host Disease (cGVHD) as followed: 23pts (22%) mild, 17pts (16%) moderate, and only 1 sever grade respectfully. Only 1 patient developed cGVHD after DLI. The overall Leukemia Free Survival (LFS) time was 16 months, the absence of cGVHD (Hazard Ratio - HR: 5,968; p = 0,01) and the pre-HSCT disease status (HR 2,353; p = 0,028) were the most important factors on LFS. All pts treated with chemo-based regimens died due to progression or infective complications. 1 patient of Aza/DLI group is still alive with a extramedullary relapse; 2 pts treated with Bl/DLI are in CR. OS was better for the DLI group compared to the chemotherapy group (28 vs 2 months respectfully; p < 0,001).
Conclusions: DLI after allo-HSCT has exhibited definite anti-leukemic effects in post-transplant patients. Bl and Aza were reported to increase DLI's Graft vs-Leukemia (GVL) effect. Although cGVHD could be the most important protective factor against the relapse but it remains the main cause of morbidity. Maximising the GVL effect without putting the patient at risk of GVHD still represents an unmet need. Our data show that the combination of either Bl or Aza with DLI infusion is safe and might represent an improvement in disease control in the early phase of relapse.
Disclosure: Nothing to declare
P018 Increased detection of (Leukemiaspecific) adaptive and innate immune-reactive cells under treatment of AML-diseased rats and one therapy-refractory AML-patient with blastmodulating, clinically approved response modifiers
M. Atzler1, A. Rank2, M. Inngjerdingen3, A. Rabe1, D. Deen1, R. Wang1, B. Eiz-Vesper4, C. Schmid2, H. Schmetzer1
1 Klinikum Grosshadern, Munich, Germany, 2 Augsburg University Hospital, Dept Med II, Hematopoetic Stem Cell Transplantation, Augsburg, Germany, 3 Oslo University Hospital, Rikshospitalet, Oslo, Norway, 4 Hannover Medical School, Institute for Transfusion-Medicine, Hannover, Germany
Background: Kits (combinations of immune-modulatory compounds:GM-CSF+Picibanil (Kit-I), Prostaglandine (PG-E2,Kit-K) or +PGE1 (Kit-M),patent 102014014993) convert myeloid blasts into dendritic cells of leukemic origin (DCleu). After stimulation with DCleu, antileukemic T-cells can be generated ex vivo. The compounds are approved for clinical use and are therefore attractive tools for immunotherapy in myeloid leukemia.
Methods: DC/DCleu-culture from rats'/patients' wholeblood (WB) with kits, mixed lymphocyte culture (MLC) of Tcells with kit-treated blood, functional blast-cytotoxicity and leukemia-specificity assays (CSA/ELISPOT/Degranulation/intracellular cytokine-assays). In addition flowcytometric evaluations of cellular and (leukemia-specific) lymphocyte compositions were performed from rats'/pts' blood in the course of the disease.
1) AML-diseased rats: each 3rats were treated with “I”, “K” or “M” or were untreated (controls). A significant increase of DCleu could be detected in spleen/PB in kit-(esp. M) treated compared to untreated animals without induction of blasts' proliferation (Ki67positivity): a significant reduction of blasts was seen with “M” (p=0.03/0.0001 in spleen/PB) and “I”, but not “K”. Successful treatment correlated with an increase of CD62L+Tcells, most likely representing Tmem-cells, (p=0.07) and a reduction of CD4+Treg (p=0.037).
2) 6 therapy-refractory AML-patients (during the course of decitabine/LD-AraCtreatment): kit-M was shown to ex vivo generate DCleu, activate immunereactive cells and mediate leukemia-specific/antileukemic response. Activated or leukemia-specific lymphocytes were monitored in low proportions in active stages of the disease as well as of two patients during the further course of persisting disease.
One of these patients (72 yo male), was offered an individual systemic salvage-treatment (Kit-M, applied as continuous infusions) for refractory leukemia. after approval from the local ethical commitee,extensive information of the patient about the experimental nature of the treatment and obtaining his written informed consent.
Clinically the treatment was well tolerated and the patient improved clinically. Neutrophils in WBC increased from 10% to 50%, thrombocytes reached 100 G/l after 24 days. After 4 weeks of treatment, the patient was discharged in good clinical conditions. 12 days later, progression of AML was seen with high blast counts in PB and BM. The patient developed severe sepsis and died few days later.
Immune monitoring showed (other than before treatment and in the patients without kit-M-treatment) a continuous increase of proliferating and non-naïve Tcells, NK, CIK- and NKT-, TH17 cells, Bmem-cells and DC in PB. The production of IFNƔ producing T-, CIK and NKT-cells was demonstrated, suggesting an in vivo production/activation of (potentially leukemia-specific) cells. Immune stimulatory effects decreased after discontinuation of therapy.
Conclusions: Treatment of WB as well as leukemically diseased organisms with blast-modulating kits (especially GM-CSF and PGE1) was well tolerated and induced clinical and immunological improvement (adaptive and innate immune system), whereas low counts of (leukemia-specific) activated immune-reactive cells were found in non-kit-treated organisms.
Disclosure: Nothing to declare
P019 Long-term outcomes after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with non-myeloablative and myeloablative conditioning: A single-center cohort study of 438 consecutive patients
1Lars Klingen Gjærde, Niels Smedegaard Andersen1, Lone Smidstrup Friis1, Brian Thomas Kornblit1, Søren Lykke Petersen1, Ida Schjødt1, Henrik Sengeløv1
1 Rigshospitalet, Copenhagen, Denmark
Background: Since 2000, we have at our institution used a non-myeloablative (NMA) conditioning regimen for older (>50 years) or significantly comorbid younger patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML). We aimed to compare the long-term outcomes of NMA conditioned patients with myeloablative (MA) conditioned patients.
Methods: We studied 220 NMA and 218 MA conditioned adult (>15 years) consecutive patients receiving their first allo-HSCT for AML from 2000 to 2017 at Rigshospitalet. NMA conditioning consisted mainly of 2 Gy total body irradiation (TBI) and fludarabine 90 mg/m2 (95% of cases). MA conditioning consisted mainly of cyclophosphamide 120 mg/kg and either 12 Gy TBI (86% of cases) or busulfan 12.8 mg/kg (5% of cases), or fludarabine 150 mg/m2 and treosulfan 42 mg/m2 (6% of cases). Five percent and 19% of NMA and MA conditioned patients, respectively, received anti-thymocyte globulin. Patients were followed until death or end-of-follow-up on October 31st, 2018. Cumulative incidences with 95% confidence intervals (CI) of acute graft-versus-host disease (aGVHD) grade II-IV, chronic graft-versus-host disease (cGVHD), relapse and non-relapse mortality (NRM) were calculated and compared between NMA and MA conditioned patients using Gray's test with death as a competing risk (or relapse when comparing NRM). Overall survival (OS) was estimated by the Kaplan-Meier method.
Results: NMA and MA conditioned patients were comparable when regarding sex (49% and 48% female, respectively) and donor (matched related donor in 34% and 36%, respectively), but differed, as expected by indication, with regards to age (median of 60 versus 42 years, respectively) and Karnofsky score (< 90 in 18% and 11%, respectively). NMA conditioned patients had generally a lower AML stage at transplant (1st complete remission in 68% versus 49% of MA conditioned patients) and a lower AML cytogenetic risk (adverse risk in 17% versus 21% of MA conditioned patients). Patients were followed for a total of 2090 person-years (median follow-up in surviving patients was 6.2 years). aGVHD grade II-IV occurred less frequently in NMA conditioned patients (20% [CI: 15%-26%] versus 38% [CI: 32%-45%] in MA conditioned patients, p < 0.01), while cGVHD occurred in similar rates (50% [CI: 43%-56%] in NMA conditioned patients and 51% [CI: 44%-58%] in MA conditioned patients, p = 0.77). There was a trend towards a higher relapse rate in NMA conditioned patients (34% [CI: 28%-40%] versus 28% [CI: 22%-34%] in MA conditioned patients, p = 0.07), and NMA conditioned patients had, however not with statistical significance, lower NRM (20% [CI: 14%-25%] versus 25% [CI: 19%-31%] in MA conditioned patients, p = 0.27). OS (Figure) was comparable, with 5-year OS rates of 55% (CI: 48%-62%) in NMA conditioned patients and 54% (CI: 47%-61%) in MA conditioned patients.
Conclusions: Patients with AML undergoing allo-HSCT with NMA conditioning at our institution were older and frailer than MA conditioned patients, but their overall survival after transplantation was comparable. This might be explained by a generally lower AML stage and cytogenetic risk at transplant in NMA conditioned patients.
[ [P019 Image] 1 . Overall survival after allo-HSCT for AML in 220 NMA and 218 MA conditioned patients]
Disclosure: Nothing to declare.
P020 Low dose cytarabine may prevent hematologic relapse prior to hsct in patients with AML in first complete remission with minimal residual disease
Sarah Lindner1, Fabian Lang1, Heike Pfeifer1, Tobias Berg1, Salem Ajib1, Julia Riemann1, Zuzanna Jedlickova1, Saskia Güller1, Rosa Toenges1, Juliane Steinmann1, Hans Martin1, Hubert Serve1, Gesine Bug1
1 University Hospital Frankfurt, Frankfurt am Main, Germany
Background: Allogeneic HSCT is urgently indicated in patients with AML in first complete hematologic remission (CHR) after intensive chemotherapy with increasing or recurrent minimal residual disease (MRD). These patients are at high risk of hematologic relapse (HR) during preparation of their transplant and HSCT with active AML was found associated with poor outcome. Azacitidine has recently been shown to substantially delay or even prevent HR in >50% of patients (RELAZA2 trial, Platzbecker et al., Lancet Oncology 2018). We here present the outcome of a small cohort of consecutive patients with MRD-positive AML who received low dose cytarabine (LDARAC) as bridging therapy prior to HSCT.
Methods: MRD was assessed by quantitative polymerase chain reaction (qPCR) using mutated NPM1 (n=5), RUNX1-RUNX1T1 (n=2), CBFB-MYH11 (n=1) or KMT2A-PTD (n=1). MRD negativity was defined as ratio of oncogene to control gene (ABL1) ≤0,01% while increased or recurrent MRD required a ratio >1% (Shayegi et al., Blood 2013). Primary endpoint of our retrospective analysis was progression to HR (≥5% bone marrow blasts or extramedullary disease); secondary endpoints were achievement of molecular remission prior to HSCT, neutropenia G4 according to CTCAE, thrombocytopenia G4, anemia ≥G3, admission to hospital, OS and RFS. OS and RFS were calculated from the first dose of LDARAC. LDARAC was self-administered subcutaneously by the patients at home at a flat dose of 20mg BID over 10 days and repeated after 4 weeks if necessary.
Results: Between 12/2015 and 10/2018, nine patients (median age 55, range, 22-68 years) with low (n=7), intermediate (n=1) or high-risk cytogenetics (n=1) according to ELN criteria 2017 were treated in continuous CHR for increasing (n=2) or recurrent MRD (n=7) starting at a median of 260 (range, 154-651) days after the last consolidation therapy, i.e., duration of CHR was >6 months in all pts. Patients received one (n=4), two (n=2) or three cycles (n=3) of LDARAC prior to HSCT. In three patients, neutropenia G4 occurred and one patient needed platelet transfusion. All patients were managed in the outpatient setting. In eight out of nine patients (89%), HR was successfully prevented and 3 patients (33%) even became MRD negative prior to HSCT. One patient (RUNX1-RUNX1T1 positive AML) progressed to HR after one cycle of LDARAC and received salvage therapy with high-dose ARAC and mitoxantrone (HAM) prior to HSCT. All patients proceeded to HSCT from a matched related (n=1), unrelated (n=7) or haploidentical donor (n=1) and are still alive (median follow-up of 666 days). Conditioning regimens included fludarabine (FLU)/melphalan (MEL)/TBI (n=5), FLU/MEL (n=1), FLU/TBI (n=1), FLU/busulfan(BU)4 (n=1) and thiotepa/BU3/FLU (n=1). After HSCT, only the LDARAC-refractory patient relapsed, resulting in a probability of RFS of 88% at 2 years.
Conclusions: Our data suggest that a bridging therapy with up to three cycles of LDARAC prior to HSCT is feasible and was associated with favorable outcomes in patients with NPM1-mutated or core binding factor AML and molecular relapse >6 months after achieving a first CHR. The treatment has low costs, can be administered on an outpatient basis and is very well tolerated.
Clinical Trial Registry: Not applicable
Disclosure: Nothing to declare
P021 Matched sibling vs haploidentical transplant for acute myeloid leukemia: A single centre experience from developing country
Shilpa Prabhu1, Sharat Damodar1, K.S Nataraj1, Sunil Bhat1, V.M Annapandian2, Shobha Badiger1, K Vasundhara1, Ruchi Chaudhary1
1 Narayana Health City, Hematology and Stem Cell Transplant, Bangalore, India, 2 Narayana Hrudayalaya Foundations, Academic Research, Bangalore, India
Background: Allogenic hematopoietic stem cell transplant (HSCT) is the only curative treatment for all the patients with AML. High risk disease qualifies for upfront HSCT irrespective of the presence of matched sibling donor (MSD). In the absence of MSD, haploidentical stem cell transplant is easier option with success rates as high as MSD in a high volume transplant centre. We present our experience from a single centre.
Methods: We analyzed retrospective data of AML patients who have undergone HSCT at our centre between January-2013 and August-2018. For MSD transplant we used Fludarabine + Busulfan or Fludarabine + Melphalan conditioning regimen, in matched unrelated donor transplant (MUD) regime used was Fludarabine + Busulfan + ATG. We followed John Hopkins's protocol for haploidentical HSCT. Cyclosporine + methotrexate was used as GVHD prophylaxis in MSD and unrelated donor group and cyclophosphamide + tacrolimus + mycophenolate was used for haploidentical post-transplant. Day 100 Survival, overall survival (OS), incidence of GVHD and CMV reactivation was computed.
Results: A total of 96 AML patients underwent HSCT during the study period, the basic and clinical characteristics of the study patients are presented in Table 1. Conditioning regime did not have significant impact on OS. Survival at day 100 was 78%. The OS function and relapse free survival (RFS) function did not significantly differ between MSD and Haploidentical transplantation (68.3% vs 60.0%; p=0.225) and (68.3% vs 75.0%; p=0.760) (Graph 1). Disease status at latest follow up showed that 82% were in remission and 18% had relapsed. Overall one year survival and five year survival in the entire cohort was 68% and 58% respectively. The average cost of MSD transplant at our centre is INR 10,00,000 (€ 10000-12000), haploidentical transplant is INR 20,00,000 (€ 25000-27000) and MUD transplant is INR 32,00,000 (€ 30,000 + 10000 for stem cell procurement).
Conclusions: Our study showed comparable outcomes in MSD and Haploidentical transplant with respect to Day100 survival, OS, and rate of GVHD. In a developing country like India where patients are not covered under state health insurance, the additional cost of procurement of stem cells in a MUD transplant would add to the financial burden to the patients. Haploidentical transplant is a feasible option in case of non-availability of MSD, due to ease of donor availability and strong motivation from the family donor to donate the stem cells.
|Total patients = 96||N (%) or Mean ± SD|
|Gender (M / F)||65 (66.7%) / 31 (32.3%)|
|Age (Years)||28.01 ± 17.09|
|Matched Sibling Donors (MSD), Haplo-identical, Matched Unrelated Donors (MUD)||60 (62.5%), 30 (31.3%), 6 (6.3%)|
|Mean CD34 cell dose||6.8 ± 2.8 x 106/mcl|
|Acute GVHD||50 (52.1%)|
|Chronic GVHD||9 (9.4%)|
|CMV reactivation||70 (72.9%)|
|Platelets engraftment day||14.9 ± 5.9|
|Neutrophil engraftment day||13.8 ± 3.3|
[ [P021 Table] 1 . Basic demographics and clinical details of the study patients]
Disclosure: Nothing to declare
P022 Favorable-risk acute myeloid leukemia with mutant NPM1: The role of allogeneic hematopoietic stem cell transplantation
Chara Giatra1, Ioannis Baltadakis1, Ioannis Tsonis1, Zois Mellios1, Dimitra Oikonomopoulou1, Konstantinos Gkirkas2, Maria Garofalaki1, Eirini Tziotziou1, Zoi Arapidou1, Tatiana Tzenou1, Maria Stamouli2, Maria Bouzani1, Sosana Delibasi1, Maria Pagoni1, Stavros Gigantes1, Panagiotis Tsirigotis2, Nikolaos Harhalakis1, Dimitrios Karakasis1
1 Evangelismos General Hospital, Athens, Greece, 2 University of Athens, Attikon Hospital, Athens, Greece,
Background: Allogeneic stem cell transplantation (allo-HSCT) is not indicated as consolidation of first complete remission (CR1) in favorable-risk acute myeloid leukemia (AML) bearing mutations in nucleophosmin (NPM1) in the absence of FLT3 internal tandem duplication (FLT3-ITD). Nevertheless, a substantial proportion of patients eventually proceed to allo-HSCT beyond CR1 or for chemoresistant minimal residual disease (MRD) while in CR1, which might compromise transplantation outcomes. The study aimed at examining the characteristics and results of allo-HSCT in AML cases with mutated NPM1 and wild-type FLT3 (NPM1mut/FLT3wt), with special focus on molecular monitoring of MRD following transplantation.
Methods: From 11/2010 until 04/2018, 16 patients (women/men, 9/7) underwent allo-HSCT for NPM1mut/FLT3wt AML. At transplant, median age of patients was 44.5 years (range, 35-63), and disease phase was CR1 (n=5), CR2 (n=9), or primary refractory (n=2). Among the 13 patients who were transplanted in CR and had available molecular MRD assessments, 10 had detectable mutant NPM1 transcripts by real-time quantitative PCR (RQ-RCR). Also, 4 patients fulfilled criteria of molecular relapse (increasing levels of NPM1-mutated transcripts in two successive bone marrow samples), with mutant NPM1 load of 386-4,900 transcripts/10,000 ABL transcripts). The conditioning regimen was myeloablative in the majority of cases (n=14) or reduced-intensity (n=2). The type of donor varied, namely HLA-identical sibling (n=6), matched unrelated (n=5), haploidentical relative (n=3), or double umbilical cord blood (n=2).
Results: Engraftment was achieved in all cases, with a median time to absolute neutrophil count >500/uL of 16 days (range, 12-29). Among the 13 patients with post-transplant monitoring of MRD by RQ-PCR, 9 exhibited a stable molecular remission whereas a rising level of NPM1-mutated transcripts was observed in 4 cases due to either hematologic (n=3) or molecular (n=1) relapse of disease. The cumulative incidences (CIN) of hematologic relapse and non-relapse mortality (NRM) were 18.75% and 25% at 12 months, respectively. No events of relapse or NRM were encountered beyond 6 months from allo-HSCT. Out of 3 patients with hematologic relapse post transplant, 2 died of disease whereas one achieved a stable complete remission after withdrawal of immunosuppression. At a median follow-up time of 40 months (range, 14-89), 10/16 patients continue to be alive in CR. The estimated disease-free (DFS) and overall survival (OS) at 3 years is 56.2% (95% CI, 36.5-86.7%) and 62.5% (95% CI, 42.8-91.4%), respectively.
Conclusions: Although the majority of patients are transplanted in relatively advanced phase of disease, allo-HSCT remains a highly curative modality for NPM1mut/FLT3wt AML cases with refractory disease or molecular relapse following conventional therapy. Regular monitoring of MRD by RQ-PCR, as well as identification of additional prognostic molecular markers by next-generation sequencing (NGS) may allow better timing of allo-HSCT with further improvement of outcomes.
Disclosure: Nothing to declare.
Abstract already published.
P024 Pooled clinical safety analysis of CPX-351 versus conventional chemotherapy in patients with newly diagnosed or relapsed/refractory acute myeloid leukemia (AML)
Jorge E Cortes1, Robert J Ryan2, Arthur C Louie2, Michael Chiarella2, Geoffrey L Uy3
1 University of Texas MD Anderson Cancer Center, Houston, TX, United States, 2 Jazz Pharmaceuticals, Inc., Palo Alto, CA, United States, 3 Washington University School of Medicine, St. Louis, MO, United States
Background: CPX-351 (Vyxeos®) is an advanced liposomal encapsulation of cytarabine/daunorubicin at a synergistic 5:1 molar ratio. CPX-351 is approved by the US FDA and EMA for the treatment of adults with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.
Methods: Safety data were pooled from 5 studies of CPX-351 in adults aged 18-75 years with newly diagnosed or relapsed/refractory AML. CPX-351 induction consisted of 100 units/m2 (cytarabine 100 mg/m2 + daunorubicin 44 mg/m2) on Days 1, 3, and 5 (second induction: Days 1 and 3). CPX-351 consolidation consisted of 65 or 100 units/m2 (varying by study) on Days 1 and 3. CPX-351 was evaluated against standard-of-care controls.
Results: Baseline characteristics were generally balanced between CPX-351 (n=375) and controls (n=236); the majority of patients were aged ≥60 years (78%; 87%) and had secondary AML (55%; 72%). Controls included 7+3 (n=192) and salvage therapy with mitoxantrone/etoposide/cytarabine (n=23), idarubicin/cytarabine (n=8), other cytarabine-based chemotherapy (n=12), and mitoxantrone/etoposide (n=1). The treatment-emergent adverse event (TEAE) profile of CPX-351 100 units/m2 was comparable to induction controls, but associated with a greater proportion of patients with TEAEs, grade ≥3 TEAEs, and serious TEAEs during consolidation (Table). Therefore, the CPX-351 consolidation dose was reduced to 65 units/m2 in latter studies; this dose demonstrated an improved TEAE profile similar to consolidation controls. The most frequent system organ class was gastrointestinal disorders for both CPX-351 and controls; a lower incidence was reported for CPX-351 (90%) versus controls (95%), with this difference driven by the lower incidence of diarrhea for CPX-351 (46%) versus controls (66%). The most frequently reported grade ≥3 TEAEs were febrile neutropenia (CPX-351: 62%; controls: 59%), pneumonia (16%; 13%), hypoxia (10%; 11%), and bacteremia (10%; 3%). Early mortality rates, both overall and by treatment period, appeared lower with CPX-351 versus controls at Day 30 and Day 60 (Table); the majority of early deaths were attributable to TEAEs.
Conclusions: Across the 5 studies comprising the CPX-351 clinical development program, CPX-351 demonstrated a safety profile comparable to conventional chemotherapy in adults with newly diagnosed or relapsed/refractory AML.
|Induction period||Consolidation period||Overall treatment period|
|n (%)||100 units/m2 CPX-351 (n=375)||All controls (n=236)||65 units/m2 CPX-351 (n=52)||100 units/m2 CPX-351 (n=63)||All controls (n=55)||CPX-351 (n=375)||All controls (n=236)|
|Any TEAE||375 (100)||236 (100)||44 (85)||61 (97)||49 (89)||375 (100)||236 (100)|
|Grade ≥3 TEAE||342 (91)||211 (89)||28 (54)||46 (73)||30 (55)||346 (92)||212 (90)|
|Serious TEAE||145 (39)||76 (32)||25 (48)||33 (52)||24 (44)||189 (50)||91 (39)|
|Treatment-related TEAE||362 (97)||220 (93)||36 (69)||49 (78)||39 (71)||363 (97)||220 (93)|
|TEAE leading to discontinuation||7 (2)||3 (1)||0||0||0||7 (2)||3 (1)|
|TEAE leading to death||28 (7)||25 (11)||1 (2)||5 (8)||4 (7)||34 (9)||29 (12)|
|30-day mortality||14 (4)||15 (8)||1 (2)||2 (3)||2 (6)||21 (6)||19 (10)|
|60-day mortality||23 (6)||17 (9)||1 (2)||2 (3)||2 (6)||47 (13)||38 (20)|
[ [P024 Table] 1 . Table]
Clinical Trial Registry: NCT00389428, NCT00788892, NCT00822094, NCT02238925, NCT01696084
Disclosure: JE Cortes has received consulting fees from Jazz, Novartis, Daiichi Sankyo, Pfizer, and Astellas Pharma, and research funding from Jazz, Novartis, Daiichi Sankyo, Pfizer, Astellas Pharma, and Arog. RJ Ryan, M Chiarella, and AC Louie are employees of and hold stock ownership in Jazz; AC Louie additionally has patents/royalties with Jazz. GL Uy has received consulting fees from Curis and GlycoMimetics.
P025 Comparison of outcomes after HLA-haploidentical related versus unrelated hematopoietic stem cell transplantation with post-transplantation cyclophosphamide for acute leukemia
László Gopcsa1, Hajnalka Andrikovics2, Anikó Barta1, Árpád Bátai1, Ottó Csacsovszki1, Zoltán Csukly1, János Dolgos1, János Fábián1, Zita Farkas1, Anikó Fodor1, Apor Hardi1, Ágnes Király1, Gergely Lakatos1, Enikő Lehoczki1, Lilla Lengyel1, Nora Lovas1, Zoltán Mátrai1, Gábor Mikala1, Nora Meggyesi2, Melinda Paksi1, Mónika Pető1, Katalin Rajczy3, Marienn Réti1, Eszter Sári1, János Sinkó1, Andrea Sipos1, Anikó Szilvási3, Éva Torbágyi1, István Vályi-Nagy1, Tamás Masszi4, Péter Reményi1
1 Central Hospital of Southern-Pest, National Institute of Hematology and Infectious Diseases, Haematology and Stem Cell Transplantation, Budapest, Hungary, 2 Central Hospital of Southern-Pest, National Institute of Hematology and Infectious Diseases, Molecular Genetic Laboratory, Budapest, Hungary, 3 National Blood Transfusion Service, Budapest, Hungary, 4 Semmelweis University 3 rd. Budapest, Hungary
Background: Haploidentical hematopoietic stem cell transplantation (HSCT) with post-transplantation Cyclophosphamide (PGCY) marked improved clinical outcome. Recent studies comparing allogeneic HSCT using unrelated donors versus haplo donors in patients with acute leukemia have suggested equivalent outcomes. The depletion of T-cells with PGCY was subsequently applied for unrelated HSCT setting for patients with unrelated donor.
Methods: We performed a retrospective study on 90 patients with acute leukemia in order to compare the outcome after HLA haploidentical (n=30) and unrelated HSCT (n=60) with PGCY. The main characteristics of patients were similar in both groups. Baseline disease were: 19 AML (63%) and 11 ALL (37%) for Haplo group and 33 AML (55%) and 27 ALL (45%) for unrelated group. Disease state at time of haplo and unrelated-HSCT were following: 19 and 50 patients in CR1 (63% and 83%) and 11 and 10 non CR1 (37% and 17%). For AML recipients mainly received thiotepa, busulfan and fludarabine and for ALL recipients received TBI and Etoposide conditioning. All patients who received PBSC graft were treated with rabbit antithymocyte globulin (ATG) on days -2 and -1.
Results: At the time of analysis, the OS and DFS did not differ between the Haplo and unrelated groups (67% vs 63%, and 63% vs 56%). Incidence of severe (grade 3-4) acute GVHD was the same in two groups (10% versus 8%). Recipients of Haplo-HSCT transplant were statistical significance less likely to experience disease relapse (3% vs 28%) and chronic GVHD (20% vs 47,5%). However, GVHD free relapse free survival (GRFS) rate was slightly higher after Haplo-HSCT (77% vs 64%). Addition, cumulative incidence of TRM rate was higher after Haplo-HSCT (30% vs 15%).For Haplo and unrelated groups who underwent HSCT in CR1, the OS were 84% and 67% versus 22% and 45% for those in non CR1. For AML, the OS was same in two groups (Haplo 63% versus unrelated 67%). However patients with ALL, the OS was higher in Haplo group compared with unrelated group (72% versus 59%). The impact of pretransplant disease state have a more powerfull effect on survival in the Haplo-HSCT setting (for AML CR1 77% versus non CR1 33% and for ALL CR1 100% versus non CR1 0%). Viral reactivations were significant concern in both groups.
Conclusions: Our retrospective analysis suggests largerly similar OS and DFS with Haplo versus unrelated transplants with PGCY for acute leukemia. Our data indicate that Haplo-HSCT results in a lower incidence relapse and of chronic GVHD and higher GRFS compared with unrelated HSCT. In addtion, the pretransplant disease state have the important effect on the outcomes in both groups. Allo-PBSC with ATG can be used safely and effective as graft source in Haplo-HSCT with acceptable post-transplant outcomes and replaced BM in this settings. More statistical data for transplant related characteristics will be provided at the presentation.We emphasize that use the same PGCY GVHD prophylaxis for all types of allogeneic transplant. Based on our results, we recommend Haplo-HSCT with PGCY against unrelated transplant for patients with acute leukemia.
Disclosure: Disclosure of conflict of interest: None.
P026 Excellent efficacy and tolerability of inotuzumab ozogamicin in B-cell all relapsed after allo-HSCT
Teresa Artola1, José Guinea2, Lourdes Aguirre1, Nagore Argoitia1, Nerea Uresandi1, Carmen González1, María Araiz1, M. José Pizarro1, Dolores de Juan1, Carlos Vallejo1
1 University Hospital Donostia, San Sebastián, Spain, 2 University Hospital of Araba, Hematology, Vitoria/Gasteiz, Spain,
Background: allo-HSCT is a potentially curative approach for high-risk B-cell ALL. However, relapse after-HSCT continues to be an issue, and the management of this situation is difficult, challenging, and with a very poor survival. Inotuzumab ozogamicin is a humanized CD22 monoclonal antibody linked to the cytotoxic agent calicheamicin. Inotuzumab has shown striking clinical activity even among heavily pretreated relapsed/refractory ALL patients. However, the experience in the post-allo-HSCT setting is very limited.
Methods: 211 pts underwent first allo-HSCT between January 2015 and October 2018 in our center, including 28 pts with ALL (our series). Median follow-up of the series was 17 months (range: 2-47). Characteristics of the series are shown in table 1. Five pts died in CR from non-relapse mortality (17.9%); three of those pts died during the first 3 months after HSCT, and the other two at 8 and 15 months post-HSCT. Seven pts (25%) relapsed after-HSCT; the disease was CD22 and CD19 positive in all the 7 cases. One patient, with a Down syndrome, received palliative care and died due to the relapse. The rest of the patients (6) received treatment for the ALL as reflected in table 2. The only patient with Ph+ ALL received ponatinib, while the 5 Ph-neg patients received treatment with Inotuzumab.
|Allo-HSCT for ALL (n=28)||ALL-relapse after allo-HSCT (n=7)|
|Age (years) (median [range])||43 [7-66]||31 [22-53]|
|Gender (male/female)||13 (46,4%) / 15 (53,6%)||2/13 (15,4%) -- 5/15 (33,3%)|
|ALL status at allo-HSCT (RC1 // RC 2)||17 (60,7%) // 11 (39,3%)||2/17 (11,8%) // 5/11 (45,5%)|
|Phenotype (B // T)||25 (89,3%) // 3 (10,7%)||7/25 (28%) // 0/3 (0%)|
|Ph/bcr-abl (negative // positive)||20 (71,4%) // 8 (28,6%)||6/20 (30%) // 1/8 (12,5%)|
|Donor (URD // MSD // Haplo)||16 // 11 // 1||4/16 (25%) // 2/11 (18,2%)// 1/1 (100%)|
|SC source (PB // BM)||25 // 3||6/25 (24%) // 1/3 (33,3%)|
|Conditioning type (TBI-Cy // TBF // others)||14 // 11 // 3||5/15 (33,3%) // 1/11 (9,1%) // 1/1 (100%)|
|Conditioning intensity (Intensive // RIC // NMA)||20 // 7 // 1||6/20 (30%) // 0/7 (0%) // 1/1 (100%)|
[ [P026 Table] 1 . TABLE 1: Characteristics of patients and transplants.]
Results: None of the 5 Inotuzumab-treated patients developed VOD/SOS or major toxicities. Of note, majority of the doses were administered in the outpatient setting. As shown in table 3, all the patients reached a new CR, recovered donor chimerism, and were focused to received anti-CD19 CAR-T cells.
1) In our knowledge, this is the first series of ALL pts relapsed after allo-HSCT treated with Inotuzumab;
2) The tolerance of Inotuzumab in the post-transplant setting was very good;
3) The reported treatment approach resulted in an excellent outcome with all the patients reaching a new CR, and recovering the donor chimerism;
4) Anti-CD22 therapy with Inotuzumab was successfully employed as a bridge to CAR-T consolidation strategy with a different leukemic molecular target (CD19);
5) The presented approach seems to be a feasible, well-tolerated, and effective strategy for CD22-positive ALL patients who relapse after allo-HSCT.
Disclosure: Nothing to declare.
P027 Prophylactic donor lymphocyte infusion after haploidentical versus matched-sibling PBSCT in very high-risk acute myeloid leukemia: Similar safety and efficacy for reducing relapse
Xiao-Ning Gao1, Ji Lin2, Li-Jun Wang1, Fei Li1, Hong-Hua Li1, Shu-Hong Wang1, Wen-Rong Huang1, Chun-Ji Gao1, Li Yu1, Dai-Hong Liu1
1 Chinese PLA General Hospital, Beijing, China, 2 Chinese PLA General Hospital, Institute of Basic Medicine, Beijing, China
Background: Donor lymphocyte infusion (DLI) could be used prophylactically to reduce relapse after allogeneic hematopoietic stem cell transplantation for very high-risk leukemia/lymphoma without effective targeted therapy. To compare the safety and efficacy of prophylactic DLI for prevention of relapse after allogeneic peripheral blood stem cell transplantation from haploidentical donors (HID-SCT) and matched-sibling donors (MSD-SCT) in patients with very high-risk acute myeloid leukemia (AML), we performed a retrospective, observational cohort study enrolled in 21 HID-SCT and 13 MSD-SCT recipients.
Methods: The very high-risk features were defined as:
(i) in the non-remission (NR) state prior to transplantation, including primary induction failure, relapse untreated or refractory to reinduction chemotherapy, or untreated AML evolution from MDS;
(ii) achieving complete remission 1 with ≥3 cycles of induction of chemotherapy;
(iii) carrying TP53, DNMT3a, TET2 or FLT3-ITD gene mutation.
The scheduled time of the prophylactic DLI was +30-60 days after transplantation for MSD-SCT recipients and +60-90 days for HID-SCT recipients. The G-CSF-mobilized peripheral blood stem cells were infused to the recipient at a dose of 2×107 CD3+ cells/kg. CsA was given at 2 mg/kg b.i.d from day -3 to day +90 (HID-SCT) or to day +60 (MSD-SCT), and then tapered at 33% per month to be discontinued on day +150-180 (HID-SCT) or on day +120-150 (MSD-SCT) unless graft-versus-host disease (GVHD) developed. If the patients received DLI before day +90 (HID-SCT) or day +60 (MSD-SCT), CsA was given 8 weeks after DLI in HID group and 4 weeks in MSD group at a though concentration of 150-250 ng/ml for DLI-associated GVHD prophylaxis, and then tapered and discontinued within 2 weeks unless GVHD developed. If GVHD occurred before the scheduled time of prophylactic DLI, it would be delayed for 8 weeks when GVHD was well controlled.
Results: Prophylactic DLI was administered at a median of 71 (34-240) days for HID-SCT recipients and 53 (35-97) days for MSD-SCT recipients (p=0.008), and both groups displayed similar baseline characteristics except for donor's gender distribution (Table 1). Grade 2-4 acute graft-versus-host disease (GVHD) at 100-day post-DLI was higher in HID-SCT group than that in MSD-SCT group (59.5% vs. 30.8%, p=0.05). Grade 3-4 acute GVHD (17.5% vs. 7.7%), 1-year chronic GVHD (36.6% vs. 33.2%) and severe chronic GVHD (15.3% vs. 27.3%) were similar between two groups (p>0.05). One-year non-relapse mortality was higher in HID-SCT group than that in MSD-SCT group with marginal significance (27.9% vs. 0.0%, p=0.061). One-year relapse rate was similar between HID-SCT group and MSD-SCT group (21.6% vs. 36.5%, p>0.05). Estimated 1-year overall survival (OS, 55.1% vs. 83.9%) and relapse-free survival (RFS, 50.1% vs. 74.0%) rates were both similar between HID-SCT group and MSD-SCT group (p>0.05). In multivariate analyses, non-remission status prior to transplant, poor-risk gene mutations and donor's age ≥ 48 years predicted a higher risk of relapse after DLI. Non-remission status prior to transplant predicted inferior OS and RFS. Patient's age ≥ 40 years also predicted an inferior OS.
Conclusions: Prophylactic DLI after HID-SCT demonstrated similar tolerance and efficacy for reducing relapse compared to that after MSD-SCT for very high-risk AML.
Disclosure: The authors declare no conflict of interest.
P028 Prognostic impact of pre-transplant TIM3 levels on transplant outcome in acute leukemia patients
Zeynep Arzu Yegin1, Ferda Can1, Lale Aydın Kaynar1, Sanem Gokcen1, Rezzan Eren Sadıoglu1, Zubeyde Nur Ozkurt1, Ozlem Karacaoglu1
1 Gazi University Faculty of Medicine, Ankara, Turkey
Background: T cell immunoglobulin and mucin domain-containing protein-3 (TIM3), a negative regulator of T cells, is expressed on a variety of tumors including hematological malignancies like acute myeloid leukemia (AML) and some lymphoma types in which it was shown to be associated with an adverse prognosis. The aim of this study is to identify the prognostic impact of pre-transplant TIM3 levels on early and late transplant related complications as well as post-transplant relapse and survival
Methods: A total of 177 hematopoietic stem cell transplantation (HSCT) recipients with an initial diagnosis of acute leukemia [median age: 36(16-66) years; male/female: 111/66] were included in the study. AML was the initial diagnosis in 99 patients (55.9%), acute lymphoblastic leukemia (ALL) in 74 patients (41.8%), mixed phenotype acute leukemia in 3 patients (1.7%) and blastic plasmacytoid dendritic cell neoplasm in 1 patient (0.6%). Soluble TIM-3 levels in pre-transplant serum samples were measured with Enzyme Linked Immunosorbent Assay (ELISA).
Results: Median pre-transplant TIM3 level was 955.6 (65.8-3784.4) pg/mL in the whole cohort. Pre-transplant TIM3 levels were significantly higher in AML patients when compared to ALL [1063.7(409.5-3784.4) vs 831.4(65.8-3254.4); p=0.01]. TIM3 levels were significantly lower in patients with abnormal cytogenetics when compared to normal karyotype (p=0.017). Cytogenetic abnormalities, including mainly a complex karyotype or chromosome 8 abnormalities, were more frequent in patients with low TIM3 levels (p=0.053). Pre-transplant TIM3 levels were significantly higher in patients who developed post-transplant viral hemorrhagic cystitis (p=0.034). A positive correlation was demonstrated between TIM3 levels and acute graft versus host disease (GvHD) grade (p=0.013; r=0.299). At a median follow-up of 14.6 (0.2-160.9) months, overall survival (OS) was found to be better in low-TIM3 group when compared to high-TIM3 group, without statistical significance (%35.2 vs %20.4; p>0.05) (Figure 1). Probability of OS was relatively better in both AML (42.6% vs 26.7%; p>0.05) and ALL patients (29.5% vs 19%; p>0.05) representing low pre-transplant TIM3 levels in the subgroup analysis
Conclusions: In this study, elevated levels of pre-transplant TIM3 levels in AML patients were compatible with the previous reports which had underlined an increased TIM3 expression on AML stem cells. The possible association of TIM3 expression with cytogenetic features should be confirmed with further studies as there is no adequate data except its relationship with FLT3-ITD mutational status. TIM-3 is also expressed on exhausted T cells in patients with viral infections, including human immunodeficiency virus, hepatitis B and hepatitis C virus. It plays an essential role in the regulation of antiviral and antitumor immune responses which may be an explanation for the increased frequency of hemorrhagic cystitis in patients with higher TIM-3 levels. The adverse prognostic impact of TIM3 on GvHD and OS was confirmed without statistical significance which may be related to small sample size. As TIM3 has a wide spectrum of action in the tumor microenvironment including stimulatory and inhibitory activities, further clues are required to define the exact role of this molecule in the clinical course of allogeneic HSCT in order to develop targeted therapeutic strategies
Clinical Trial Registry: N/A
Disclosure: Nothing to declare
P029 Homozygous HLA-C1 is associated with increased risk of relapse after HLA-matched transplantation in recipients with acute lymphoid leukemia: A Japanese national registry study
Nobuyoshi Arima1, Junya Kanda2, Toshio Yabe3, Yasuo Morishima4, Junji Tanaka5, Shinichi Kako6, Hirotoshi Sakaguchi7, Motohiro Kato8, Kazuteru Ohashi9, Yukiyasu Ozawa10, Takahiro Fukuda11, Shuichi Ota12, Heiwa Kanamori13, Makoto Onizuka14, Tatsuo Ichinohe15, Yoshiko Astuta16,17, Yoshinobu Kanda6,18
1 Medical Research Institute Kitano Hospital, Osaka, Japan, 2 Kyoto University, Kyoto, Japan, 3 Japanese Red Cross Kanto-koshinetsu Block Blood Center, Tokyo, Japan, 4 Central Japan Cord Blood Bank, Seto, Japan, 5 Tokyo Women's Medical University, Tokyo, Japan, 6 Saitama Medical Center, Jichi Medical UniversitySaitama, Japan, 7 Japanese Red Cross Nagoya First Hospital, Children's Medical Center, Nagoya, Japan, 8 National Center for Child Health and Development, Children's Cancer Center, Tokyo, Japan, 9 Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan, 10 Japanese Red Cross Nagoya First Hospital, Nagoya, Japan, 11 National Cancer Center Hospital, Tokyo, Japan, 12 Sapporo Hokuyu Hospital, Sapporo, Japan, 13 Kanagawa Cancer Center, Yokohama, Japan, 14 Tokai University School of Medicine, Hematology and Oncology, Isehara, Japan, 15 Hiroshima University Hospital, Hiroshima, Japan, 16 Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan, 17 Nagoya University Graduate School of Medicine, Nagoya, Japan, 18 Jichi Medical University, Shimotsuke, Japan
Background: After hematopoietic stem cell transplantation (HSCT), the role of natural killer (NK) cells which express killer-cells immunoglobulin-like receptors (KIRs) and recognize HLA-class 1 ligands is important. KIR2DL1 recognizes not HLA-CAsp80 (C1), but HLA-CLys80 (C2) and has polymorphism based on the 245th amino acid of the transmembrane domain. Low frequency of C2 and high frequency of strong KIR2DL1 are characteristics observed in Japanese. By using large transplant database, we reported that homozygous HLA-C1 (C1/C1) recipients displayed lower relapse rates than did C1/C2 recipients after HLA-matched HSCT for acute myeloid leukemia (AML; HR = .79, P = .006) or chronic myeloid leukemia (CML; HR = .48, P = .025). This effect seemed to be independent of acute graft-versus-host disease (aGVHD) or cytomegalovirus reactivation occurrence (Arima N et al BBMT 2018).
Methods: Relapse rates of Japanese recipients who first underwent HLA-matched HSCT between 1996 and 2016 for the treatment of acute lymphoid leukemia (ALL) were compared between C1/C1 pairs and C1/C2 pairs, using data from Japanese Data Center for Hematopoietic Cell Transplantation and adjusting for transplant characteristics. Cord blood transplantation was excluded. Multivariable competing risk regression analyses were performed to evaluate relapses and relapse-free survival (RFS) was estimated using Kaplan-Meier method.
Results: After 61 recipients who did not achieve remission or experienced graft failure and 41 recipients not-expressing C1 were excluded, resting 2779 recipients aged 0-72 years (median, 31.2 years) were analyzed. The median follow-up period for survivors was 5.0 years. There were 2447 recipients expressing C1/C1 and 332 recipients expressing C1/C2, respectively. After HLA-matched HSCT, C1/C1 recipients had higher relapse rates than C1/C2 recipients (HR = 1.55, P = .003), resulting in worse RFS among C1/C1 recipients (HR = 1.27, P = .034). The frequent relapse in C1/C1 recipients than in C1/C2 was noticeable among recipients with aGVHD (HR = 1.89, P = .002), those without cytomegalovirus reactivation (HR = 1.84, P = .002), and those with Ph-negative ALL (HR = 1.88, P = .001).
Conclusions: KIR2DL1-positive NK cells may promote graft-versus-leukemia (GVL) in C1/C1 recipients with AML or CML but suppress GVL in C1/C1 recipients with ALL. One interpretation is that transplant-activated NK cells impair antigen-presenting cells or deprive cytotoxic T-lymphocytes of their GVL effects on ALL cells. This hypothesis may be explained by the fact that aGVHD was necessary for the recessive relapse in C1/C1 recipients with ALL. Furthermore, Ph-positive ALL cells sometimes mimic AML cells in terms of their frequent myeloid antigen expression and might be directly targeted by NK cells. It would be necessary to further clarify in vitro the character of NK cell-affecting in the transplant immunity against residual leukemia cells.
Disclosure: Authors have nothing to declare.
P030 Hematopoietic stem cell transplantation with sequential conditioning for children with relapsed/refractory acute leukemia
Nao Yoshida1, Kazuki Matsumoto1, Daiki Yamashita1, Yiqing Zhu1, Daichi Sajiki1, Ryo Maemura1, Hirotoshi Sakaguchi1, Asahito Hama1
1 Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan
Background: Patients with acute leukemia who fail to achieve complete remission show a dismal prognosis even with allogeneic hematopoietic stem cell transplantation (HSCT). This study evaluated whether sequential conditioning approach that is cytoreductive chemotherapy applied shortly prior to the main conditioning followed by HSCT can improve prognosis in such high-risk patients.
Methods: We retrospectively analyzed the outcomes of 90 children (median 8, range 0-18 years old) with primary refractory (n = 11) or refractory relapsed (n = 79) acute leukemia (AML n = 43, ALL n = 47) who received HSCT in our department between 1990 and 2016. The stem cell source was related peripheral blood (PB) in 4 patients, related bone marrow in 31, unrelated bone marrow in 40, or unrelated cord blood in 15. The grafts were HLA serologically matched (n = 63) or mismatched (n = 27) with the recipient. In total, 29 patients received the sequential conditioning approach. As cytoreductive chemotherapy, fludarabine/cytarabine/idarubicin/G-CSF (FLAG-IDA) was used in 12 patients, mitoxantrone or daunorubicin/cytarabin in 10, or other regimens in 7, and 6 of them were combined with gemtuzumab ozogamicin. Without waiting for hematological recovery, the patients promptly underwent HSCT; therefore, the median interval between cytoreductive chemotherapy and main conditioning was 11 days. The main conditioning regimens were total body irradiation-based myeloablative (n = 22), busulfan-based myeloablative (n = 4), or reduced intensity (n = 3).
Results: In 90 children with relapsed/refractory acute leukemia, the 5-year overall survival (OS), leukemia-free survival (LFS), cumulative incidence of relapse (RI), and transplantation-related mortality (TRM) were 24%, 21%, 53%, and 26%, respectively. In multivariate analysis, the use of sequential conditioning was identified as the most favorable factor for LFS (hazard ratio [HR] 0.37; P = 0.001), although there were no differences in the outcomes according to the types of cytoreductive chemotherapy or the main conditioning regimen. HLA-matched donor (HR 0.46; P = 0.005) and PB blasts-negative at the beginning of conditioning (HR 0.49; P = 0.02) were also independently associated with better LFS. With sequential conditioning, leukemia burden prior to the HSCT was significantly reduced; PB blasts became undetectable at the beginning of conditioning in 66% patients given the approach, while in 38% patients without the approach (P = 0.02). Notably, the outcomes in the patients without PB blasts at the beginning of conditioning who received sequential conditioning were promising; the 5-year OS and LFS reached 73% and 62% and the 5-year RI and TRM were 33% and 5%, respectively.
Conclusions: Our study reveals that HSCT with sequential conditioning can be an effective and tolerable treatment option for children with relapsed/refractory acute leukemia. The treatment strategies that focus on the reduction of leukemia burden immediately prior to HSCT may contribute to the induction of long-term remissions in patients with high-risk acute leukemia.
Disclosure: This research was funded by Japanese Red Cross, Nagoya 1st. Hospital Research Grant NFRCH18-0028.
P031 Use of blinatumomab to achieve remission and consolidation with haploidentical transplant with cyclophosphamide post for the treatment of children with refractory acute lymphoblastic leukemia (ALL)
Alberto Olaya Vargas1, Roberto Rivera Luna2, Yadira Melchor Vidal3, Haydeé Del Pilar Salazar Rosales1, Gerardo López Hernández1, Rosa María Nideshda Ramírez Uribe1
1 Instituto Nacional de Pediatria, Mexico City, Mexico, 2 Instituto Nacional de Pediatria, Hem/Oncology, Mexico City, Mexico, 3 Medical Center ABC, Mexico City, Mexico
Background: Most of patients with ALL in relapse or refractory to conventional treatment have only 30% possibilities to achieve long term remission. This report refers to the therapeutic efficacy and adverse events from the blinatumomab to achieve molecular remission in patients with pre-B CD19+ which lead to haploidentical with cyclophosphamide post transplant as a consolidation.
Methods: A pilot study was conducted in children with refractory ALL preB-CD19 +. As a strategy to achieved remission blinatumomab was used at a dose 10 µg/m2 for continous infusion of 48 hours, increasing the dose to 15 µg/m2 during 28 days, patients with a MRD of < 0.002 Log, after 2 cycles received an haploidentical bone marrow transplant as a consolidation, the conditioning regimen was with total body irradiation scheme at 200 cGy/day/3 days, cyclophosphamide and etoposide. Receiving prophylaxis for GVHD with cyclophosphamide.
Results: A total of 10 patients were included, seven of them achieved complete remission after 2 cycles of blinatumomab, one with partial remission (Table 1), these seven patients, six received an haploidentic transplant achieving graft in 6 of the transplanted patients. One patient had a bone marrow relapse in the first 6 months of the follow-up and 5 patients are free of disease with a follow-up to 20 months (figure 1). As a acute complication the 10 patients presented cytokine release syndrome, during the infusion of blinatumumab 10 patients presented tachycardia (Table 3) and the 6 patients presented aGVHD after HSCT (5 grade I-II and I grade IV).
Conclusions: Allogeneic bone marrow transplant constitutes a treatment option on those patients that relapse or become refractory to treatment, one of the major problem is basically to identify a HLA-identical donor, the alternative is an haploidentical donor. The most important factor to get these results is the disease status before transplant. The use of blinatumomab has proven to be effective in achieving remission in relapse Acute Linfoblastic Leukemia pre-B CD 19+ or refractory to treatment.
|Median age at diagnosis, (range), years||9.22||(7-12)|
|Status of disease|
|2 o + 3 relapse||6||60%|
|Refractory to primary or salvage therapy||4||40%|
|Complete remission after Blinatumomab||7||70%|
|Partial remission after Blinatumomab||1||10%|
[ [P031 Table] 1 . Table N°1. Demographic characteristics of patients undergoing Blinatumomab (n=10)]
Disclosure: A. Olaya-Vargas, R. Rivera-Luna, Y. Melchor-Vidal, H. Salazar-Rosales, G. Lopez-Hernandez, N. Ramirez-Uribe. We wish to confirm that there are no known conflicts of interest associated with this abstact, the only financial support was provided by Mexican Associations that helping children wiht cancer in a few patients.
P032 Sequential high-dose chemotherapy reinduction followed by myeloablative allogeneic transplant for active acute myeloid leukemias
Lucia Brunello1, Roberto Passera1, Marco Cerrano1, Luisa Giaccone1, Ernesta Audisio1, Dario Ferrero1, Stefano D'Ardia1, Semra Aydin1, Chiara Maria Dellacasa1, Alessandro Busca1, Benedetto Bruno1
1 A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy,
Background: The sequential use of intensive chemotherapy and reduced-intensity hematopoietic stem cell transplantation (HSCT) represents a possible approach for the treatment of relapsed-refractory acute myeloid leukemias (AML) (Schmid C, JCO 2005; Ringdén O, Br J Haematol. 2017, Mohthy M, Haematologica 2017).
Methods: At our Center, 27 relapsed/refractory AML patients were transplanted during chemo-induced neutropenia after high-dose salvage chemotherapy. Median age at transplant was 52 years (range 21-62). Patients suffered from de novo (n= 18/27, 67%) or secondary AML (n=9/27, 33%). Genetic risk stratification was reported using stardardized groups proposed by the European Leukemia Net (ELN) in 2010. Favorable, Intermediate I and II and Adverse risk category at diagnosis was observed in 1/27 (4%), 19/27 (70%), 7/27 patients (26%) respectively. All patients had active disease at the time of Sequential Therapy and median marrow blast count was 25% (range 7-88%). Patients received a high-dose Cytarabine based (MEC in 17/27, 63%) regimen as salvage therapy. Donors were haploidentical relatives for 15/27 (56%) patients, identical siblings and matched-unrelated for 6/27 patients (22%) and 6/27 (22%), respectively. A myeloablative conditioning was used to further implement anti-leukemic effects. Conditioning, Thiotepa-Busulfan-Fludarabine in 89% patients, was started at a median of 8 days (range 3-14) after the last day of chemotherapy. Bone marrow and peripheral blood stem cells were used as graft source in 11/27 (41%) and 16/27 (59%) patients. Graft-versus-host disease (GVHD) prophylaxis and supportive care were administered accordingly to each HSCT platform.
Results: All patients engrafted. Median day of neutrophil recovery was day +16 (range 12-23). Median follow-up of survivors was 31 months (range 4-125). Non Relapse Mortality and Relapse Incidences (NRM, RI) were 16% and 48% at 1 year and 16% and 58% at 3 years, respectively. Overall cumulative incidences of acute and chronic GVHD were 48% and 43% at day +100 and + 400. One and 3 year Overall Survival (OS) were 58% and 34%, while 1 and 3 year Event-Free Survival (EFS) were 35% and 26%. Significant better OS and EFS were observed in patients with Favorable-Intermediate I-II versus Adverse risk score (1-3 years OS 64% and 50% vs 43% and 0% p=0.022; 1-3 years EFS 43% and 36% vs 14% and 0% p=0.013). Adverse risk had a significant impact on OS (HR 3.24, p=0.030) and EFS (HR 3.33, p=0.018) by univariate analysis and on RI (SDHR 3.02, p=0.031) by Fine and Gray Test.
Conclusions: Though small the patient cohort, our findings suggest that sequential therapy with a myeloablative HSCT is feasible in treating relapsed/refractory AML. Transplant-related toxicity was low (16%) and relapse was the major treatment-failure. However, even with this approach, patients with adverse cytogenetic features have a very dismal prognosis. For these patients, the use of new drugs before HSCT and/or maintenance therapy after transplant is highly encouraged to improve outcomes.
Disclosure: Alessandro Busca: Honoraria from Gilead Sciences, Merck, Pfizer Pharmaceuticals and Jazz Pharmaceuticals; speaker for Gilead Sciences, Merck, Pfizer Pharmaceuticals, Astellas Pharma, and Basilea.
Benedetto Bruno Honoraria from: Gilead, Pfizer, Hospira, Honoraria and research funding from Celgene; Research funding from Pierre Fabre, Adienne, Hospira italia, MSD Italia
P033 The significance of minimal residual disease (MRD) in children AML on outcome after allogeneic stem cell transplantation with myeloablative or reduced intensity conditioning
Zhemal Rakhmanova1, Olesya Paina1, Polina Kozhoka1r, Anastasiya Frolova1, Kirill Ekushov1, Maria Galas1, Lyubov Tsvetkova1, Aygul Khabirova1, Elena Babenko1, Tatyana Gindina1, Aleksandr Alyanskiy1, Ildar Barkhatov1, Elena Semenova1, Ludmila Zubarovskaya1, Boris Afanasyev1
1 First Pavlov Saint Petersburg State Medical University, Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Saint Petersburg, Russian Federation
Background: In spite of satisfactory results of overall survival (OS) after AlloHSCT in 1st and 2nd CR AML, relapse free survival (RFS) and graft-versus-host-disease free/relapse free survival (GRFS) require further improvement. The detection of MRD is one of the factors which influence on the outcome of AlloHSCT in AML is unclear but identification is important to improve risk-adapted relapse prophylactic treatment after AlloHSCT.
Aim. To evaluate outcomes of AlloHCST in 1st and 2nd CR pediatric AML depending on the level of MRD status before myeloablative (MAC) or reduced intensity conditioning regimens (RIC).
Methods: The data of 72 children with AML in 1st and 2nd CR underwent AlloHSCT between 2008 and 2018 were analyzed. Median age at the moment of AlloHCST was 8 years old (2-18). MRD negative status had 42 (58%) patients, 30 (42%) were MRD positive by flow cytometry. MAC based on busulfan (16 mg/b.w.) received 27 (37%) patients, on treosulfan - 7 (10%) patients. RIC based on melphalan received 20 (28%) patients, based on busulfan (8 mg/b.w.) - 18 (25%) patients. Patients received prophylaxis of aGVHD by ATG 20 (28%) or PTCy - 48 (66%) patients plus CsA - 23 (32%) or tacrolimus ± sirolimus - 43 (60%) patients that depended on source of transplant (related, unrelated or haplo donor).
Results: At the median follow up 3 years in the cohort of MRD positive patients OS is 66% vs 72% in MRD negative (p>0,05). RFS is 56% vs 83% accordingly (p=0,01). Graft-versus-host-disease free/relapse free survival (GRFS) in MRD positive patients is 37% vs 51% in MRD negative (p>0,05). OS, RFS, GRFS in MRD positive patients after MAC is 57%, 42%, 30% vs 75%, 68%, 43% after RIC accordingly (p>0,05). OS, RFS, GRFS in MRD negative patients after MAC is 75%, 85%, 55% vs 65%, 82%, 47% after RIC accordingly (p>0,05). OS, RFS in MRD negative patients with/without PTCy is 82%, 86% vs 42%, 78% (p>0,05); GRFS is 62% vs 28% accordingly (p=0,042). OS, RFS, GRFS in MRD positive patients with/without PTCy is 66%, 55%, 54% vs 66%, 57%, 27% (p>0,05).
Conclusions: MRD status does not statistically significant affect on OS that can be related to different approaches to the treatment of relapse after AlloHSCT. MRD positive status statistically significant decreases RFS that underline the necessity of posttransplant therapy improvement. RIC vs MAC in all patients in first and second remission do not show statistically significant impact on OS, RFS, GRFS. PTCy significantly improves GRFS in MRD negative patients.
Disclosure: None of the authors has anything to disclose.
P034 Allogeneic HSCT in therapy-associated AML and MDS after treatment for lymphoma: A retrospective single-center analysis
Daniela Vanessa Wenge1, Christian Reicherts1, Jan-Henrik Mikesch1, Christoph Groth1, Klaus Wethmar1, Christoph Schliemann1, Rolf Mesters1, Torsten Kessler1, Cyrus Khandanpour1, Norbert Schmitz1, Georg Lenz1, Matthias Stelljes1
1 University Hospital Muenster, Medicine A, Muenster, Germany
Background: With increasing overall-survival (OS) of lymphoma patients, higher incidences of therapy-related clonal bone marrow diseases, such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are occuring. Generally, the outcome is considered poor. Allogeneic hematopoietic stem cell transplantation (allo HSCT) often remains the only potentially curative treatment option. Nonetheless, there is only little data available concerning this patient group.
Methods: We retrospectively collected data from 33 patients with therapy-related AML (tAML) and MDS (tMDS) after treatment for Hodgkin's lymphoma (HL; n=7 and n=2) or non-Hodgkin's lymphoma (NHL; n=10 and n=14), who received an allo HSCT between 2000 and 2018. Median follow-up of surviving patients was 3.1 years (range 2.6 months- 9.4 years).
Results:Median interval between lymphoma diagnosis and onset of tAML or tMDS was 10 years (range 1.5 years- 38.8 years). On average, patients were transplanted 7 months after diagnosis of tAML/tMDS (range 1- 61 months) at a median age of 56 years (range 37- 69 years). Remission status of tAML-patients at allo HSCT (n=17) was 1st complete remission (CR; 35%), 2nd CR (12%) or relapsed/refractory disease (53%). Prior to transplant, patients received dose-reduced conditioning therapy (n=24), melphalan-based sequential conditioning (n=7) or FLAMSA-based conditioning (n=2). Patients were transplanted with peripheral stem cell grafts from 10/10 HLA-matched unrelated donors (n=21), HLA-identical sibling donors (n=10) or haploidentical donors (n=2). Cumulative incidence of relapse for all patients at 3 years was 25.2% (95% CI: 12.6% - 50.5%). Cumulative incidences of non-relapse mortality (NRM) at 1 year and 3 years were 24.2% (95% CI: 13.3% - 44.3%) and 41.9% (95% CI: 25.2% - 69.6%), respectively. Relapse-free survival and OS at 3 years post-allo HSCT were 42.0% (95% CI: 22.6% - 61.5%) and 44.4% (95% CI: 25% - 63.8%), respectively.
Patients with a history of HL had a 3-year-OS of 62.2% compared to 40.7% and 35.6% for patients with indolent or aggressive NHL. More than one line of therapy for NHL/HL prior to onset of tAML/tMDS resulted in a trend towards higher NRM rate and lower 3-year-OS (one treatment line: 9.1% and 70.7%, 2 lines of treatment: 33.3% and 22.2%, >2 lines of treatment 63.9% and 32.5%). 5 patients died from relapsing tAML/tMDS and 11 patients died in CR after transplantation. The major causes of non-relapse related lethality were early death due to infection/toxicity (death between d0- d20 post-allo HSCT, n=5), infectious complications without GvHD (n=1), infections due to GvHD treatment (n=2) and toxic pneumonitis/severe lung complications (n=3, all patients with history of NHL).
Conclusions: Outcomes in this patient cohort are comparable with those reported for patients transplanted with primary AML or MDS. More than one line of therapy for HL/NHL may be considered as a relevant risk factor for NRM and, consequently, inferior survival following allo HSCT for tAML/tMDS.
Disclosure: Nothing to declare.
P035 Clinical outcome of sequential conditioning regimen followed by allogeneic stem cell transplantation for refractory acute leukemia: Experience of one center
Lucia Garcia1, Leyre Bento1, Bernardo Lopez1, Andrés Novo1, Antonio Gutiérrez1, Maria Antonia Duran1, Antonia Sampol1
1 Son Espases University Hospital, IdISBa, Palma de Mallorca, Spain
Background: The prognosis of relapsed/refractory acute leukemia (R/R AL) is poor and the treatment is challenging. In this setting, allogeneic stem cell transplantation (allo-SCT) constitutes the only curative option although the high relapse rate and non-relapse mortality (NRM). The sequential conditioning regimen followed by allo-SCT has been used for persistent disease and aims to improve disease control by intensified chemotherapy, thus conceding more time for the presumed graft-versus-leukemia effect to occur.
Methods: The clinical outcome of R/R AL with the sequential conditioning regimen combining a chemotherapy rescue followed by RIC allo-SCT in our center is described. Patients who underwent a sequential allo-SCT from 2005 to 2017 are included. The primary endpoint was progression free survival (PFS) and overall survival (OS) that were estimated by the Kaplan- Meier method. Secondary endpoints were non-relapse mortality (NRM).
|Diagnosis: AML, APL, ALL B||16 (89%), 1 (5.6%), 1 (5.6%)|
|CG/molecular risk: Favorable, Intermediate, Advers||1 (5.9%), 10 (58.8%), 6 (35.3%)|
|Rescue chemotherapy: FLAG-Ida, Clofarabine-Cytarabine,Fludarabine-Cytarabine, Fludarabine-Carboplatin-Topotecan||6 (33.3%), 8 (44.4%), 3 (16.7), 1 (5.6%)|
|Sequential conditioning régimen: Melphalan, Fludarabine-Busulfan, Busulfan-Thiotepa, Thiotepa-Fludarabine-Busulfan, Busulfan, TBI||5 (27.8), 1 (5.6%), 1 (5.6%), 5 (27.8%), 2 (11.1%), 1 (5.6%)|
|Donor type: HLA-id sibling, MUD, MMRD (haplo)||6 (33.3%), 3 (16.7%), 9 (50%)|
[ [P035 Table] 1 . Main characteristic of the patients]
Results: We retrospectively analyzed 18 patients with active disease at the time of transplantation. The median age at allo-SCT was 48 years (range 15-65). The main characteristic of the patients are shown in Table 1. Complete response was achieved in 15 patients (83%) at day 100 post SCT. At a median follow-up of 21 months (2.5-53), 50% relapsed, 5 patients are alive in CR and 13 died. The main causes of death were SCT-related in 33.4% (27.8% bacterial and 5.6% fungal infections) and disease in 38.9%. The median OS was 10.8 months (IC 95%: 3-18.6) and the median PFS was 5.6 months (IC 95%: 3.6-7.5). Comparing Clofarabine-Cytarabine with FLAG-Ida as a rescue chemotherapy regimen, the CR rate at day 100 post SCT were similar (87% and 83% respectively) but we found interesting results in PFS: 6 months (IC 95%: 4.9- 7.1) in the group of Clofarabine-Cytarabine and 3.6 months(IC 95%: 2.7-4.5) in the group of FLAG-Ida. The median OS was more than double in the group of Clofarabine-Cytarabine (10.8 vs. 4 months).
Conclusions: The sequential conditioning regimen combining chemotherapy rescue followed by allo-SCT represents a promising approach for patients with R/R AL. We confirm high CR rate but early relapses taking into account this high risk population. Therefore, there is a need to find new drugs or maintenance strategies in order to prolong the OS and the PFS.
Disclosure: Nothing to declare.
Abstract already published.
P037 Potential role of autologous stem cell transplant in favorable-risk genetics NPM1 positive acute myeloid leukemia - A retrospective single center analysis
Pedro Chorão1, Pedro Medeiros1, Eliana Aguiar1, Maria Luís Amorim1, Maria José Soares1, Paula Gomes1, Ricardo Pinto1,2, Fernando Príncipe1, José Eduardo Guimarães1,2
1 Centro Hospitalar de São João, Porto, Portugal, 2 Faculdade Medicina da Universidade do Porto, Porto, Portugal
Background: Recommendations of the 2017 European Leukemia Net (ELN) for favorable-risk genetics (FRG) acute myeloid leukemia (AML) favor consolidation over transplantation, although reviews suggest advantage of autologous stem cell transplant (ASCT) in event free survival. Our objective was to compare the progression free survival (PFS) and overall survival (OS) of normal karyotype NPM1 mutated without FLT3 ITD or allelic ratio < 0.5 (NPM1+) AML patients treated with consolidation chemotherapy alone (CC), ASCT or allogeneic stem cell transplant (AlloSCT).
Methods: Retrospective review of NPM1+ FRG-AML patients, treated in one institution (2008 to 2017) with the following induction regimens: cytarabine (Ara-C) and VP-16 with daunorubicin (ADE) or mitoxantrone (MiCE). Consolidation regimens were Ara-C with daunorubicin (AC-D), idarubicin, VP-16 and Ara-C (mini-ICE) or high-dose Ara-C (HiDAC). In ASCT, conditioning regimens were BuCy or BVAC and in AlloSCT were BuCy or FluBu. PFS and OS were calculated from the start of the last consolidation or stem cell infusion.
Results: A total of 39 patients were evaluated, with a median age of 53 years (y) (23-68y), 69% female, 95% with ECOG performance status (PS) 0-1 and 36% with age-adjusted Charlson comorbidity index (aaCII) ≥2 at diagnosis. Patients were treated with CC in 33% (n=13), ASCT in 36% (n=14) and AlloSCT in 21% (n=12) of cases. There were no differences between groups for age, aaCII, PS, leucocytes at diagnosis or extra-medullary disease. FLT3-ITD was more frequent in AlloSCT group (64%) than CC (23%) or ASCT (8%; p=0.07).
At induction, ADE was used in 82% and MiCE in 18% of patients, with a complete remission (CR) rate of 95%. There were no differences between groups for induction regimen or CR. In CC group, consolidation regimens were 1 cycle (8%) and 2 cycles AC-D (61%) and 2 cycles mini-ICE (31%). ASCT patients received consolidation with 1-2 cycles AC-D (78%) and 1 cycle mini-ICE (22%), while AlloSCT patients received 1-2 cycles AC-D (84%), 2 cycles HiDAC (8%) and no consolidation in 8%.
[ [P037 Image] 1 . Figure 1. PFS at 3y in CC, ASCT and AlloSCT groups.]
Median follow-up was 39 months, PFS at 3y was 53% and OS at 3y was 64%. PFS at 3y for ASCT group was superior then CC and AlloSCT groups (61%, 51% and 44%, respectively; Figure 1), although not statistically significant. OS at 3y was statistically similar between groups, although inferior in AlloSCT comparing to CC and ASCT (44%, 77% and 70%, respectively).
Conclusions: In this historical cohort review, although there was no advantage in OS for ASCT in NPM1+ FRG AML, our data suggests that there might be a PFS improvement in ASCT over CC, which needs to be further addressed in prospective studies.
Disclosure: Nothing to declare
P038 Early tapering of immunosuppressive drugs after haplo-identical transplantation in patients with high risk leukemia
Seong Kyu Park1, Se Hyung Kim1, Sung Hee Lim2, Chan Kyu Kim2, Jong Ho Won3, Dae Sik Hong2
1 Soonchunhyang University Bucheon Hospital, Hematology, Bucheon, Korea, Republic of, 2 Soonchunhyang University Bucheon Hospital, Bucheon, Korea, Republic of, 3 Soonchunhyang University Seoul Hospital, Seoul, Korea, Republic of
Background: Disease recurrence is the most important obstacle to achieve long-term survival for patients with advanced acute leukemia after allogeneic hematopoietic stem cell transplantation (HSCT). Several studies showed that early tapering of immunosuppressive agents could achieve graft versus leukemic (GVL) effects at early time after transplantation and the relapse most occurred at the first 6 months after transplantation. In order to reduce the relapse risk and improve the survival, the strategy of early tapering of immunosuppressive agents was retrospectively evaluated in haplo-identical stem cell transplantation patients with high risk leukemia.
Methods: Thirty patients with advanced leukemia received early tapering of immunosuppressive drugs between days 30 and 60 after HSCT according symptoms and signs with no grade II~IV acute or significant chronic graft versus host disease (GVHD).
Results: At the time of transplantation, 21 patients reached first or subsequent complete remission (n=15 for CR1, n=6 for CR2). The other 9 patients were non-CR or refractory to salvage therapy. Median time to stop immune-suppressants was 66 days after HSCT (32~98 days). Acute GVHD ± chronic GVHD was developed in 13 patients (43.3%) at median 27 days (13~113) after stopping immunosuppressive drugs. Only 3 patients had chronic GVHD with limited grade. During median follow-up duration (15.3 months), overall survival was 54.5% (58% in CR vs 50% in non-CR or refractory, P=0.777). Twelve patients (40%) died during the follow-up period and relapse was the most frequent cause of death (n=8, 26.7%). Other causes included secondary cancers (n=2) and acute GVHD (n=1), and fungal infection (n=1). In multivariate analysis, risk group based on cytogenetics and CMV reactivation was an independent prognostic factor for better survival; acute and chronic GVHD tended to be associated with better survival.
Conclusions: In patients with high risk acute leukemia, the strategy of early tapering of immunosuppressive agents may facilitate post-transplantation strategies for relapse reduction and can lead to improve survival after allogeneic stem cell transplantation from haplo-identical donor.
Clinical Trial Registry: None
Disclosure: Nothing to declare
P039 Autologous stem cell transplantation in patients with acute myeloid leukemia. single center experience
Borce Georgievski1, Irina Panovska1 Stavridis1, Aleksandra Pivkova Veljanovska1, Zlate Stojanoski1, Lidija Cevreska1, Dusko Dukovski1, Dijana Milovska1, Lazar Cadievski1
1 University Clinic for Hematology, Skopje, Skopje, Macedonia, the Former Yugoslav Republic of
Background: Acute myeloid leukemia is a hematological malignant disease that motivates the persistent struggle in the scientific world to provide effective cure that can establish acceptable survival rates in this group of patients. Autologous stem cell transplantation with myeloablative conditioning is still a powerful weapon that can be used against this entity
Methods: We have evaluated retrospectively patients with AML where autologous stem cell transplantation was performed in the period from 2000 till 2018. Our group consisted of 94 patients; male patients 45 (47.8%), female patients 49 (52.2%). Median age at diagnosis was 44 years (16-68). The average period from time of diagnosis to autologous SCT was 7.05 months.
Results: In the majority of our group, we used myeloablative conditioning regimen with Busulphan-Cyclophosphamide, 60 patients (63.8%), in 2 patients (2.1%) we have added melphalan to Bu-Cy conditioning, in 22 (23.4%) patients we used BEAM conditioning and in the rest, 10 patients (10.6%) we used BAM conditioning regimen. As auto graft we used peripheral blood stem cells (PBSC) in 78 patients (82.9%), and in 16 patients (17.1%) we used bone marrow. The main mobilising regimen for PBSC was G-CSF + etoposide and it was performed in 44 patients (46.8%), and in the remaining 34 patients (36.1%) mobilising of PBSC was performed only with G-CSF. The mean number od apheresis procedures done in our group was 1.55, and the mean number of collected mononuclear cells was 3.05x108/kg TT. The mean time to engraftment was 12.8 days (9-23). The transplant related mortality (TRM) was 2.1 %. The 5 year Overall Survival of our patients was 46.7 patients. The main reason for death was relapse of the primary disease(73%). 20 patients (21%)were treated with salvage chemotherapy regimen (FLAG-Ida) because with the standard induction regimen 7+3 there was absence of adequate therapeutic response, or predominantly no Complete remission was achieved. All patients were transplanted in Complete Remission
Conclusions: Autologous stem cell transplantation could be an acceptable therapeutic solution for patients with AML as a consolidation therapy, where neither suitable compatible donor is available nor allogeneic stem cell transplantation could not be performed from various reasons depending on the bone marrow transplant unit
Disclosure: Nothing to declare
P040 Prophylaxis DLI alone may not prevent relapse of FLT3-ITD positive AML after allogeneic HCT
LiQin Cao1, JiMin Shi1, YanMin Zhao1, Yi Luo1, Jian Yu1, Ya-Min Tan1, Xiao-Yu Lai1, Yuan-Yuan Zhu1, Guo-Qing Wei1, Jie Sun1, Jing-Song He1, Wei-Yan Zheng1, Zhen Cai1, He Huang1
1 Zhejiang University, First Affiliated Hospital, Hangzhou, China
Background: Compared with traditional chemotherapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) can improve the prognosis of patients with FLT3-ITD positive AML. Relapse after transplantation is still an important factor affecting survival. Prophylaxis donor lymphocyte infusion (DLI) often used to prevent relapse after allo-HSCT. However, its role to patients with FLT3 positive after allo-HSCT had not determined.
Methods: From January of 2014 to December of 2017, 50 patients with FLT3-ITD positive AML who underwent allo-HSCT in our center were taken into this syudy, among them13 patients underwent prophylaxis DLI after allo-HSCT.
Results: The estimated three years OS and LFS in all patients was 58.2% and 69.3% respectively. The three years cumulative incidence of relapse was 30.3%. 13 of 50 patients underwent prophylaxis DLI, the median time was 105 days (range 63 to 227 days) after allogeneic HSCT. The three years estimated OS was higher in prophylaxis DLI patients than those without prophylaxis DLI, but not reached significant difference (65.9% VS 35.2%, P=0.86), and the 3 years estimated LFS as well as cumulative incidence of relapse was also similar in two group (75.2% VS 64.8%, p=0.66; 23.9% VS 35.1%, P=0.61).
Conclusions: Thus, prophylaxis DLI alone to prevent relapse of patients with FLT3-ITD positive AML after allo-HSCT may has limited effect. Additional targeted and coordinated interventions are needed to maintain durable remission after allo-HSCT in this high-risk population.
Clinical Trial Registry: No
Disclosure: Nothing to declare
P041 Role of allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients with NPM1 WT AND FLT3-ITD negative group
Sang Kyun Sohn1, Ju-Hyung Kim1, Jungmin Lee1, Ji Yeon Ham2, Jang Soo Suh2, Joon Ho Moon1
1Kyungpook National University Hospital, Hematology/Oncology, Daegu, Korea, Republic of, 2Kyungpook National University Hospital, Laboratory Medicine, Daegu, Korea, Republic of
Background: One of the most potent prognostic factors affecting outcomes in AML is the presence of cytogenetic and molecular markers which can guide the selection of post-remission therapies. Recently, favorable outcomes of NPM1wt/FLT3-ITDneg/non-CEBPAdm group after allogeneic hematopoietic cell transplantation (allo-HCT) have been reported, that is similar to those of favorable risk by the ELN risk classification. However, the role of allo-HCT compared to consolidation chemotherapy has not yet been elucidated.
Methods: The data of 88 patients who were diagnosed with AML and received intensive induction therapy from 2015 March to 2017 July were included in the current study. To address the time dependence of the allo-HCT, the Simon and Makuch method was used in the graphical representation and the Mantel-Byar test and Andersen and Gill methods for identifying risk factors for long-term survival.
Results: Median age of the patients were 53 years (range 21-69), and 49 patients (56%) were male. NPM1 mutation was detected in 14 patients (16%), and FLT3-ITD were none, low, and high ratio in 69 patients (78%), 9 (10%), and 10 (12%), respectively. The ELN risk classification divided the patients into favorable, intermediate, and adverse risk group in 31 patients (35%), 38 (43%), and 19 (22%), respectively. NPN1 and FLT3-ITD both negative group included 29 patients (33%). Allo-HCT was performed in 48 patients (55%). Overall, complete response (CR) after induction therapy achieved in 63 patients (72%), and 7 patients (8%) were primary refractory disease. CR rates did not differ between NPM1wt/FLT3-ITD negative group (n=17/29, 58.6%) and other intermediate risk group (n=6/9, 66.7%; p=0.967). With median follow-up duration of 12.9 months (range 1.3-39.0 months), one-year OS rate were 100%, 83.5±6.9%, 56.1±12.8% in favorable, intermediate, and adverse risk group (p < 0.001). Among intermediate risk group, OS rate of NPM1wt/FLT3-ITD negative group was similar to other intermediate risk (p=0.403). Allo-HCT was performed in 11 patients of NPM1wt/FLT3-ITD negative group. One-year OS rates did not differ between NPM1wt/FLT3-ITD negative and other intermediate risk (Mantel-Byar test p=0.622). In the multivariate analysis, ELN risk group was identified as the only risk factor for OS (HR 2.76, 95% CI 1.51-5.02, p< 0.001). Allo-HCT was not an independent favorable factor for OS in NPM1wt/FLT3-ITD negative group (HR 0.47, 95% CI 0.09-2.47, p=0.372).
Conclusions: NPM1wt/FLT3-ITD negative group showed similar CR and OS rates compared to other ELN intermediate group. Allo-HCT did not improve the OS rate of this group. Therefore, the implication of allo-HCT to this group needs to be carefully considered considering other high risk factors.
Disclosure: The authors declare no conflict of interest.
P042 Low-dose decitabine as maintenance after allogeneic hematopoietic stem cell transplantation for high-risk acute myeloid leukemia
Alessandro Bucalossi1, Monica Tozzi1, Mariapia Lenoci1, Francesca Toraldo1, Valeria Del Re1, Giuseppe Marotta1
1 Azienda Ospedaliera Universitaria Senese, UOC Terapie Cellulari e Officina Trasfusionale, Siena, Italy
Background: Aberrant DNA methylation occurs in Acute Myeloid Leukemia (AML) blasts. Therapy with hypomethylating agents may reverse the abnormal epigenetic silencing to modify the malignant phenotype.
Decitabine incorporates into DNA after phosphorylation and forms irreversible covalent bonds with DNA methyltransferase-1, leading to genome-wide global DNA hypomethylation.
The administration of decitabine at doses of 15-20 mg/sm/die for 5-10 days every months in high-risk AML patients resulted in high frequency of complete remission. However, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative therapy for high-risk AML, but disease relapse is the principal cause of treatment failure for these patients, depending on the diagnosis characteristics and status of disease at the time of transplantation. The outcomes of salvage treatments are very poor. Therefore, early maintenance therapy, directed at eliminating minimal residual disease and promoting a graft versus-leukemia (GVL) effect, could be an effective method to improve outcome after allo-HSCT.
Decitabine enhances FOXP3 expression in CD4+CD25+ T cells (T regs). The Tregs are thought to play an important role in modulating graft versus-host-disease (GVHD) without sacrificing the beneficial of GVL effect. These studies provide a rationale for the administration of decitabine after allo-HSCT for high-risk AML. Our study, open-label and prospective, aims to expand the current knowledge about the use of low-dose decitabine as maintenance therapy in high-risk AML patients after allo-HSCT.
Methods: Seven patients with high-risk AML (2 with secondary AML, 5 with cytogenetics or molecular adverse factor) in complete remission, were enrolled in the study between day 50 and 80 after allo-HSCT to evaluate the prophylactic effect of decitabine. Other major eligibility criteria included performance status < 2 (ECOG), no grade 3 or 4 acute GVHD, no uncontrolled infections, creatinine < 1.5 x upper limit of normal (ULN), bilirubin < 1.5 x ULN, and hepatic enzymes < 2.5 x ULN.
All patient received a myelo-ablative conditioning regimen with busulfan (12.8 mg/kg) and fludarabine (150 mg/sm). The source of graft was peripheral blood in six patients and bone marrow in one patient. Four patients had transplanted using unrelated HLA-compatibile donors and three using HLA-identical sibling. Acute and chronic GVHD prophylaxis it was carried out with Thimoglobulin, Metothrexate and Cyclosporine.
Decitabine was administered as an intravenous infusion over 1 hour at the dose of 10 mg/sm/day for 5 consecutive days every 6 weeks for up to 8 - 10 cycles (to cover the first year post allo-HSCT).
The endpoints of study included toxicity, AML relapse, incidence and severity of GVHD, overall and disease free survival.
Results: All patients completed the treatment without any toxicity and nobody has developed a GVHD. The mean follow-up time was 22 months (16 - 35 months). Five patients are alive and in complete remission, while two patients relapsed (one after 19 months, and 1 after 20 months from allo-HSCT); of the two relapsed patients, one died and the other is alive with active disease.
Conclusions: Our study shows that post-transplant decitabine is safe and may play a role in the maintenance of remission in high-risk AML patients.
Disclosure: Nothing to declare
P043 Allogenic hematopoietic stem cell transplant consolidation therapy in older acute myeloid leukemia patients - survival and toxicities
Carla Alves1, Isabelina Ferreira2, Gilda Teixeira2, Nuno Miranda1, Sofia Jorge1, Manuel Abecasis1
1Instituto Portugues de Oncologia de Lisboa Francisco Gentil, Hematologia, Lisbon, Portugal
Background: Reduced-intensity conditioning (RIC) allowed selected patients (pts), with acute myeloid leukemia (AML) and over 60 years old (y.o.), to become candidates for allogenic hematopoietic stem cell transplant (allo-HSCT), as a strategy to prolong survival.
Methods: Data from AML pts over 60 years, who underwent RIC allo-HSCT in our institution between September 2011 and September 2017, was retrospectively collected from clinical files to evaluate the overall survival (OS) up to November 2018. We calculated the OS using Kaplan-Meyer curves.
Results: We identified 15 pts, median age 62 y.o. (60-67) and median HTC-I score 2. The median follow-up was 25 months. One patient (pt) had CML blast crisis and was on first major molecular remission. Of the remaining 14 AML pts, 7 were in 1st complete remission (CR), 4 in 2nd CR and 1 with progressive disease (PD); the other 2 pts could be classified as MDS according to 2016 WHO diagnostic criteria and were in CR1. Donors (D) were: 3 matched unrelated (MUD), 5 mismatched unrelated (MMUD - 9/10), 6 matched siblings and 1 haploidentical. Thirteen pts were infused with peripheral blood HSC and 2 with bone marrow. Conditionings were: FLUBCNUMEL in 5 unrelated donor (UD) pts and 4 siblings, FLUMEL in 1 UD pt and 1 sibling, FLUBU in 2 UD pts and FLUTBI 2Gy in 1 sibling and in the haploidentical. Graft versus host disease (GVHD) prophylaxis was Tacrolimus (TAC) + MMF in 5 UD pts and 1 sibling, TAC + MTX in 2 UD pts and Cyclosporine (CyA) + MMF in 1 UD pt and 5 siblings. All MMUD pts had ATG. PTCy was done in the haploidentical setting with TAC + MMF. The median time to neutrophil and platelet engraftment for the whole cohort was 14 and 11 days, respectively. One pt with secondary engraftment failure required re-infusion of selected CD34+ cells. Ten pts presented with mild acute skin GVHD. Eleven pts had chronic GVHD, 2 classified as severe; 7 required systemic therapy, 5 of those beyond 1 year. The median time on immunosuppressants was 404 days. At 2 years the OS was 63.5%. There were 6 deaths: 3 disease-related (2 relapses at 22 and 58 months and 1 PD at d+30), 2 infection complications (2 septic shock) and 1 to secondary neoplasia. Other relevant complications were hypoxemic pneumonia in 5 pts, 1 urinary sepsis, CMV and EBV reactivation respectively in 8 and 4 pts; pulmonary and renal toxicity either in 2 pts. At end of follow-up, 9 pts were in remission, 8 without negative measurable residual disease (MRD), the other MRD negative pt died of septic shock and severe intestinal GVHD.
Conclusions: In this small cohort, chronic GVHD and infectious complications were major causes of morbidity but there were no treatment related deaths before d+100. Pts maintaining or achieving MRD negativity after transplant had better survival. Although with only 15 pts, these results suggest that allo-HSCT is feasible as consolidation strategy in selected AML pts over 60 years.
[ [P043 Image] 1 . Overall Survival]
Disclosure: Nothing to declare.
P045 Outcome of hematopoietic stem cell transplantation in fanconi anaemia: A single centre study from Pakistan
Tariq Mehmood Satti1, Muhammad Farhan1, Syed Kamran Mehmood1, Tariq Azam Khattak1, Qamar-Un-Nisa, Chaudhry1, Tariq Ghafoor2, Mehreen Ali Khan1
1 Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan, 2 Armed Forces Bone Marrow Transplant Centre, Paediatrics, Rawalpindi, Pakistan
Background: Hematopoietic stem cell transplantation (HSCT) is the only curative option for Fanconi anaemia (FA); an inherited disorder characterized by congenital anomalies, progressive bone marrow failure (BMF) and a predisposition to develop malignancies.
Methods: We retrospectively analysed the data of 27 consecutive patients that underwent HSCT at this centre from 2001 till June 2018. The data was analysed for variables affecting the outcome in terms of overall survival (OS).
Results: Median age at diagnosis was 10 years (2-20 years). Median age at transplant was 11.3 years (4-25 yrs). All patients at transplant were in aplastic phase. Male to female ratio was 1.2:1. Twenty-four (88.9%) patients had congenital anomalies along with BMF while 3 were phenotypically normal. Twenty-three (85.2%) patients were 10/10 HLA matched with siblings, 2 with parents and 2 with cousins. Eleven (40.7%) patients had gender mismatch transplant.
Three patients had major and 6 had minor ABO mismatch.
Conditioning protocol included, Fludarabine 120mg/m2, ATG 20 mg/kg and Cyclophosphamide at a dose of 20-40 mg/kg. Mean time to neutrophil and platelets engraftment was 12.3±2.92 days and 20 ±10.3 days, respectively. Average hospital stay was 18.5±7 days. Major transplant complications were neutropenic fever (95%), hypertension (62%), mucositis I-II (41%), azotaemia (27%) and gut toxicity grade I-II (25%).
Four patients (14.8%) had acute graft versus host disease (GVHD) II-IV of skin and gut. Seven (26%) patients had chronic GVHD; 4 had limited chronic GVHD of skin, 3 had extensive chronic GVHD of skin, gut, liver and lungs.
Overall survival (OS) after HSCT at 6 months, 1, 5 and 8 years was 67%, 63%, 59% and 55% respectively. OS with Cy30mg/kg is 62%, Cy20mg/kg is 33% and Cy40mg/kg is 50%, though the number of patients in Cy20 (n=6) and Cy40 (n=2) is very small.
Post-transplant mortality is 12 (44.4%). The major causes of mortality include; respiratory infections (04), Primary graft failure (03), grade IV gut GVHD (02), diffused alveolar haemorrhage (01), CMV disease (01) and acute myeloid leukaemia (01) 4.5 years post-transplant.
Overall survival in patients transplanted at younger age (< 11 years) was 81.8% compared to 37.5% in older age group (>11years) and was statistically significant (p value =0.03)
No statistically significant association was found between OS and ABO mismatch, sex mismatch, time since diagnosis, source of stem cells and GVHD.
Conclusions: Our study demonstrated a survival advantage in Fanconi anaemia when transplanted at a younger age and conditioning with cyclophosphamide 30 mg/kg, fludarabine 120mg/m2 and ATG 20mg/kg an acceptable conditioning protocol.
Disclosure: No conflict of interest
Abstract already published.
P047 Incidence and outcome of severe complications in patients with paroxysmal nocturnal hemoglobinuria: A real life scenario from a single center 30 years experience
Anna Paola Iori1, Luisa Quattrocchi1, Stefania De Propris1, Walter Barberi1, Ursula La Rocca1, Matteo Salvini1, Maria Lucia De Luca1, Giovanni Assanto1, Antonella Bruzzese1, Sara Pepe1, Michela Ansuinelli1, Daniel Piamonti1, Alessandra Napoli1, Marco Brunori1, Robin Foà1
1 Policlinico Umberto I, Sapienza University, Rome, Italy,
Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal non-neoplastic hematopoietic stem cell disease whose incidence is 1.5-2.9 cases/million of individuals worldwide. Disease characteristics and natural history have been mostly analyzed by multicenter, retrospective studies, with the limit of heterogeneous approaches. Herein we report the incidence of severe complications and outcome in a real life setting scenario of PNH patients consecutively diagnosed and managed at our PNH referral Center between January 1985 and June 2018.
Methods: Patients received a homogeneous diagnostic and treatment approach according to the period of observation (availability of diagnostic tests and eculizumab). All patients treated with eculizumab received vaccination with conjugated anti-meningococcus ACWY-serotypes and, since 2016, conjugated anti-meningococcus B-serotype. In the event of any complication, patients could refer to dedicated Hematology Emergency Rooms (ER) 24 hours daily. The occurrence of renal failure and pulmonary hypertension was specifically evaluated. The renal function was studied according to the Cockcroft-Gault formula and the lung function was prospectively monitored by daytime-on exertion, nocturnal pulsoximetric profiles and complete spirometric tests, with DLCO measurement.
Results: Overall,48 PNH patients, median age 36 years (range 17-84), were analyzed. At diagnosis, 26 patients had classic PNH, 19 aplastic PNH and 3 an intermediate form. The cumulative incidences (CI) of thrombosis, and clonal hematologic neoplasm were 29%, and 6%, respectively. CI of pancytopenia in the 26 patients with classic PNH was 23%. One patient showed a spontaneous disappearance of the PNH clone. Since 2005, eculizumab was administered in 28 patients. After eculizumab treatment 50% and 32% of patients reached hemoglobin level > 11g/dL and >8< 11g/dL without transfusion, respectively, while 18% were non-responsive. During eculizumab treatment no thrombotic event was observed while two severe infectious episodes (respiratory tract and urinary tract infection) were observed in only one of the 28 patients. Extravascular hemolysis was demonstrated in 50% of patients. No patient showed a significant reduction of the renal function.Out of 24 patients prospectively monitored for lung function no pathological alteration in any diurnal or nocturnal pulseoximetric test was observed. No patient showed obstructive or restrictive ventilatory deficiency, nor reduced DLCO values. 30-years overall survival (OS) was 90% (4 patients who died for non-PNH related reasons were censored at the last follow-up).A better OS, even if not statistically significant,was associated to the absence of thrombotic events (90%vs70%), and the period of diagnosis (100% in 2006-2018, 91% in 1996-2005, 75% in 1985-1995).
Conclusions: Our study reports a better OS and lower rate of severe complications in PNH compared to previous experiences. Although renal failure and lung hypertension have been reported by other groups, we did not observe these complications along a prolonged follow-up. We can assume that the availability of a dedicated ER service enabled an early diagnosis and prompt treatment in case of hemoglobinuria crises (reducing the risk or organ damage) or other complications. The use of eculizumab, together with improved supportive approaches, presumably accounts for the trend towards a better survival witnessed over the last decade in the management of PNH patients.
Disclosure: Nothing to declare
P048 Haploidentical and unrelated allogeneic stem cell transplantation in aplastic anemia:Single center experience
Zafer Gulbas1, Elif Birtas Atesoglu1, Meral Sengezer1, İmran Dora1, Cigdem Eren1, Suat Celik1, Demet Cekdemir1
1 Anadolu Medical Center, Hematology, Kocaeli, Turkey
Background: Aplastic anemia is a syndrome of bone marrow failure characterized by peripheral pancytopenia and marrow hypoplasia. Allogeneic stem cell transplantation from HLA-matched sibling is performed in the firstline setting in young aplastic anemia patients and in elderly patients who are refractory to immunosuppressive treatment. But if the patient does not have a HLA-matched sibling, allogeneic stem cell transplantation is performed from unrelated and haploidentical donors. In this study, we analyzaed and compared the results of aplastic anemia patients who had undergone allogeneic stem cell transplantation either from matched unrelated or haploidentical donors.
Methods: We collected and analyzed data of aplastic anemia patients who had undergone allogeneic stem cell transplantation from matched unrelated or haploidentical donor between 2011 and 2018.
Results: There were 10 patients who had received allogeneic stem cell transplantation from unrelated donors and there were 10 patients who had undergone haploidentical transplantation. But in 4 patients who had undergone haploidentical transplantation, engraftment failure had occurred and they were transplanted from different haploidentical donors fort he second time. So a total of 10 unrelated and 14 haploidentical transplants were performed. The median age of patients who had undergone unrelated transplantation was 29(16-55) and the median age of patients who had undergone unrelated transplantation was 22(19-61). The results of the haploidentical and unrelated transplantations are shown in Table 1. The neutrophil and platelet engraftment times were significantly longer in haploidentical transplantations (p=0,006 and p=0,005, respectively). However, VOD, GVHD and 100 day mortality rates were not different in the 2 groups. Similarly overall survival (OS) of the patients who had undergone haploidentical or unrelated transplantation were not significantly different (p=0,38) (Figure 1).
Conclusions: Although the number of patients are low in this study, we can conclude that urelated and haploidentical transplantation in aplastic anemia have comparable toxicity and efficacy.
|Neutrophil engraftment time, day||17(12-54)||12(10-18)||0,006|
|Platelet engraftment time, day||17(14-41)||13(10-26)||0,005|
|100 day mortality||2(14,3%)||1(12,5%)||0,9|
[ [P048 Table] 1 . Table 1: Results of transplantation groups]
[ [P048 Image] 1 . Figure 1:Overall Survival]
Disclosure: Nothing to declare
P049 Allogeneic hematopoietic stem cell transplantation in adult aplastic anaemia patients: Promising treatment modality
1Eren Arslan Davulcu, 1Hale Bülbül, 1Yusuf Ulusoy, Nur Akad Soyer1, Fatma Keklik Karadağ1, Ayşenur Arslan1, Fahri Şahin1, Mahmut Töbü1, Güray Saydam1, Murat Tombuloğlu1, Filiz Vural1
1 Ege University, Izmir, Turkey
Background: Aplastic anaemia (AA) is a rare and serious hematologic disorder. Immunosuppression and allogeneic hematologic stem cell transplantation (ASCT) are two main treatment options. Related and unrelated HLA full-matched ASCT is very promising especially in young patients. Our aim is to retrospectively evaluate clinical characteristics and outcome in AA patients who were undergone ASCT in Ege University Hematology Department Stem Cell Transplantation Unit.
Methods: Patients who were undergone ASCT in our department between January 2012 and September 2018 retrospectively evaluated. Patients demographic data, age at diagnosis, time between diagnosis and ASCT, treatment until ASCT, source of stem cell and number of CD34+ stem cell infused, transplantation regimen, prophylaxis for graft-versus host disease (GVHD), time of neutrophil and thrombocyte engraftment, information about acute and chronic GVHD, overall survival and final status were analyzed. Overall and progression free survival was calculated.
Results: In six years, 13 AA patients were transplanted. 4 patients had severe, 7 of them had very severe, 1 patient had not severe but transfusion depended and unresponsive to immunosupressive treatment AA. One of the patients was Fanconi AA. Paroxysmal nocturnal hemoglobinuria clone detected in two patient's follow-ups, they received eculizumab until ASCT. Male/female ratio was 8/5. Mean age in ASCT was 29.61 years (19-44), mean time from diagnosis to transplantation was 43.61 months (1-192). The source of stem cells was peripheral blood in all donors. 3 of the donors were unrelated. Mean CD34 + stem cell was 8,51x106/kg (5-14.87). Standard GVHD prophylaxis regimen was methotrexate 15 mg/m2 on day +1, 10 mg/m2 on day +3, +6, +11. and cyclosporin 5 mg/kg starting on day +1. and titrated according to blood drug level. Patients conditioning regimen and clinical course after ASCT summarized in table 1. There was no acute GVHD but 5 patients had chronic GVHD. One patient had grade 3 skin GVHD in 6th month of transplantation and eye GVHD in 12th month. Another patient grade 2 skin GVHD in 4th month and eye GVHD in 5th month. Other two patients had grade 1 skin GVHDs in 15th and 7th months, 1 patient had grade 2 skin GVHD in 5th month. 2-year overall and progression free survival were 82.1% and 84.6% respectively.
Conclusions: ASCT is the only curative treatment in AA. In our group mortality rate was 15.4% and deaths were in early post-transplantation period because of the septic complications. Other patients are alive (84.6%) and didn´t encounter serious or life-threatening complications. In young patients with HLA matched donors, ASCT is a very effective and safe treatment modality.
Disclosure: No conflict of interest
P050 Management of viral reactivation in multiple sclerosis patients after autologous transplantation with BEAM/ATG conditioning regimen
Chiara Innocenti1, Massimo Di Gioia1, Maria Pia Amato1, Nunziata Ciccone1, Ilaria Cutini1, Marta Giannini2, Antonella Gozzini1, Stefano Guidi1, Alice Mariottini1, Luca Massacesi1, Chiara Nozzoli1, Annamaria Repice1, Rossolini Gian Maria1, Riccardo Saccardi1
1 University Hospital Careggi, Florence, Italy, 2 Prato Hospital, Prato, Italy,
Background: Autologous stem cells transplantation (aHSCT) is an effective treatment for very aggressive autoimmune diseases such as multiple sclerosis (MS). However, toxicity remains the major concern to a wide application of this approach. Post transplant viral reactivations may induce severe complications and a rigorous monitoring of peripheral blood viral load for a prompt and effective therapy is required. A higher rate of EBV and CMV reactivation has been observed in patients affected by MS and conditioned with BEAM plus ATG compared with a controlled group of lymphoma patients without ATG in the conditioning regimen. We report here the policy of our Center about both monitoring and treatment of such side effect.
Methods: A series of 37 consecutive patients with MS, transplanted between 2014 and 2018 is included in this analysis. All patients were mobilized with Cyclophosphamide 4g/sqm + G-CSF and conditioned with BEAM plus rabbit ATG (Thymoglobulin©, 7.5mg/Kg). Monitoring of CMV/EBV DNA on whole blood by quantitative PCR was performed after the engraftment, weekly for at least one month, then at longer intervals. Pre-emptive treatment with valgancyclovir was started in case of CMV viral load ³1x10^4 copies/mL. In case of EBV assay between 1x10^4 and 1x10^5 copies/mL further determinations were performed and Rituximab-based treatment was started if the viral copies exceeded 1x105copies. Patients received treatment in case of symptomatic disease for any value of the PCR of both viruses or EBV titer ³1x10^5 copies/mL.
Results: Detectable DNA for CMV was observed in 15/37 (40,5%) patients at a median time from transplant of 23 days (range 12-36) and 6/37 (16%) required pre-emptive treatment. All patients promptly responded to treatment within 2 weeks. EBV viral load was detectable in 19/37 patients (51,3%) at a median time of 22 days (range 12-52). One patient out of 19 started the treatment on first determination for high viral load (>1x10^6/mL); nine presented an EBV viral load over 1x10^4 copies/ml, three of them were treated thereafter for the persistent increase of the viral load (> 105/ml). Six patients spontaneously recovered the EBV reactivation. Previous treatments were not predictive of any higher risk of viral reactivation. No impact on engraftment related to the reactivation was observed.
Conclusions: This policy shows that, despite a high rate of CMV and EBV reactivation, no grade III-IV adverse events were observed, suggesting the key role of viral monitoring in these patients and the efficacy of the preemptive treatment. EBV reactivation at low titers should be monitored to identify those cases that could achieve a spontaneous resolution and avoid the induction of further immunosuppression by Rituximab. These data confirm that patients diagnosed with AD undergoing autologous HSCT need a more intense pattern of care than hematological patients.
1. CMV AND EBV REACTIVATION AFTER AUTOLOGOUS HAEMOPOIETIC STEM CELL TRANSPLANTATION WITH BEAM CONDITIONING REGIMEN FOR MULTIPLE SCLEROSIS AND LYMPHOMA: A RETROSPECTIVE SINGLE CENTER CASE-CONTROL STUDY M. Di Gioia1,*, C. Innocenti1, R.Saccardi EBMT2014
Disclosure: Chiara Innocenti: Nothing to declare, Massimo Di Gioia: Nothing to declare, MariaPia Amato: Nothing to declare, Nunziata Ciccone: Nothing to declare, Ilaria Cutini: Nothing to declare, Marta Giannini: Nothing to declare, Antonella Gozzini: Nothing to declare, Stefano Guidi: Nothing to declare, Alice Mariottini: non-financial support from Biogen idec, Sanofi Genzyme, Novartis, Luca Massacesi: non-financial support from Biogen, Novartis, Merck Serono, Genzyme and Teva, Chiara Nozzoli: nothing to declare, Annamaria Repice: personal fees and non-financial support from Biogen idec, Sanofi Genzyme and Novartis; non-financial support from Teva; personal fees from Merck
Gian Maria, Rossolini: personal fees, grant and/or financial support from Accelerate Diagnostic, Angelini, Astra-Zeneca, Basilea, Becton-Dickinson, bio-Merieux, Biotest, Cepheid, Elitech, Merck, Novartis, Nordic Pharma, Pfizer, Seegene, Shionogi, Zambon, Roche, Curetis, ThermoFisher, Beckman Coulter, Menarini, Arrow, Symcel. Other with VenatorX (strains sold by the department)
Riccardo Saccardi: personal fees from Sanofi Genzyme
P051 Autologous haematopoietic stem cell transplantation for autoimmune diseases: Experience of a tertiary referral center in Colombia
Claudia Lucia Sossa Melo1,2, Sara Ines Jimenez1,2, Angela María Peña1,2, Luis Antonio Salazar1,2, Manuel Rosales2, Jose Patricio López1, Manuel Ardila-Báez1, Claudia Marcela Chalela1, Maria Luna-Gonzalez1, Maria Fernanda Ortiz1, Diego Saaibi1,2, Ivan Mauricio Peña1,2
1 Universidad Autónoma de Bucaramanga, Bucaramanga, Colombia, 2 Clinica FOSCAL, Bucaramanga, Colombia
Background: Autoimmune diseases are chronic serious conditions that are often refractory to standard therapies. Since 1996, autologous haematopoietic stem cell transplantation (HSCT) has been a very promising alternative that has shown satisfactory long-term results. The aim of this study is to evaluate immune reconstitution and mortality following HSCT in patients with autoimmune disease.
Methods: A retrospective study was conducted on patients with diagnosis of autoimmune diseases that underwent autologous HSCT between July 2012 and January 2018 at a tertiary referral center in Colombia, South America. Descriptive statistics were used to analyze patient's demographic and clinic characteristics.
Results: Seven patients were included, with a mean age of 37 years (range 26-57). Five patients were female (71%). The indications for HSCT were systemic sclerosis (n=3), multiple sclerosis (n=2), and myasthenia gravis (n=2). The conditioning regimen administered in patients with systemic sclerosis was cyclophosphamide + human anti-T lymphocyte immunoglobulin, BEAM (Carmustine, Etoposide, Cytarabine (Ara-C), and Melphalan) + Human anti-T lymphocyte immunoglobulin in patients with multiple sclerosis, and cyclophosphamide + Human anti-T lymphocyte immunoglobulin in myasthenia gravis. Median time to myeloid engraftment (neutrophils>0.5×109/L) was 12 days post-transplantation, and platelet engraftment, defined as >20,000 platelets/mm3 untransfused, was 11 days post-HSCT.
Median time of hospitalization was 21 days (range 11-66); longer in-patient management was due to infectious complications. Infectious complications included bacteremia caused by E. Coli and pneumocystis pneumonia that resulted in septic shock and acute respiratory failure, respectively.
Evaluating T-cell immune reconstitution, none of the patients had reached normal CD4+ cell value after one year of HSCT follow-up. Four patients (57.1%) reached normal CD8+ cells value at 3 months post-HSCT. Regarding B-cell immune reconstitution, 85.7% of the patients (6/7) had reached both IgG and IgA normal levels at one-month post-HSCT, and four patients (57.1%) had achieved normal IgM level at 6 months post-transplantation. In the 10 months to 6 years of post-HSCT follow-up, there has not been evidence of disease relapse in any of the patients. There were no deaths in the present cohort.
Conclusions: Autologous HSCT has proved to be a successful treatment alternative in patients with severe refractory autoimmune disease, achieving sustained remissions for more than 5 years.
Disclosure: Nothing to declare
P052 Autologous haematopoietic stem cell transplantation in multiple sclerosis - A single centre experience
Adriana Roque1,2, Telma Nascimento1, Emília Cortesão1,2, Ana Isabel Espadana1, Luís Francisco Araújo1,2, Raquel Guilherme1,2, Maria Carmo Macário1, Lívia Sousa1,2, Ana Bela Sarmento-Ribeiro1,2, Letícia Ribeiro1, Catarina Geraldes1,2
1 Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal, 2 University of Coimbra, Coimbra, Portugal
Background: Multiple sclerosis(MS) is an inflammatory disease caused by autoimmune reactivity of T cells against myelin.
There is accumulating evidence of the efficacy of high-dose chemotherapy followed by autologous haematopoietic stem cell transplantation(aHSCT) in MS patients who failed response to standard immunotherapy, despite a variability in eligibility criteria, conditioning regimens and outcome.
Methods: We retrospectively reviewed MS patients submitted to aHSCT in our centre(2014-2018). Patient eligibility criteria were active relapsing remitting(RRMS) or secondary-progressive MS (SPMS), with prior failure to treatment with disease-modifying therapies and evidence of disease activity (clinical relapse or new active lesions in magnetic resonance [MR]).
Mobilization of CD34+cells to peripheral blood was performed with granulocyte colony-stimulating factor(G-CSF 10µg/kg/day) and conditioning regimen according to BEAM protocol.
The severity of MS disability was classified according to the Expanded Disability-Status Scale (EDSS) and aHSCT toxicity was evaluated by CTCAEv5.0.
Results: Seven MS patients had undergone aHSCT (4 female/3 male), with a median age at aHSCT of 39.9 years(32-42).
Median age at MS diagnosis was 31.6 years(27-36) and median time from diagnosis until aHSCT was 6.8 years(3-13).
Four patients (57.1%) had SPMS and 3(42.9%) had RRMS, with 4(57.1%) having MR active lesions. Pre-aHSCT relapse rate per year was 2(1-4). Median baseline EDSS was 6.5(5.5-7.5).
Median number of previous DMTs was 6(3-9). All patients had been treated with corticosteroids and copaxone, 5(71.4%) received rituximab, 6 (85.7%) natalizumab, 1(14.3%) alemtuzumab, 2(28.6%) fampridine and 2(28.6%) fingolimod.
All patients collected enough CD34+ cells in a single apheresis session. Median number of CD34+ cells infused was 7.2±3.8x10^6/kg, for a mean DMSO volume of 50.4±14.8 mL.
Median inpatient stay during aHSCT was 28 days(21-47). All patients developed febrile neutropenia, one was admitted to intensive care unit due to sepsis. One patient developed an anaphylactic reaction to transfusion and another a self-limited encephalopathy. Two (28.7%) patients had grade≥2 oral mucositis, and all had gastrointestinal toxicity (grade 2-3).
Median time until neutrophils>500/µL was 11(6-12) days, to platelets>20,000/µL was 9 days(5-12), and to engraftment was 13 days(12-14). Patients were transfused with a median of 1(0-2) unit for erythrocytes and 3(1-8) for platelets.
There was no treatment-related mortality and no long term side effects have been observed so far.
For a median post-aHSCT follow-up of 8.7 months, no patient developed new lesions in MR, but 2(28.6%) experienced symptoms consistent with a clinical relapse, at a median time of 20.5(5-35) months, effectively rescued with corticosteroids. The absence of evidence of disease activity at 6-months was 71.4%.
Although there was no variation concerning EDSS punctuation, 4(57.1%) patients self-reported significant benefits, especially concerning limb strength and sphincter continence improving.
Conclusions: Our real life results claim a stabilization effect of MS patients with highly active/progressive disease after aHSCT, with no significant toxicity.
The failure in reporting benefits in EDSS punctuation is probably due to a small sample size and short follow-up.
More studies are needed to establish the best patient selection criteria and define the ideal time to include these patients in transplantation programs, as well as to evaluate its long term outcome.
Disclosure: Nothing to declare.
P053 The direct antiglobulin test in oncohematological patients
Elena Poponina1, Elena Butina1, Anna Yovdiy1, Galina Zaytseva1, Natalia Minaeva1, Igor Paramonov1
1 Kirov Scientific Research Institute of Hematology and Blood Transfusion of the Federal Medical-Biological Agency, Kirov, Russian Federation
Background: The development of oncohematological diseases may be complicated by the autoimmune pathology, including the production of antibodies to own red blood cells. The direct antiglobulin test (DAT) is used to detect antibodies and complement components on the surface of red blood cells. A differentiated DAT allows to semi-quantitatively assess the immunoglobulins fixed on red blood cells and determine their subclass.
Methods: The results of DAT were analyzed in 250 oncohematological patients first hospitalized at the Institute clinic in 2018 with the diagnosis: multiple myeloma (MM) — 67, acute myeloid leukemia (AML) — 55, non-Hodgkin lymphoma (NHL) — 44, acute lymphoblastic leukemia (ALL) — 32, Hodgkin disease (HD)— 26, chronic lymphocytic leukemia (CLL) — 19, chronic myelogenous leukemia (CML) - 7 patients. DAT was performed by gel method using anti-IgG/C3d, DC-Screening I and DAT IgG1/IgG3 cards (BioRad, Switzerland). The frequency of positive DAT in patients was compared with the same in 200 healthy residents of the region - donors of blood components.
Results: All blood donors were DAT-negative. Autoantibodies to red blood cells were detected in 15,2% of oncohematological patients. The most often positive DAT was revealed in patients with MM — 26,9%. Autoantibodies were detected in 18,2% patients with NHL, 15,4% — with HD, 10,9%— with AML, 10,5% — in patients with CLL. In patients with ALL and CML the DAT result was negative.
The intensity of the reaction (+) was observed in 57,9% of patients with positive DAT, (++) - in 34.2%, (+++) - in 5,3%, (++++) - 2.6%. In the majority of cases (92,1%) IgG2,4 were fixed on the surface of red blood cells, associated with a low risk of immune hemolysis. Only in 3 patients (7,9%), with the DAT reaction (+++) and (++++), DAT was positive due to IgM and complement components.
Autoantibodies in the plasma of patients can interact not only with their own red blood cells, but also with test and donors red blood cells, being detected in an indirect antiglobulin test (IAT). A positive IAT was in 13,2% of patients with positive DAT. These patients had difficulties in donors due to non-specific agglutination.
Conclusions: Despite the fact that the development of oncohematological diseases is often accompanied by the production of autoantibodies, not in every case a positive result of DAT should be regarded as a sign of autoimmune hemolysis. To correctly assess the risk of hemolysis, the physicians should analyze other laboratory and clinical data. Positive DAT may be correlated with the difficulties of selection of the donor for such patient.
Disclosure: Nothing to declare.
P054 Single cell identification of defined ebv epitope-specific TCRαβ pairs for adoptive T cell transfer against EBV infection and EBV-associated malignancies
María Fernanda Lammoglia Cobo1, Christian Pircher1, Kerstin Dietze1, Thomas Kammertöns1, Regina Gary2, Andreas Moosmann3, Josef Mautner3, Klaus Dornmair4, Anna Takvorian1, Lars Bullinger1, Thomas Blankenstein1,5, Armin Gerbitz1, Leo Hansmann1
1 Charité - University Medicine Berlin, Berlin, Germany, 2 University Medicine Erlangen, Erlangen, Germany, 3 Helmholtz Center Munich, Munich, Germany, 4 Biomedical Centre and Hospital of the LMU, Institute of Clinical Neuroimmunology, Munich, Germany, 5 Max Delbrück Centre for Molecular Medicine, Berlin, Germany
Background: Reactivation of Epstein-Barr virus (EBV) represents a potentially life-threatening condition in approximately 30% of patients after allogeneic stem cell transplantation, with no specific treatment available.
Methods: We have previously developed a manufacturing protocol for the expansion of Cytomegalovirus (CMV) and EBV-specific T cells by stimulation of G-CSF-mobilized stem cell grafts with defined peptide pools (Gary, 2018). This Advanced Therapeutic Medicinal Product is currently investigated in an ongoing phase I/IIa trial (EudraCT Number: 2012-004240-30). However, the expansion of virus-specific T cells relies on a pre-existing virus-specific memory compartment in the stem cell donor. In virus-seronegative donors, no expansion can be achieved. We therefore aim to identify EBV peptide-specific T cell receptors (TCRs) that can be translated into off-the-shelf cell products for the treatment and prophylaxis of EBV infection and EBV-associated malignancies.
Leftover cells from five allogeneic stem cell grafts were expanded in vitro in the presence of HLA-B35*01-restricted peptides (HPVGEADYFEY from EBNA1, EPLPQGQLTAY from BZLF1) associated with latent and lytic EBV infection. After expansion, single EBV-specific T cells were FACS sorted using peptide-MHC (pMHC) tetramers, and individual TCR α- and β-chain pairs were determined with single cell sequencing (Han 2014, Penter 2018). To confirm peptide specificity, dominant TCR pairs were transfected into a murine 58α-β- reporter T hybridoma cell line with NFAT-driven GFP expression (Siewert, 2012). Functional TCRαβ candidates were transduced into human peripheral blood T cells and co-cultured with allogeneic and autologous EBV positive lymphoblastoid cell lines (LCL) to test for recognition of EBV-infected cells.
Results: Frequencies of HPV- and EPL-specific T cells, as determined by pMHC tetramer staining, indicated an average 40-fold increase after in vitro expansion. Three dominant TCRαβ pairs were re-expressed in 58α-β- cell lines and recognized their respective target peptides -as presented by NFAT-driven GFP expression and IL-2 secretion- upon co-incubation with HLA-matched peptide-loaded antigen presenting cells. After transduction into human T cells from HLA-matched and unmatched donors, all three TCRs recognized the HLA-B*35:01 pMHC tetramers, and T cells transduced with two EPL-specific TCRs resulted in IFN-γ secretion in the presence of HLA-matched EBV-LCLs.
Among the five HLA-B*35:01 donors, 10 HPV- and EPL-specific TCR clones in total were found in at least 2 patients with different extents of dominance. The repertoires indicate an antigen-directed oligoclonal expansion. Meanwhile, sequence comparison between an in vitro and in vivo expansion after EBV reactivation in one patient revealed the presence of several identical sequences.
Conclusions: We present a system for highly efficient identification of EBV epitope-specific TCRs that can be re-expressed on human T cells and recognize EBV-infected cells. The expansion of common peptide-specific TCRs across HLA-matched patients and the in vivo expansion upon EBV reactivation suggest high relevance for virus control. The translation of defined sets of TCRs into cellular products for adoptive transfer will help to overcome unmet clinical needs in the treatment and prophylaxis of virus reactivation, primary infection, and EBV-associated malignancies such as post-transplant lymphoproliferative disease (PTLD) and Hodgkin lymphoma. Furthermore, it opens the possibility to treat CMV-reactivation after solid organ transplantation through the identification of CMV-specific TCRs.
Clinical Trial Registry: Not applicable.
Disclosure: Nothing to declare.
Abstract already published.
P056 NKG2D-CAR T cells as an immunotherapy against pediatric hematological malignancies
Lucía Fernández1, Adrián Fernández1, Adela Escudero2, Leila Cardoso2, Jaime Valentín3, Alejandra Leivas4, María Vela3, Joaquín Martínez-López4, Mar Valés5, Antonio Pérez-Martínez3,6
1 CNIO, Clinical Research, Madrid, Spain, 2 INGEMM, Madrid, Spain, 3 IdiPAZ, Madrid, Spain, 4 Hospital 12 de Octubre, Hematology, Madrid, Spain, 5 CNB, Madrid, Spain, 6 Hospital La Paz, Madrid, Spain
Background: Lymphoid and myeloid acute leukemia are the most frequent cause of cancer related death in children. Interactions between NKG2D receptor, expressed in cytotoxic immune cells, and its ligands (NKG2DL), that are upregulated in many types of tumor cells including leukemic blasts, are important for anti-tumor immune surveillance. Nevertheless, tumor cells may develop immune scape strategies like ligand shedding, which reduces NKG2DL expression and may cause NKG2D receptor downregulation. Engineering T lymphocytes with NKG2D CAR may overcome immune evasion and become an effective therapeutic strategy.
Methods: CD45RA- T cells were obtained by depletion of non-mobilized apheresis with CD45RA magnetic beads using CliniMACS. NKG2D-CAR T cells were generated by lentiviral (NKG2D-41BB-CD3z) transduction of CD45RA- T cells with MOI=2.
The expression of NKG2D ligands was analyzed in peripheral blood or bone marrow samples from a total of 97 leukemia patients (AML=13, B-ALL=52 and T-ALL=19), at different status of the disease (Diagnosis, Remission, Relapse/refractory), and in 10 different leukemia cell lines by qPCR and flow cytometry. Cytotoxicity of NKG2D-CAR T cells against leukemia cells was evaluated by performing conventional-4 hours Europium-TDA assays. Soluble NKG2DL (sNKG2DL) concentration was measured in the sera of leukemia patients by ELISA.
To evaluate the effect of sNKG2DL on NKG2D-CAR T cells, those were cultured in the presence or absence of different concentrations of sNKG2DL for 7 days. One week later, cell proliferation and CAR downregulation were measured by flow cytometry using Cell Trace Violet and NKG2D labeling, respectively. The production of IFN-g and TNF-a was measured in the supernatants by ELISA. The effect on cytotoxicity was evaluated in a 2 hours-degranulation assay by co-culturing sNKG2DL pretreated NKG2D-CAR T cells against K562 cell line.
Results: NKG2D ligands were expressed in leukemia cell lines and leukemic blasts. NKG2DL expression changed with disease status with a trend to decrease at diagnosis and relapse/refractory compared to remission. NKG2D-CAR T cells were cytotoxic against 8/10 leukemia cell lines with a percentage of specific lysis over 50%. Myeloid and T-ALL cell lines were more susceptible to NKG2D-CAR T cells (specific lysis ranging from 50-78%) compared to B-ALL cell lines (19-52%). Physiological concentrations of sNKG2DL caused an increase in NKG2D-CAR expression. However, supra-physiological levels of sNKG2DL decreased NKG2D-CAR expression up to 5 times and increased cell proliferation up to 4 times. CD4+ subpopulation was more affected by downregulation, while proliferation had more impact on CD8+ subset. The effects of sNKG2DL were dose-dependent and attenuated by IL-2.
Conclusions: NKG2D-CAR T cells are cytotoxic against leukemia cells, specially AML and T-ALL, and thus could be a novel therapeutic approach for non-B leukemia, or those B-ALL that relapse with undetectable CD19 after CD19-CAR treatment. NKG2D-CAR expression may be downregulated only by supra-physiological levels of sNKG2DL, although antitumor activity is not affected. IL-2 softens the negative effects of sNKG2DL inducing NKG2D expression, cell proliferation and cytokines production. The changes observed in NKG2DL surface expression at the different stages of the disease could be related to ligands release and immune escape.
Disclosure: Nothing to declare
P057 anti-leukaemia and anti-viral T-cell immunotherapy of photodepleted allogeneic T cells using TH9402 photosensitiser
Denis-Claude Roy1,2, Ines Adassi1,2, Céline Leboeuf1,2, Vibhuti P. Dave1,2
1Hôpital Maisonneuve-Rosemont Research Center, Montréal, Canada, 2University of Montréal, Montréal, Canada
Background: For patients with high-risk leukaemia, allogeneic haematopoietic stem cell transplantation is the only curative treatment. The presence of alloreactive T cells in the donor graft, however, leads to a high probability of developing graft-versus-host disease (GVHD). T-cell depletion minimises the presence of GVHD-causing alloreactive cells, but often results in an increased incidence of infections and disease relapse. Photodepletion treatment (PDT) can specifically deplete activated alloreactive T cells while conserving resting T cells. PDT-treated cells have been utilised after T-cell-depleted haploidentical transplant to help reduce infection and relapse. The efficacy and safety of such PDT-treated cells is currently under clinical investigation in a phase III trial (HATCY, NCT02999854; Kiadis Pharma).
Here the reactivity of PDT-treated donor T cells was assessed toward tumour-associated and viral antigenic peptides derived from Wilm's Tumour protein 1 (WT1p), preferentially expressed antigen in melanoma (PRAMEp), and from cytomegalovirus and Epstein-Barr virus (CMV/EBVp).
Methods: Healthy donor (HLA-A*0201) peripheral blood mononuclear cells (PBMCs) were co-cultured with irradiated PBMCs from another mismatched donor (1:1) in a 4-day mixed lymphocyte reaction. TH9402, a photoactive rhodamine derivative, was added and cells were exposed to visible light to deplete the TH9402-containing activated alloreactive cells. Elimination of alloreactive cells post-PDT was assessed using CD25 and HLA-DR as activation markers. An ex vivo expansion protocol was exploited to evaluate the impact of PDT on reactivity to tumour and viral antigenic peptides. Post-PDT T cells were co-cultured with irradiated autologous monocyte-derived dendritic cells (10:1) pulsed with WT1p, PRAMEp or CMV/EBVp. Antigen-specific T cells were re-stimulated on Days 7 and 14 with WT1p- or PRAMEp-pulsed autologous PBMCs or with CMV/EBVp added directly to the culture. MHC-tetramer staining was performed on Days 14 and 21; IFN-γ ELISpot was conducted on Day 21.
[ [P057 Image] 1 . Functional WT1-specific and viral-specific T cells can be expanded post-PDT]
Results: PDT resulted in a drastic decrease of CD25 and/or HLA-DR activation marker-expressing CD4+ and CD8+ T cells. PDT-treated cells showed a significant increase in the frequency and number of WT137-45-specific T cells on Day 14 of culture, greater than the increase seen in untreated cells, with some cultures continuing expansion on Day 21 (Figure A). PDT-treated WT137-45-specific T cells secreted IFN-γ upon exposure to WT137-45 peptide and were highly cytotoxic against WT137-45-pulsed T2 cells. These data demonstrate that PDT preserves functional WT1-specific T cells. Detection of T-cell responses to PRAMEp in some donors showed preservation of anti-leukaemic T cells post-PDT, not restricted to WT1. HLA-A*0201 CMV pp65495-503 and HLA-A*0201 EBV BMLF1280-288 tetramers detected significant numbers of specific T cells in both PDT-treated and untreated cultures on days 14 and 21 of expansion (Figure B). Similar IFN-γ secretion was seen in untreated and PDT-treated cells after re-stimulation with pp65495-503 and BMLF1280-288 peptides, demonstrating that PDT did not affect the functionality of the antiviral T cells.
Conclusions: PDT selectively eliminates alloreactive GVHD-causing T cells, while preserving functional anti-leukaemic and antiviral T cells to prevent both disease relapse and viral infection/reactivation without the need for immunosuppression. These results corroborate the low infection and relapse rates observed in patients treated with PDT-treated cells.
Clinical Trial Registry: N/A
Disclosure: Funding for this study and medical writing support was provided by Kiadis Pharma. Denis-Claude Roy discloses patents and royalties and is an author on patent at the University of Montreal and Hôpital Maisonneuve-Rosemont. Denis-Clauide Roy also discloses travel support and consultancy with Kiadis Pharma. No other authors have conflicts of interest to declare.
P058 Sleeping beauty based engineering of chimeric antigen receptor NK cells for treatment of acute lymphoblastic leukemia
Tobias Bexte1,2, Lacramioara Botezatu3, Stephan Mueller1,2, Hanna Steigerwald1,2, Michael Hudecek4, Axel Schambach5, Ute Modlich2,6, Winfried S. Wels7,8, Zoltan Ivics3,8, Evelyn Ullrich1,2,8
1 Hospital of the Goethe University Frankfurt, Frankfurt am Main, Germany, 2 Johann Wolfgang Goethe-University, LOEWE Center for Cell and Gene Therapy, Frankfurt am Main, Germany, 3 Paul Ehrlich Institute, Langen, Germany, 4 Universitätsklinikum Würzburg, Medizinische Klinik und Poliklinik II, Würzburg, Germany, 5 Hannover Medical School, Institute of Experimental Hematology, Hannover, Germany, 6 Paul-Ehrlich-Institute, Research Group Gene Modification in Stem Cells, Langen, Germany, 7 Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany, 8 German Cancer Consortium (DKTK), Frankfurt am Main, Germany
Background: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and relapsed or refractory ALL is still difficult to treat. Engineered T cells equipped with a synthetic chimeric antigen receptor (CAR) targeting CD19 have demonstrated remarkable efficacy to treat ALL. However natural killer (NK) cells are known for their target-independent cytotoxic potential without induction of cytokine release syndrome (CRS) or graft-versus-host-disease (GvHD), CAR-NK cells can overcome the persisting problem in the therapy with CAR T cells. As the use of viral vector generated CAR NK cells is limited by theire genotoxicity, cost and regulatory demands, we are developing an innovative protocol using non-viral Sleeping Beauty (SB) transposition of third party NK cells as a source to produce 'off the shelf' CAR-engineered cell products.
Methods: NK cells are isolated from peripheral blood mononuclear cells (PBMCs) using CD56 selection kits. They are successfully expanded ex vivo with IL-15 cytokine stimulation under feeder-cell free conditions. After few days of expansion NK cells are electroporated using pmaxGFP. Transfection efficiency and percent of living cells after electroporation is analyzed by flow cytometry. Transposition based nucleofection using an SB100X mRNA and a minicircles (MC) DNA vector is performed at different time points after NK cell isolation. The transient MC-Venus longtime expansion and the viability after SB100X based nucleofection is measured over two weeks.
Furthermore, α-retroviral (α-RV) CD19-CAR transduction of NK cells with different viral amounts (MOI) is conducted and the cytotoxicity of the engineered CD19-CAR-NK cells against the CD19 positiv cell line SupB15 is addressed.
Results: For an α-RV CD19-CAR transduction of maximal 1x104 NK cells we could show transduction efficiency of 68,96% for MOI10. The α-RV CD19-CAR modified NK cells had a high killing activity against CD19 positiv SupB15 cells (E:T ration 1:1 90,85%) compared to CD19 negativ K562 cell lines (E:T ration 1:1 16,42%) and the non-transduced NK cells (E:T ratio 1:1 9,03%).
In first experiments with pmaxGFP vector based nucleofection, we could show an increasing efficiency of 55,9% 48h post electroporation with a only slightly decreas of living cells (21,5%) comparing to the non-electroporated NK cell viability. Using SB100X mRNA with MC-Venus DNA we electrotransfected 1x106 NK cells after fews days of cultivation and we reached 36,6% of transfected NK cells 24h post electroporation and a transient expression of MC-Venus positive NK cells up to 54,6% efficiency with an increasing rate of live cells over 14 days after electroporation.
Conclusions: The Sleeping Beauty based nucleofection of NK cells is a very promising non-viral method to generate more easy, safer and higher amounts of genetically modified third party NK cells for therapy of ALL and has also a broad range of clinical applications.
Disclosure: Winfried S. Wels is an inventor on a patent describing chimeric antigen receptors with an optimized hinge region. Axel Schambach is an inventor on a patent describing alpharetroviral SIN vectors. Michael Hudecek and Zoltan Ivics are inventors on patents related to Sleeping Beaut gene transfer technology. The remaining authors have nothing to disclose.
P059 NK and NKT cell doses in allogeneic stem cell grafts affect relapse-free survival and graft-versus-host disease after transplantation
Lia Minculescu1, Hanne Marquart1, Lars Peter Ryder1, Lone Smidstrup Friis1, Ida Schjødt1, Brian Thomas Kornblit1, Niels Smedegaard Andersen1, Søren Lykke Petersen1, Eva Haastrup1, Anne Fischer-Nielsen1, Henrik Sengeløv1
1 Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
Background: Mature immune cells from the stem cell graft are essential for the graft-versus-tumor (GVT) effect to eliminate residual malignant cells after hematopoietic stem cell transplantation (HSCT), but donor cells are also involved in complications such as graft-versus-host disease (GVHD).
Methods:We performed a prospective study of the detailed graft composition in 102 recipients of peripheral blood stem cells (PBSC) or bone marrow (BM) in order to identify correlations to clinical outcomes, table 1. Grafts were characterized with concentrations of T cells and NK cells together with a multi-color flow cytometry panel with staining for TCRαβ, TCRγδ, Vδ1, Vδ2, CD3, CD4, CD8, HLA-DR, CD196, CD45RO, CD45RA, CD16, CD56, CD337 and CD314 for detailed immune phenotyping. Cell contents in stem cell grafts were analyzed both as fractions of CD45 positive lymphocytes and as absolute concentrations converted to transplanted cells/kg. Fractions were evaluated in patients receiving both BM and PBSC (n=102), while concentrations (cells/kg) were only analyzed in patients transplanted with PBSC (n=88).
|Follow-up, days, median, min-max||662 (386-884)|
|Age, years, median, min-max||59 (20-74)|
|Disease, n,percent AML, ALL, MDS, Myelofibrosis,NHL,Chronic leukemia, Other||41 (40%), 14 (14%), 25 (24%), 8 (8%), 5 (5%), 4 (4%), 5 (5%),|
|Graft source, n, percent BM, PBSC||14 (14%), 88 (86%)|
|Donor, n, percent MRD, MUD||23 (23%), 79 (77%)|
|Donor, HLA-match, n, percent 10/10 or 9/10 allele math, 1 Ag mismatch, Haplo-identical||91 (89%), 9 (9%), 2 (2%)|
|Donor-recipient, sex, n, percent M/M, M/F, F/F, F/M||49 (48%), 26 (25%), 17 (17%), 10 (10%)|
|Conditioning intensity, n, percent Myeloablative, Non-myeablative||48 (47%), 54 (53%)|
|Conditioning regimen, n, percent TBI-Flu, Flu-Treo, TBI-Cy, TBI-Etopophos, Other||50 (49%), 26 (25%), 19 (19%), 4 (4%), 3 (3%)|
[ [P059 Table] 1 . Table 1]
[ [P059 Image] 1 . Figure 1]
Results: We found, that patients transplanted with graft NK cell doses above the median of 27x106/kg and fractions of NK cells out of lymphocytes above the median of 8.1% had significantly increased relapse-free-survival compared to patients transplanted with grafts containing NK cell doses below these values, figure 1; results stayed significant in multivariate analyses. Relapse incidence was significantly lower in uni- and multivariate analyses in patients receiving grafts with high NK cell fractions compared with low fractions, p=0.01, with 1-year relapse rates of 8% versus 27% in patients transplanted with high versus low fractions of NK cells, p=0.01. Peripheral blood concentrations of NK cells obtained from samples from 17 PBSC donors before G-CSF mobilization were significantly correlated to graft concentrations- and fractions of NK cells.. Analyses of graft contents of NKT cells showed that the incidence of grade II-IV acute GVHD were significantly lower in patients transplanted with graft doses below the median of 14.5x106/kg (p=0.04) and 4% NKT cells out of lymphocytes (p=0.03) compared to patients transplanted with grafts containing NKT cell doses above these values. Of note, the graft concentrations of CD3-, CD4- or CD8 positive T cells were not associated with overall survival, relapse-free survival or GVHD.
Conclusions: Our observations suggest that a more detailed graft characterization could benefit in risk assessment in HSCT and that donor selection, graft manipulation and additional cell infusions could optimize graft compositions regarding doses of cells beneficial for the transplantation.
Clinical Trial Registry: Not relevant
Disclosure: The authors have nothing to declare
P060 Extracorporeal photopheresis in the treatment of refractory acute GVHD: Analysis of mononuclear cell infusion
Gillen Oarbeascoa1, Maria Luisa Lozano2,3,4, Luisa Maria Guerra5, Cristina Amunarriz6, Nuria Revilla2,3,4, Pastora Iniesta2,3,4, Cynthia Acosta Fleitas5, Jose Luis Arroyo6, Eva Martinez Revuelta7, Andrea Galego8, Dolores Hernandez-Maraver9, Mi Kwon1,10, Aurora Viejo9, Jose Maria Garcia Gala7, Concepcion Andon Saavedra8, Jose Luis Diez-Martin1,10,11, Cristina Pascual1,10, GEA Grupo Español de Aferesis (GEA)12
1 Hospital General Universitario Gregorio Marañon, Hematology, Madrid, Spain, 2 Hospital Universitario Morales Meseguer, Murcia, Spain, 3 Centro Regional de Hemodonacion, Murcia, Spain, 4 IMIB-Arrixaca, Murcia, Spain, 5 Hospital Universitario de Gran Canaria Dr Negrin, Las Palmas de Gran Canaria, Spain, 6 Banco de Sangre y Tejidos de Cantabria – Hospital Universitario Marqués de Valdecilla, Santander, Spain, 7 Hospital Universitario Central de Asturias, Hematology and Hemotherapy Service, Oviedo, Spain, 8 Complexo Hospitalario Universitario A Coruña, A Coruña, Spain, 9 Hospital Universitario La Paz, Madrid, Spain, 10 Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain, 11 Universidad Complutense de Madrid, Madrid, Spain, 12 Grupo Español de Aferesis, Madrid, Spain
Background: Extracorporeal photopheresis (ECP) is an immunomodulatory treatment that has shown efficacy in steroid refractory acute GvHD, but the mechanism of action is only partially understood. There is no clear relationship between the ECP-treated mononuclear cells (MNC) or lymphocyte numbers and response to ECP. The objective of the study was to analyse the relationship between the infused subpopulation cellularity and response.
Methods: 65 patients from 7 different centers with a total of 1008 ECP procedures were retrospectively analized. ECP procedures were performed from January-2011 to June-2017. All ECP procedures were performed with the off-line system. The response was defined as Responder (Complete and Partial Response) and Non-responder. Infused cell numbers for lymphocytes, monocytes and mononuclear cells (Lym+Mon, MNC) were calculated. For analytic purposes, the median number of cells infused per procedure until response (or until the median number of procedures until response for non-responding patients) and the cumulative number of cells infused until response (or until the median in non-responders) were calculated for all the subgroups. Same procedures were performed with the number cells infused until day 30 of ECP. Finally, the response and survival impact of infusing a number of cells above or below the median and in different tertiles was assessed until the median number of procedures needed to achieve a response.
[ [P060 Image] 1 . Table 1: Patient and ECP characteristics]
Results: The median number of procedures until response was 3. We observed a trend towards a higher median number of monocytes per procedure and cumulative infused monocytes in responding patients (median number infused 19.0 vs 13.5 x106/kg p=0.071, cumulative infused median number 71.5 vs 41 x106/kg p=0.067) that was lost in the day 30 of treatment. There was also a trend toward higher median infused MNC until response for responders (54 vs 37 x106/kg p=0.087). We observed no differences in the number of lymphocytes infused, but patients who received a number of lymphocytes per procedure over the first tertile (31 x106/kg) presented higher response rates (75% vs 45%, p=0.0317). None of the other analysed parameters showed a significant impact in overall survival.
Conclusions: Patients with acute GvHD who responded to ECP received higher numbers of monocytes and MNC in the early phase of the treatment (a median of the first 3 processes). Also the patients who received higher numbers of lymphocytes in the first procedures achieved a higher response rate. These findings suggest the possibility that higher number of treated and infused cells could influence the response to ECP, but specifically designed prospective studies are need to asses this possibility.
Disclosure: Nothing to declare
P061 Donor-specific immunomodulation via induction of regulatory B cells by clinical MIC cells infusion
Christian Morath1, Anita Schmitt1, Christian Kleist1, Volker Daniel1, Gerhard Opelz1, Caner Süsal1, Florian Kälble1, Claudia Sommerer1, Lei Wang1, Ming Ni1, Peter Dreger1, Angela Hückelhoven-Krauss1, Arianeb Mehrabi1, Uta Merle1, Pego Da Silva Luiza1, Carsten Müller-Tidow1, Martin Zeier1, Matthias Schaier1, Michael Schmitt1, Peter Terness1
1 University Hospital Heidelberg, Heidelberg, Germany
Background: The field of kidney transplantation has made enormous progress over the last decades towards being a standard treatment for patients with end‐stage renal disease. However, administration of immunosuppressive drugs is still one of the major limitations of long-term allograft survival. Therefore, strategies for induction of donor-specific tolerance are highly desirable. To this aim, a clinical phase I study with donor-derived modulated immune cells (MICs) was conducted.
Methods: Donor-derived MICs were manufactured under GMP conditions. Potency of MICs was tested by different in vitro bio-assays. MICs were administered to patients with an escalation from 1.5 x 106 MICs/kg on day -2 (N=3, group A), to 1.5 x 108 MICs/kg on day -2 (N=3, group B) or on day -7 (N=4, group C) before kidney transplantation accompanied by standard immunosuppressive medication post-transplantation. Frequency of adverse events (AE) was assessed from day 30 until day 360 post-transplant. Dynamic changes of various lymphocyte subsets in patients after MIC therapy were detected by multicolor flow cytometry. Donor-specific immunosuppression was assessed by measuring anti-donor antibodies and mixed lymphocyte reaction (MLR) against donor and third-party cells.
Results: In all kidney transplant recipients, we observed a median serum creatinine of 1.4 mg/dL at day 30 which remained stable until day 360 (median creatinine of 1.4 mg/dL) without significant proteinuria. None of patients experienced rejection episode. 69 AEs were observed while three AEs being severe. Most importantly, none of them was associated with MICs transfusion. Besides two infectious complications, no post-transplant positive cross match results against the donor or titers of de novo donor-specific antibodies were recorded. Notably, immunosuppressive therapy could be reduced without signs of rejection in group C.
After infusion, we observed a dramatic increase of CD19+ B cells up to a median of 300 cells/µL until day 30, followed by a reduction to 35 cells/µL on day 180 in group C. Notably, regulatory B cells significantly increased from a median of 2% on day 30 to 20% on day 180. In parallel, the plasma IL-10/TNF-α ratio increased from a median of 0.05 before cell therapy to 0.11 on day 180. After MIC cell therapy recipient lymphocytes showed no or only minimal reactivity against irradiated donor PBMCs in vitro, while reactivity against 3rd-party-donor PBMCs was not impaired.
Moreover, in vitro MICs product demonstrated their immunomodulatory potency by inducing tolerogenic dendritic cells (tDCs) characterized by low expression of co-stimulatory (CD80, CD86) and maturation (CD83) as well as high expression of inhibitory marker CD103. Functionally, tDCs could inhibit not only the release of IFN-γ but also the proliferation of CMV specific CD8+ T cells. Moreover, MIC-induced tDCs showed the capacity to inhibit donor-specific allo-reactive CD4+ and CD8+ T cell proliferation.
Conclusions: MIC cell therapy modulates the immune system of kidney transplant recipients by increasing the ratio of regulatory B cells and facilitates the reduction of conventional immunosuppressive therapy without allograft injury or rejection episodes. Therefore, MIC cell therapy represents a promising strategy in transplantation medicine. We currently prepare a phase II trial with MIC cell therapy.
Disclosure: Nothing to declare
P062 genome editing of graft-derived T cells for post-transplant immunotherapy in combination with TCRαβ+/CD19+-depleted haploidentical HSCT
Volker Wiebking1, Ciaran M. Lee2, Nathalie Mostrel1, Rasmus O. Bak3,4, Gang Bao2, Alice Bertaina1, Matthew H. Porteus1
1 Stanford University, Palo Alto, CA, United States, 2 Rice University, Houston, TX, United States, 3 Aarhus University, Aarhus C., Denmark, 4 Aarhus University, Aarhus Institute of Advanced Studies (AIAS), Aarhus C., Denmark
Background: Treatment with αβ+ T-cell/CD19+ B-cell depleted haploidentical HSCT (αβhaplo-HSCT) is now a valid option for children with high-risk leukemia lacking a fully matched related donor. The low risk of transplant-related mortality and acute or chronic graft-versus-host disease (GvHD) render this approach more and more appealing. However, additional treatments need to be developed to further reduce the frequency of relapse.
Methods: At Lucile Packard Children's Hospital, Stanford, we prospectively collected TCRαβ+ T-cells left-over (non-target fraction) during the αβ+ T-cell/CD19+ B-cell depletion process from 6 haploidentical donors. We used genome editing with Cas9 ribonucleoprotein(RNP)/recombinant adeno-associated virus type 6 (rAAV6) to disrupt the T-cell receptor (TCR) and integrate a CD19-specific CAR in-frame into the TRAC locus. We evaluated the functionality of the genome edited CAR T cells in in-vitro and in-vivo assays with CD19+ target cells. We use bioinformatics and targeted deep sequencing to evaluate the specificity of the genome editing process.
Results: Our data show that after αβhaplo-HSCT, the non-target fraction consists of >90% αβ+ T-cells which can be expanded and genome editing performed achieving high editing frequencies (>90% knockout of the TCR and >70% of transgene expression). In addition, the residual TCRαβ+ cells can be efficiently depleted by more than 2-log folds with clinically-scalable reagents. After editing, the cells continue to rapidly expand and show antileukemic activity and cytokine production when co-cultured with the CD19+ Nalm6 cell line. Moreover, they are able to eradicate leukemia xenografts in an NSG mouse model, without signs of GvHD.
Conclusions: αβhaplo-HSCT represents an attractive platform for post-transplant immunotherapy. Our preclinical data demonstrate that the non-target fraction can be efficiently engineered by genome editing to manufacture a new cell product characterized by high antileukemic activity and without the risk for GvHD.
Disclosure: Nothing to declare.
Abstract already published.
P064 Automated manufacturing of clinical grade NKG2D-CAR memory T cells using clinimacs prodigy
Adrián Fernández1, Lucía Fernández1, Isabel Mirones2, Adela Escudero3, Leila Cardoso3, Alejandra Leivas1,4, Joaquín Martínez-López1,4, Ana Belén Romero5, Antonio Marcos5, Diego Lanzarot6, Raquel De Paz5, Antonio Pérez-Martínez5
1 CNIO, Madrid, Spain, 2 IdiPAZ, Madrid, Spain, 3 INGEMM, Madrid, Spain, 4 Hospital 12 de Octubre, Madrid, Spain, 5 Hospital La Paz, Madrid, Spain, 6 Miltenyi Biotec GmbH, Madrid, Spain
Background: Immunotherapy using CAR T cells has shown promising results to fight cancer. However, CAR-T cell production requires specialized infrastructure and operators, which implies high cost and centralized production. Automated production of CAR-T cells in CliniMACS Prodigy device allows clinical-grade manufacturing of CAR T cells.
Methods: 100 million CD45RA- memory T cells from healthy donors were cultured in TexMACS supplemented with 100 IU/ml IL-2. At day 0 cells were activated with T Cell TransAct for 24h. At day one, activated CD45RA- memory T cells were transduced with NKG2D-CD8TM-41BB-CD3z lentiviral vector at MOI = 2. Then, NKG2D-CAR T cells were expanded for 10-13 days. NKG2D-CAR T cell products were next harvested, counted and analyzed for viability, NKG2D-CAR expression and anti-tumor cytotoxicity. Different quality tests including sterility, vector copy number, genetic stability, quantification of viral particles in the supernatant, myc/tert expression and endotoxin detection were performed. Spare cells were cryopreserved either in autologous plasma and 10% DMSO, M199 35% Albumin and 9%DMSO or Hypothermosol. After 12 months, cryopreserved NKG2D-CAR T cell products were analyzed for viability, NKG2D-CAR expression and cytotoxicity.
Results: NKG2D-CAR memory T cells expanded up to 2076 ± 697 million with 77,8 ± 20% NKG2D-CAR expression and 76 ± 10% viability. Harvested CAR T cells showed 90 ± 14% of specific lysis against Jurkat cells and 31 ± 16% against 531MII osteosarcoma cell line. No microbiological contamination was observed in final CAR T cells products. Vector copy number was ≤5 in all validations except for one. CGH and karyotype showed no genetic alterations. Free viral particles were undetectable in the supernatants. No overexpression of myc/tert was found except for one validation. Endotoxins were ≤0.25EU/ml. All cryopreserved NKG2D-CAR T cell products kept NKG2D-CAR expression one year after freezing. However, viability and cytotoxicity was best preserved using autologous plasma 10%DMSO.
Conclusions: Automated production of large-scale clinical-grade NKG2D-CAR T cells using CliniMACS Prodigy is feasible and reproducible, allowing a decentralized protocol to generate CAR T cells for clinical use.table.
Disclosure: Nothing to declare
P065 Safety and outcome of high-dose donor CD45RO+ memory T-cells infusion after allogeneic transplantation
Mercedes Gasior Kabat1, David Bueno1, Raquel De Paz1, Yasmina Mozo1, Blanca Rosich1, Luisa Sisinni1, Antonio Marcos1, Ana Belen Romero1, Aida Constanzo1, Victor Jimenez Yuste1, Antonio Perez Martinez1
1 Hospital Universitario La Paz, Madrid, Spain
Background: Immune Reconstitution (IR) is essential to control severe infections after Hematopoietic Stem Cell Transplantation (HSCT). Reconstitution of adaptive immunity may take up to 2 years to recover T-Lymphocytes (LT). Delay in early LT recovery increases the risk of relapse, viral infections and transplant related mortality. Adoptive transfer of selected T cell subset with low alloreactivity potential is emerging as a strategy to improve IR.
Methods: Depletion of CD45RA+ naive T cells, preserving CD45RO+ memory T cells could provide functional lymphocytes to protect against infection and leukemia relapse with low risk of graft versus host disease (GvHD). We present our experience with high-dose donor CD45RO+ memory T cell as donor lymphocyte Infusions (DLI) to assess safety and outcome.
A total of 58 DLI of CD45RO+ after HSCT was performed in cases of CMV/EBV reactivation (50%), mixed chimerism (26%), persistent lymphopenia (8,5%), graft rejection (3,5%), relapse (3%) or to boost IR (7%). DLI product was obtained performing a CD45RA depletion on donor leukapheresis product using the CliniMACS® device.
Results: Twenty-two pediatric patients, median age 11 years (range 3-18), with malignant (n=15) and non-malignant diseases (7), received CD45RA+ (n=14), TCR alpha/beta (n=2) depleted grafts from haploidentical and CD45RA+ depleted grafts from match unrelated (n=6) and match related (n=2) donors. At a median of 97 days (range 15-462) after transplantation, patients received a total of 58 DLI of CD45RO+ cells, median 2 (range 1-6), containing a median of 2.87x107/Kg (range 4.8x104-2x108/Kg), CD3+CD45RO+ 1.05x107/Kg (range 4.8x104-1.09x108/Kg) and CD45RA+ cells 5 x102/Kg (range 0-9.8x104/Kg). All infusions were well-tolerated and did not develop or worsen GvHD. A total of 11/29 episodes of CMV/EBV viral reactivations decreased viral load, 4/29 cleared viral load and 5/29 showed a clinical improvement. A total of 4/5 patients with persistent lymphopenia there was a slightly increase in total lymphocyte count, but not to normal levels. Prophylactic DLI of CD45RO+ to boost IR increased lymphocyte count in 2 of 3 cases. None of the DLI administered in cases of mixed chimerism, graft failure or relapse were effective in reverting those situations.
Conclusions: Our preliminary data suggest that infusions of high dose CD45RO+ memory T cells are a safe adoptive immunotherapy strategy. Efficacy has been observed in patients with lymphopenia and CMV/EBV reactivation, with no positive results in patients with mixed chimerism, graft failure and relapse. However, to determine the real efficacy of this strategy, prospective studies are required.
Disclosure: Nothing to declare.
Abstract already published.
P067 Successful treatment of two relapsed/refractory T(8;21) acute myeloid leukemia patients by CD19-directed chimeric antigen receptor T cells
Changju Qu1, Zheng Li1, Liqing Kang2, Ying Wang3, Haiping Dai1, Jia Yin1, Guanghua Chen1, Mingqing Zhu1, Li Yao1, Ting Xu1, Xiaopeng Tian1, Yang Xu1, Jia Chen1, Xiaming Zhu1, Lei Yu1, Depei Wu1, Xiaowen Tang1
1 First Affiliated Hospital of Soochow University, Suzhou, China, 2 East China Normal University, Shanghai Unicar-Therapy Bio-medicine Technology Co., Ltd., Shanghai, China, 3 First People's Hospital of Lianyungang, Lianyungang, China
Background: Increasing clinical trials have confirmed that chimeric antigen receptor T cells (CAR-T) targeting CD19 antigen (CAR-T-19) is a promising effective approach for the treatment of relapsed/refractory(R/R) B-cell lineage malignancies. Considering CD19 is frequently expressed in large part of t(8;21) acute myeloid leukemia (AML) cells, we suppose that CAR-T-19 may be used as an approach to rescuing R/R t(8;21) AML patients.
Methods: Both patients received lymphodepletion chemotherapy with Decitabine 20mg/m2×5d, Fludarabine 30mg/m2×3d and Cyclophosphamide 300mg/m2×3d (DAC+FC). Two days after chemotherapy, autologous/allogeneic CART-19 cells provided by the unicar-therapy bio-medicine technology co.(Shanghai, China) at a total dose of 5-10×106 cells per kilogram(kg) were infused dose escalation within 2 to 3 days. The research protocol was approved by the institutional review boards of the first affiliated hospital of Soochow University and both patients gave written informed consent.
Results: Both cases responded well with transient and reversible toxicities. Case 1 presented with grade 1 cytokine release syndrome (CRS), manifested by intermittent fever and chill from day 4 after CAR-T-19 infusion for half months associated with neutropenia. CAR-T cells expansion were observed in blood without obvious increase of cytokines. After infusion, Case 1 achieved and maintained molecular complete remission (CR) for more than 10 months.
Case 2 presented with grade 3 CRS manifested by continuous high fever, hypotension and grade 1 liver disfunction from day 1 after CAR-T-19 cell infusion for 1 week. Obvious cytokines releasing (peak IL-6 serum concentration 1774.5 pg/ml, peak CRP serum concentration 367pg/ml) were detected which were associated with CAR-T-19 cell expansion in blood and no severe off-tumor effect was observed. After infusion, case 2 achieved hematological CR and cytogenetic CR and got 3 months disease free survival.
Conclusions: Our report implicates that CAR-T-19 is a safe and promising approach to managing R/R t(8;21)AML with CD19 expression, and may provide a salvage treatment approach for all AML patients with CD19 expression and benefit a certain population with AML besides B-linage malignancies.
Clinical Trial Registry: NA
Disclosure: Nothing to declare.
This work was supported by research grants from the National Key R&D Program of China (2016YFC0902800), National natural science Foundation of China (81873443,81270645,81400155,81500146), Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), Frontier Clinical Technical Project of the Science and Technology Department of Jiangsu Province (BE2017655), Jiangsu Provincial Medical Talent (ZDRCA2016045),Jiangsu Natural Science Foundation of China (BK20140374) and top-notch young health talents, 5th Suzhou Health professionals program(2018 to CQ)
P068 Challenge of cryopreservation for gmp grade CD19 CAR-T cells
Wenjie Gong1, Lei Wang1, Sanmei Wang1, Brigitte Neuber1, Leopold Sellner1,2, Maria-Luisa Schubert1, Angela Hückelhoven-Krauss1, Alexander Kunz1, Ulrike Gern1, Birgit Michels1, Mandy Hinkelbein1, Stefanie Mechler1, Petra Richter1, Carsten Müller-Tidow1,2, Peter Dreger1,2, Michael Schmitt1,2, Anita Schmitt1
1 Heidelberg University Hospital, Heidelberg, Germany, 2 German Cancer Consortium (DKTK), National Center for Tumor Diseases (NCT), Heidelberg, Germany
Background: Chimeric antigen receptor engineered T (CAR-T) cells have emerged as a powerful cellular therapy to treat malignant disease, which is currently revolutionizing field of cancer immunotherapy. A cryopreservation step post-manufacture is not only a logistical necessity for large scale cell manufacturing processes but also a mandatory request by regulatory authorities. In case relapse after 1st CAR-T cell transplantation, a second application, maybe at a higher dose constitutes a therapeutical option. However, data concerning clinical grade CAR-T cell stability and functionality after months of cryopreservation have not been released by companies so far. To investigate the effect of cryopreservation on CAR-T cells, we performed this study.
Methods: Different batches of CD19 CAR-T cells were manufactured according to GMP requirements at our institution. Final CAR-T products were frozen at concentrations of 1 x 107 cells/ml (high batch) and 2 x 106 cells/ml (low batch) by a controlled freezing process with the Biofreeze BV40 device and stored in liquid nitrogen tanks below -150°C until release. Quality control tests for sterility, endotoxin and mycoplasma were performed for each batch according to European Pharmacopoeia and United States Pharmacopoeia guidelines. Stability of CD19 CAR-T cells in terms of viability, recovery, transduction efficiency and functional capacity were determined by microscopy, multi-parametric flow cytometry as well as chromium-51 release tests following our SOPs.
Results: All the results of quality controls fully met the requirements of the regulatory authorities. Stability results were highly robust and reproducible over time for all our GMP CAR-T batches. Duration of cryopreservation (up to 90 days) had no negative influence on cell viability, recovery of viable CD19 CAR-T cells and transduction efficiency. However, the cell concentration for cryopreservation has a significant impact on the post-thawing viability (low batches vs. high batches: 96.33 ± 2.17 vs. 74.87 ± 8.68, p < 0.05) and recovery (low batches vs. high batches: 89.67 ± 6.76 vs. 74.90 ± 9.19, p < 0.05) of cryopreserved CD19 CAR-T cells, but not the transduction efficiency. Moreover, we observed four transient side-effects of cryopreservation on the amount of cytokines released by CAR-T cells, the cytokine release on a per-cell basis, the multifunctionality of CAR-T cells and the killing capacity. Of note, functional capacity of cryopreserved CAR-T cells after overnight resting was comparable or even enhanced for INF-γ and TNF-α release by CD4+ and CD8+CD19 CAR-T cells when compared to fresh CAR-T cells. The multi-functionality of CAR-T cells could be preserved. Furthermore, the killing capacity of cryopreserved CD19 CAR-T cells after overnight resting could reach the level of non-cryopreserved/fresh CAR-T cells.
Conclusions: Cryopreservation up to 90 days has no harmful effect on transduction efficiency and functionalities of CAR-T cells. However, the cell number per milliliter freezing medium matters. Dose over 1 x 107 cells/ml should be avoided. For the conduction of in vitro bio-assays to determine the function of CAR-T cells, an overnight resting process could mimic the situation after clinical application and eliminate the transient side-effects of cryopreservation to fully regain the functional potency of CAR-T cells.
Disclosure: Nothing to declare
P069 AML-blast conversion to leukemia-derived dendritic cells (DCLEU) in 'DC-culture-media' shifts the (SERUM) chemokine-release to a more 'inflammatory' (in culture) going along with improved antileukemic T-cell-reactivity
Marion Merle1, Dorothea Fischbacher1, Anja Liepert1, Christine Grabrucker1, Tanja Kroell1, Andreas Kremser1, Julia Dreyssig1, Markus Freudenreich1, F. Schuster2, A. Borkhardt2, D. Kraemer3, C.-H. Koehne2, H.J. Kolb4, C. Schmid5, Helga Maria Schmetzer4
1 University Hospital Munich, Munich, Germany, 2 University Hospital Düsseldorf, Düsseldorf, Germany, 3 Municipal Hospital Oldenburg, Oldenburg, Germany, 4 University Hospital Munich-Großhadern, Munich, Germany, 5 Municipal Hospital Augsburg, Augsburg, Germany
Background: DC and specific T-cells are important mediators of CTL-responses. We could already show that allogeneic donor- or autologous T-cells obtained from AML-patients can be stimulated by DCleu, resulting in a very efficient lysis of naive blasts.
Methods: Chemokine-release (CXCL8, -9, -10, CCL2, -5, and IL-12) was analysed by cytometric bead array in serum of AML/MDS-pts as well as in supernatants from 5 different DC-generating-methods and correlated with pts' clinical course, DC- and T-cell-interactions as well as specific T-cell-reactions. The lytic activity of DCleu/blast -stimulated T-cells in MLC against naive blasts was quantified in a cytotoxicity assay.
Results:Minimal differences in median chemokine-levels in pts' serum subdivided in subtypes were seen, but higher release of CXCL8, -9, -10 and lower release of CCL2 and -5 tendentially correlated with more favourable subtypes (< 50 years of age, < 80% blasts in PB). In persisting disease, a higher serum-release of CCL5 and at relapse a significantly higher CCL2-release were found compared to first diagnosis - pointing to a change of 'disease activity' on a chemokine level. Whereas chemokine-levels in DC-culture supernatants compared to serum were variable, clear correlations with lateron (after stimulating T-cells with DCleu in MLC) improved antileukemic T-cell activity were seen: higher values of all chemokines in DC-culture supernatants always correlated with improved T-cells' antileukemic activity (compared to stimulation with blast-containing MNC as control) - whereas with respect to the corresponding serum values higher release of CXCL8, -9, and -10 but lower values of CCL5 and -2 correlated with higher probabilities to improve antileukemic activity of DCleu-stimulated (vs. blast-stimulated) T-cells. Predictive significant cut-off-values could be evaluated separating the groups compared. Moreover, correlations with lateron achieved response to immunotherapy and occurrence of GVHD were seen: Higher serum values of CXCL8, -9, -10 and CCL2 and lower values of CCL5 correlated with achieved response to immunotherapy. Predictive cut-off-values could be evaluated separating the groups compared in 'responders' and 'non-responders'. Higher levels of CCL2 and -5 but lower levels of CXCL8, -9, -10 correlated with occurrence of GVHD.
Conclusions: We conclude, that in AML-pts' serum higher values of CXCL8, -9, -10 and lower values of CCL5 and in part of CCL2 correlate with more favorable subtypes and improved antitumor'-reactive function. Since in DC-culture supernatants higher values of all chemokines correlated with improved antileukemic T-cell reactivity we conclude a change of functionality of CCL5 and -2 from an 'inflammatory' or 'tumor-promoting' to an 'antitumor'-reactive function. This knowledge can contribute to develop immune-modifying strategies that promote antileukemic adaptive immune-responses.
Disclosure: Nothing to declare
P070 Leukemia control after allogeneic hematopoietic cell transplantation through ex vivo expanded invariant natural killer T cells from donor lymphocyte infusions (DLI-INKTS)
Simona Jahnke1, Hannes Schmid1, Kathy-Ann Secker1, Silke Duerr-Stoerzer1, Hildegard Keppeler1, Rebecca Baur2, Michael Schumm3, Rupert Handgretinger3, Wolfgang Bethge1, Lothar Kanz1, Corina Schneidawind1, Dominik Schneidawind1
1 University Hospital Tuebingen, Tuebingen, Germany, 2 University of Erlangen-Nuremberg, Erlangen, Germany, 3 Children's University Hospital, Tuebingen, Germany
Background: Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for patients suffering from hematologic malignancies. Infusion of donor lymphocytes (DLIs) can induce sustained remission in case of minimal residual disease or relapse through potent graft-versus-leukemia (GVL) effects, although graft-versus-host disease (GVHD) represents a common dose-limiting toxicity. As invariant natural killer T (iNKT) cells are known to prevent GVHD while promoting beneficial anti-tumor effects, we investigated the role of iNKT cells for successful DLIs.
Methods: We analyzed DLI samples by flow cytometry. iNKT cells were identified by staining with PBS57-loaded CD1d tetramers. Culture-expanded and purified DLI-iNKTs were then tested against tumor cell lines and primary leukemia cells in an ex vivo tumor control model. Tumor cell viability after coincubation with DLI-iNKTs was measured by flow cytometry using 7-AAD.
Results:iNKT cells represent 0.05% (range 0.001-0.55%) of donor lymphocytes and can be expanded 300-fold following a two-week protocol with a preferential expansion of CD4+ iNKT cells. Tumor cell lines such as Jurkat were efficiently lysed after coincubation with DLI-iNKTs. CD107a as a marker of degranulation was significantly upregulated on DLI-iNKTs after stimulation by Jurkat. In addition, increased concentrations of TNF-α, IFN-γ, sFasL and Perforin were measured after coincubation of DLI-iNKTs with Jurkat. We observed that tumor cell lysis correlated with the expression of the MHC-I-like molecule CD1d. Consequently, adding a CD1d antibody to the coculture abrogated the DLI-iNKT-mediated kill of tumor cells. DLI-iNKTs also efficiently lysed primary leukemia cells such as AML blasts: expression of CD1d on these AML blasts significantly correlated with DLI-iNKT-mediated tumor cell lysis (r2=0.7, p=0.03).
Conclusions: Ex vivo expansion of DLI-iNKTs and subsequent DLI enrichment is an immunotherapeutic approach that could improve leukemia control and thus, prevent relapse after allo-HCT without exacerbating GVHD.
Disclosure: Nothing to declare.
P071 Generation of antigen-specific cytotoxic T lymphocytes targeting WT1 using activated B cells
Sun Ok Yun1, Kyung Won Baek1, Hee Young Shin1, Hyoung Jin Kang1
1Seoul National University, Seoul, Korea, Republic of
Background: The Wilms tumor antigen 1 (WT1) is highly expressed in many malignancies including leukemia and targeting WT1 as a Tumor Associated Antigen (TAA) in cancer immunotherapy is attractive. In this study, we generated WT1-specific cytotoxic T lymphocytes to confirm if activated B cells can act as a cancer antigen presenting cell and induce CTLs.
Methods: For the induction of CTLs against WT1, activated B cells were used as an antigen presenting cells. B cells were isolated from PBMCs of normal healthy donors and activated with α-galactosylceramide (α-GalCer) and nucleofected with WT1-coding plasmid DNA. Activated B cells were the cultured with PBMCs for 17days in vitro and harvested for assay.
Results: Cells expanded about 3 times after 17 days of culture. We examined characteristic of WT1-specific CTLs by their surface markers. WT1-specific CTLs had more than 90% CD3+ marker, and ratio of CD8 to CD4 was 1.7-5.8. We also examined NKT cell markers to see if NKT cells were activated by IL-15, a cytokine used in the induction of CTLs, and the portion of NKT cells was about 2%. The CTLs showed a decrease in naïve cell (CD62L+CD45RA+) and an increase in effector memory (CD62L+CD45RA-) and central memory (CD62L-CD45RA-) compared with non-stimulated PBMCs. Subsequently, the IFN-γ ELISPOT (Enzyme-linked immunospot) assay was performed to confirm the response of the induced WT1-specific CTLs to the WT1 antigen. When WT1-specific CTLs encounters a target that does not have a WT1 antigen, it did not produce IFN-γ, but when it encounters a target cells loaded WT1 antigen, it responded to secrete IFN-γ. Killing assays were also performed to determine the immunogenicity of induced CTLs. The induced WT1 CTLs was found to be killing more than 90% when the E:T ratio was 10:1 when the autologous PBMC met the target with WT1 pepmix. In addition, we found that WT1 CTLs has killing activity when it encounters leukemia cell lines that express WT1 and matched HLA-A*0201.
Conclusions: In this study, we can induce antigen-specific CTLs that specifically react to WT1 using activated B cells as antigen-presenting cells. These observations confirmed that B cells activated by α-GalCer can act as a TAA presenting cell to induce TAA specific CTLs as viral antigen, such as pp65 and IE1, and consequently WT1-specific CTLs could be induced. Moreover, CTLs induced activated B cells had ability to recognize and kill the target cells expressing WT1 correctly. Our results demonstrate that these in vitro expanded WT1-specific CTLs using activated B cells can be a promising candidate for adoptive immunotherapy against cancer.
Disclosure: Nothing to declare
P072 Validation of the clinimacs prodigy T cell transduction process to generate CD19-chimeric antigen receptor T cells for the use in clinical trials
Judith Böhringer1, Michael Schumm1, Christiane Braun1, Marina Schmidt1, Patrick Schlegel1, Christian Seitz1, Murat Aktas2, Georg Rauser2, Sandra Karitzky2, Peter Lang1, Rupert Handgretinger1
1 University Children's Hospital Tübingen, Tübingen, Germany, 2Miltenyi Biotec GmbH, Bergisch Gladbach, Germany
Background: T cells with chimeric antigen receptors (CARs) on their surface facilitate to target specific surface expressed antigens. Research and clinical trials with CD19-CAR T cells show impressive remission induction rates and increased survival in heavily pretreated patients. Therefore, CAR T cells are introduced as new potent cellular therapeutics in the clinical routine. In order to establish the manufacture of CD19-CAR T cells, validation runs with the fully automated CliniMACS Prodigy T cell transduction process have been performed using the Miltenyi anti-CD19-CAR lentiviral vector.
Methods: Unmobilized leukaphereses from 3 donors (2 x healthy, 1 x ALL) were used for the CliniMACS Prodigy T cell transduction process. Leukocytes undergo a CD4+ / CD8+ T cell enrichment via magnetic beads, followed by stimulation with MACS ® GMP T cell TransAct™, transduction with an anti-CD19-CAR lentiviral vector, expansion with IL7 and IL15, and final formulation to the cellular product. During and after the manufacture, FACS analyses were performed as well as cytotoxicity assays after CD19-CAR T cell production.
Results: Total volumes of leukaphereses were between 60 and 280 ml with 2.6 - 4.0 x 109 total mononuclear cells. After enrichment 100x106 CD4+ / CD8+ T cells were transduced with anti- CD19-CAR lentiviral vector and were further expanded. Cells were harvested on day 12. The final cell counts of the cellular products were 6.1, 7.2 and 5.0 x 109 mononuclear cells from two healthy volunteers and the ALL-patient, respectively. The transduction efficiency of the CD19-CAR T cells was 48.6%, 43.4% and 32.0% among viable CD3+ cells. The final count of CAR T cells was therefore 2.9, 3.0 and 1.5 x 109 cells. The final products exerted excellent cytolytic activity against CD19+ BCP-ALL cell line NALM-6. Importantly, CD19-CAR T cells generated from the ALL patient demonstrated complete eradication of autologous blasts at 0.3 to 1 E:T ratio after 24 hours incubation.
Conclusions: The CliniMACS Prodigy T cell transduction process has been shown to run a fully-automated manufacturing process over 12 days without any deviations in a clean room environment on a single device. The user interaction was reduced to activities at only 3 days to set up the system and provide fresh medium and reagents. The transduction process yielded a high number of T cells with a high frequency of CD19-CAR T transduced cells. The results were comparable for both unmobilized leukaphereses from healthy donors and showed expected slightly lower results in the patient. Finally, these results demonstrate that the CliniMACS Prodigy T cell transduction process is well suited to provide the clinical MB-CART19.1 r/r CD19+ BCM study with appropriate investigational medical products.
Disclosure: Murat Aktas: Employment Miltenyi Biotec GmbH
Georg Rauser: Employment Miltenyi Biotec GmbH
Sandra Karitzky: Employment Miltenyi Biotec GmbH
P073 Donor-lymphocyte infusion (DLI) after hematopoietic stem cell transplantation with post-transplant cyclophosphamide (PTCY) as GVHD prevention treatment
Susanna Gallo1, Daniela Caravelli1, Paolo Becco1, Alessandra Polo2, Milena Salierno2, Karol Giancaspero2, Delia Rota Scalabrini1, Dario Sangiolo3, Elena Vassallo4, Pio Manlio Mirko Frascione1, Stefano Poletto1, Luca Paruzzo1, Luca Crotto5, Massimo Aglietta1, Franca Fagioli4, Fabrizio Carnevale Schianca1
1 Medical Oncology, Turin Metropolitan Transplant Center, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy, 2 Collection and Processing Laboratory, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy, 3 Medical Oncology, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy, 4 Pediatric Onco-Hematology, Turin Metropolitan Transplant Center, A.O.U. Citta' della Salute e della Scienza di Torino, Ospedale Infantile Regina Margherita, Torino, Italy, 5 Clinical Research Office, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy
Background: Allogeneic hematopoietic stem cell transplantation (alloHCT) is an effective strategy in the long term control of several hematologic diseases, however, patients could experience complications, as graft versus host disease (GVHD) and disease relapse. Recently, the introduction of post-transplant Cyclophosphamide (ptCy) allowed to significantly reduce GVHD, but disease relapse remains an important issue. Donor-lymphocyte infusion (DLI) is an established adoptive cell therapy for disease relapse after alloHSCT, but, in order to be efficient and safe, patients have to be off immunosuppression treatments and GVDH-free. Here we report our data about efficacy and safety of DLI infusion as treatment for disease relapse in patients who received peripheral blood stem cell transplantation (alloPBSCT) from HLA-matched unrelated/related plus ptCy as GVDH prophylaxis in our clinical trial (NCT 02300571).
Methods: We collected data from 13 patients, treated with ptCy (50 mg/kg/die, days +3+4), mofetil mycophenolate (MMF) and tacrolimus (T) as GVHD prophylaxis after allo-PBSCT, who received DLI infusions. They were treated between January 2013 and October 2018. We report data about overall response rate (ORR), disease control rate (DCR), and DLI-related mortality and morbidity. Diagnosis were as follow: 5 had multiple myeloma, 3 had acute myeloid leukemia, 3 had acute lymphoblastic leukemia and 2 had lymphomas. All patients but one, who had chimerism loss, received DLI because of disease relapse.
Results: Median time between transplant and DLI was 9 (range 3-87) months. Median number of DLI infusions was 2 (range 1-13). 10 patients (77%) received Cyclophosphamide 300 mg/m2 preparative regimen the day before the cryopreserved DLI infusions, while in the other 3 cases DLI were associated with Lenalidomide, Ponatinib and 5-Azacitidine.
The overall response rate (ORR) was 50%, while disease control rate (DCR) was achieved in 75%. The patient who received DLI because of loss of chimerism converted it in full donor after 2 infusions. After DLI treatment the incidence of acute GVHD grade I-III was 54%, while was 46% for grade II-III and patients were started on short course of systemic immunosuppression treatments . None of these patients died because of DLI adverse events. Estimated 1-year overall survival was 77% with a limited follow-up length (6 months).
Conclusions: The infusion of non-manipulated lymphocytes from allogeneic donors is a valuable and safe strategy of treatment for patients relapsing after alloPBSCT with ptCy. ptCy showed high efficacy in GVHD prevention, allowing early discontinuation of immunosuppression drugs. Because of this, we can reach the goal to transform transplant in a platform where we could add early DLI infusions as a new strategy for disease control.
Clinical Trial Registry: NCT 02300571
Disclosure: Nothing to declare
P074 Extracorporeal photopheresis in the treatment of refractory chronic GVHD: Analysis of mononuclear cell infusion
Gillen Oarbeascoa1, Maria Luisa Lozano2,3,4, Luisa Maria Guerra5, Cristina Amunarriz6, Nuria Revilla2,3,4, Pastora Iniesta2,3,4, Cynthia Acosta Fleitas5, Jose Luis Arroyo6, Eva Martinez Revuelta7, Andrea Galego8, Dolores Hernandez-Maraver9, Mi Kwon1,10, Aurora Viejo9, Jose Maria Garcia Gala7, Concepcion Andon Saavedra8, Jose Luis Diez-Martin1,10,11, Cristina Pascual1,10, GEA Grupo Español de Aferesis (GEA)12
1 Hospital General Universitario Gregorio Marañon, Hematology, Madrid, Spain, 2 Hospital Universitario Morales Meseguer, Murcia, Spain, 3 Centro Regional de Hemodonacion, Murcia, Spain, 4 IMIB-Arrixaca, Murcia, Spain, 5 Hospital Universitario de Gran Canaria Dr Negrin, Las Palmas de Gran Canaria, Spain, 6 Banco de Sangre y Tejidos de Cantabria – Hospital Universitario Marqués de Valdecilla, Santander, Spain, 7 Hospital Universitario Central de Asturias, Hematology and Hemotherapy Service, Oviedo, Spain, 8 Complexo Hospitalario Universitario A Coruña, A Coruña, Spain, 9 Hospital Universitario La Paz, Madrid, Spain, 10 Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain, 11 Universidad Complutense de Madrid, Madrid, Spain, 12 Grupo Español de Aferesis, Madrid, Spain
Background: Extracorporeal photopheresis (ECP) is an immunomodulatory treatment that has shown efficacy in steroid refractory chronic GvHD, but the mechanism of action is only partially understood. In some studies, a correlation has been suggested between treated Mononuclear cells (MNC) or lymphocytes and response to ECP. The objective of the study was to analyze the relationship between the infused cellularity and response in chronic GvHD.
Methods: 48 patients from 7 different centers with a total of 930 ECP procedures were retrospectively analyzed. ECP procedures were performed from January-2011 to June-2017. All ECP procedures were performed with the off-line system. The response was defined as Responder (Complete and Partial Response) and Non-responder. Infused cell numbers for lymphocytes, monocytes and mononuclear cells (Lym+Mon, MNC) were calculated. For analytic purposes, the median number of cells infused per procedure until response (or until the median number of procedures until response for non-responding patients) and the cumulative number of cells infused until response (or until the median in non-responders) were calculated for all the subgroups. Same procedures were performed with the number cells infused until day 30 of ECP. Finally, the response and survival impact of infusing a number of cells over or below the median and in different tertiles (T1, T2 and T3) was assessed until the median number of procedures needed to achieve a response.
Results: The median number of procedures until response was 3. We observed no differences in the median number of lymphocytes, monocytes or MNCs infused until response or until day 30 between responding and non-responding patients. There were no differences in response if patients received lymphocytes or monocytes above or below the median number. Nevertheless, patients that received a total absolute number of MNCs above the median (64x108 cells) showed a trend towards a higher response rate (75% vs 61%, p=0.09). The patients that received a cumulative number of lymphocytes in the 3 first ECP procedures above the median showed improved overall survival (OS) (2y OS 85% vs 55%, p=0.024). Patients that received a number of monocytes above the median showed a trend towards better survival (p=0.09), that was significant when the number of monocytes infused surpassed the first tertile (2y OS 38% for T1, 79% for T2, 92% for T3, p=0.003). Finally, the patients that received a cumulative number of MNCs above the first tertile also showed improved survival (2y OS 47% for T1, 74% for T2, 94% for T3, p=0.015).
Conclusions:There were no differences in the infused cellularity between responding and non-responding patients with chronic GvHD. At the same time, we found that except for a trend toward better response with higher MNCs infused, there was no relationship between lymphocytes and monocytes with the response rate as other previous studies have suggested. However, even if there is no relationship with the response rate, the patients receiving the highest numbers of lymphocytes, monocytes and MNCs in the cohort showed an improved survival, suggesting that larger quantities of cells could exhibit a protective effect. Nevertheless, prospective studies that address this relationship are needed.
Disclosure: Nothing to declare
P075 Comparative analysis of the cytotoxic potential of cytokine-induced killer and natural killer cells for neuroblastoma therapy
Annekathrin Heinze1, Beatrice Grebe1, Eva Mudry1, Jochen Früh1, Bushra Rais1, Claudia Cappel1, Sabine Hünecke1, Eva Rettinger1, Thomas Klingebiel1, Peter Bader1, Evelyn Ullrich1,2
1 University Hospital Frankfurt, Frankfurt, Germany, 2 German Cancer Consortium (DKTK) partner site:, Frankfurt, Germany
Background: Neuroblastoma (NB) is the most common solid extracranial tumor in childhood. Despite therapeutic progress, prognosis for high-risk NB is poor and innovative therapies are of medical need. Therefore, we investigated the cytotoxic potential of interleukin (IL)-activated natural killer (NK) cells compared to activated cytokine-induced killer (CIK) cells against different human NB cell lines in vitro.
Methods: NK cells were isolated from peripheral blood mononuclear cells (PBMCs) using CD56 enrichment or CD3/CD19 depletion kits. They were successfully expanded ex vivo with different cytokine combinations such as IL-2, IL-15, IL-18 and/or IL-21 under feeder-cell free conditions. In contrast, CIK cells were generated from PBMCs by ex vivo stimulation with interferon-γ, IL-2, OKT-3 and IL-15. A comparative analysis of expansion rate, purity, phenotype and cytotoxic activity against different NB cell lines following different culturing protocols was performed.
Results: CD56 enriched NK cells showed a median expansion rate of 4.3-fold after 10 to 12 days in culture with a final frequency up to 99.0% NK cells and a median frequency of 0.5% CD3+CD56- T cells. In contrast, the starting cell product after CD3/CD19 depletion consisted of a median frequency of 43.5% NK cells that expanded significantly faster with 7.5-fold and also reached up to 98.6% purity without any relevant T cell contamination. CIK cells expanded with a median rate of 30.8-fold and contained 3.3% NK, 84.2% T and 6.2% NK-like T cells. Interestingly, NK cells, particularly after CD3/CD19, showed a significantly higher median cytotoxic capacity against NB cells depletion (46.6% for CD56 enrichment, 53.7% for CD3/CD19 depletion) compared to CIK cells that induced 7.2% killing of NB cells with E:T ratio 5:1 in a 3 hours' co-incubation assay. Interestingly, prolonging the ex vivo stimulation after CD3/CD19 depletion to 15 days enhanced the median expansion rate to 12.3-fold with a slightly reduced cytotoxic potential (40.9% for 11 days' ex vivo expansion, 31.1% for 15 days' ex vivo expansion, comparison of the same donors). The addition of an IL21-boost prior harvesting increased the expansion rate to median 12.6-fold (compared to 11.7-fold for the same donors) with an improved cytotoxicity of 51.5% (compared to 45.8%). Fortunately, all NK cell products showed a high viability and no relevant T or B cell contamination (median < 0.2%). Interestingly, further optimization of the culturing procedure with use of another cell culture medium led to an improved median 24.4-fold (compared to 9.6-fold) NK cell expansion rate in 15 days, also resulting in comparable cytotoxicity of 52.5%.
Conclusions: NK and CIK cell products may offer an innovative immune therapeutic option for patients with high-risk NB after allogenic stem cell transplantation. Our study revealed that NK cells have a significantly higher cytotoxic potential to combat NB. Interestingly, the use of IL-15 expanded and IL-21 activated NK cells developed from a CD3/19 depleted apheresis product is highly promising as additional immunotherapy in combination with haploidentical stem cell transplantation of children with NB.
Disclosure: Nothing to declare.
P076 Quantitative determination of donor allo-reactive T-cells in haploidentical donor-recipient pairs by enzyme-linked immunospot (ELISPOT) and mixed lymphocyte culture (MLC) assays
Yana Bayzyanova1, Maria Efimenko1, Natalia Khripkova1, Sergei Kovrygin1, Ruslan Nikolaev1, Rimma Khismatullina1, Elena Osipova1, Michael Maschan1
1 Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
Background: T-cell alloreactivity is responsible not only for graft versus host disease and morbidity, associated with hematopoietic stem cell transplantation (HSCT) but also for graft-versus-leukemia (GVL) activity. In this regard, monitoring and quantitation of alloreactive T-cells (allo-T) may potentially provide valuable information for individualized clinical management of transplant recipients. The aim of this study was the optimization of allo-Т detection and comparison of the ELISPOT and MLC assays.
Methods: Allo-T were determined in 20 haploidentical donor-recipient pairs before HSCT. Donor mononuclear cells (MNC) served as effector cells (EC). Patient CD3-depleted MNC were used as stimulatory cells (SC).The ratio EC:SC were 5:1 and 10:1. The frequency of allo-T in donor peripheral blood was tested in ELISPOT assay and MLC. ELISPOT provides the detection and quantitation of activated T-cells on the basis of cytokine secreted by each cell. The co-incubation time was 24 h for IFN-gamma and 48 h for IL-2 detection. In MCL assay donor MNC were labeled with CFSE and allo-T, proliferating in response to stimulation with alloantigens, were determined by flow cytometry on day 5.
Results: The median number of IFN-gamma producing allo-T per 300 000 donor MNC was 143,5 (2-1469; EC:SC ratio - 5:1) and 75,0 (1-1440; EC:SC ratio - 10:1). The median frequency of allo-T was 0,056% (0,00076 - 0,538; EC:SC ratio - 5:1) and 0,019% (0,00019 - 0,632; EC:SC ratio - 10:1) among lymphocytes. IL-2-producing allo-T were less frequent in donor MNC in comparison with IFN-gamma-producing allo-T. The median number per 300 000 MNC was 7,5 (0,5-356; EC:SC ratio - 5:1) and 6,0 (0-169; EC:SC ratio - 10:1). The median frequency of IL-2- allo-T was 0,0028% (0,0002 - 0,130; EC:SC ratio - 5:1) and 0,0022% (0 - 0,0619; EC:SC ratio - 10:1) among lymphocytes. The EC:SC ratio 10:1 is enough for stimulation of IL-2 producing by MNC in ELISPOT assay, but for optimal stimulation of IFN-gamma producing cells EC:SC ratio 5:1 is preferable. This suggests that allo-T are predominantly IFN-gamma producing cells. Alloreactive proliferating T-clones were detected in MLC in 10 of 14 donor-recipient pairs on 5 day of cocultivation. Median percentage of proliferating T-clones were 9,5% (2,1 - 32,5; EC:SC ratio - 5:1) and 7,6% (3,0 - 24,1; EC:SC ratio - 10:1) among lymphocytes. However, MLC assay only permit a qualitative analysis that confirmed the presence of alloreactive T-clones, giving no information on their frequency within the culture. Results of ELISPOT and MCL assay directly correlated.
Conclusions: Allo-T were detected in 100,0% of assayed haploidentical donor-recipient pairs by ELISPOT and only in 71,4% by MLC. This difference in detection is due to the fact that ELISPOT allows to detect single cytokine secreting cell whereas MLC can reveal proliferating аllo-T clones. The analysis of allo-T in haploidentical donor-recipient pairs may provide rationale to manipulate the allo-immune response and to exploit the powerful ability of allo-T to control hematologic malignancies.
Disclosure: Nothing to declare
P077 Allogeneic mesenchymal stromal cell as rescue therapy in an infant with life-threatening respiratory syndrome due to a filamin a mutation
Stefania Croce1, Elisa Lenta2, Melissa Mantelli2, Maria Antonietta Avanzini2, Aurelio Lillo Ferraro3, Laura Catenacci2, Gloria Acquafredda2, Valeria Calcaterra1, Gloria Pelizzo3
1 University of Pavia, San Matteo Hospital, Pavia, Italy, 2 Policlinico S. Matteo Pavia, Pavia, Italy, 3 Arnas Civico Di Cristina Benfratelli, Palermo, Italy
Background: Cell-based therapy has gained attention in the respiratory system diseases and encouraging results are reported following mesenchymal stromal cells (MSCs) administration. Due to their capacity to produce and secrete a variety of paracrine factors and bioactive macromolecules, MSCs became a key player in lung tissue injuries and function, reducing fibrosis, promoting the normal development of alveoli and pulmonary vessels. For the first time we used the MSC infusions as rescue therapy in a pediatric patient with FLNA gene mutation and life-threatening respiratory syndrome.
Methods: A child with a new pathogenic variant of the FLNA gene c.7391_7403del; (p.Val2464AlafsTer5) at the age of 18 months, due to the serious and irreversible chronic respiratory failure and dismal prognosis, was treated with 4 intravenous infusions of allogeneic bone marrow (BM)-MSCs at the dose of 1×106MSCs/kg body weight. BM-MSCs were produced at “Cell Factory”, Fondazione IRCCS Policlinico S. Matteo, Pavia,isolated and expanded ex vivo from healthy donor BM, following a previously reported protocol. Premedication with antistaminic drug, 30 min before every infusion to avoid any potential reaction was performed. The evolution of the respiratory condition was detected. Peripheral blood were collected before each MSC treatment for Treg and Th17 monitoring. Treg, defined as CD4+ CD127neg CD25+ cells expressing the forkhead box P3 (FoxP3) transcription factor, and Th17, defined as CD4+ cells expressing intracellular IL-17, evaluation was performed by flow cytometry (FACSCanto; BD Biosciences, San Diego, CA) as previously reported, following standard procedures.
Results: No acute adverse events related to MSCs infusion was recorded. During follow-up, patient maintained a good general condition and showed a regular growth. No systemic or respiratory infections occurred. After the second infusion, the child experienced a progressive improvement of his clinical respiratory condition, with a good adaptation to mechanical ventilation, in the absence of episodes of respiratory exacerbations. The baby maintains adequate volumes of exchange with substantial reduction of the inspiratory support. A reduction of trigger sensitivity was also obtained. Thorax CT scan showed a recovery of the basal parenchyma bilaterally and the improvement of the anatomical-functional alignment and aerial penetration. After the first MSC administration, an enrichment of Treg and Th17 percentage in peripheral blood, was observed. While, after the second MSC infusion a significant increase in Treg/Th17 ratio was noted.
Conclusions: This report suggest that MSC serial infusions are a promising therapy in aiding the respiratory failure, even in a pediatric patient with FLNA mutation. Intravenous administrations of allogeneic MSCs are feasible and safe without toxicity. Our results suggest that to mitigate lung injury, MSCs may act as regulators of Treg and Th17 balance. Further investigations are upcoming to establish the useful of this therapeutic proposal in interstitial lung diseases in children.
Disclosure: Nothig to declare
P078 feasibility of IL-15 stimulated donor NK cells manufacturing for early infusion in patients with high risk acute myeloid leukemia undergoing haploidentical transplantation
Gonzalo Pérez Balsera1,2, Nieves Dorado Herrero1,2, Ana Pérez Corral1,2, Mi Kwon1,2, Mariana Bastos Oreiro1,2, Cristina Pascual Izquierdo1,2, Laura Solán Blanco1,2, Rebeca Bailen Almorox1,2, Carmen Falero Ruíz1,2, María Eugenia Fernandez Santos1,2, Antonio Pérez Martínez3, Cristina Muñoz Martínez2, Pascual Balsalobre1,2, José Luis Díez Martín1,2, Javier Anguita Velasco1,2
1 Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain, 2 Hospital General Universitario Gregorio Marañón, Madrid, Spain, 3 Hospital Universitario La Paz, Madrid, Spain
Background: NK cells provide a potent antitumor effect in the setting of manipulated haploidentical hematopoietic stem cell transplant (Haplo-HSCT). We propose a novel strategy to enhance the antitumor effect of allogeneic transplant through the infusion of NK cells stimulated with IL-15 exvivo in adult high-risk acute myeloid leukemia (AML) patients undergoing unmanipulated Haplo-HSCT. The objective of this study was to provide efficiency and productivity data obtained in the manufactured cellular products infused.
Methods: Selection criteria included patients with high-risk AML undergoing unmanipulated Haplo-HSCT. Lymphoapheresis of the haploidentical donor was performed using Spectra Optia (Terumo® BCT) on days +6 and +13 after transplant. From the obtained product a double immunomagnetic cellular selection with Clinimacs system (Miltenyi Biotec®) was performed in two steps: CD3+ depletion followed by positive CD56+ selection. The obtained an enriched cellular product of CD3-CD56+ NK cells was incubated with IL-15 (10 ng/mL) between 12 and 18 hours at 37ºC and 5% CO2 in GMP conditions. Quality and microbiological controls were performed at the end of each manufacturing step. DxH cellular counters (Beckman Coulter®) and multiparametric flow cytometry were used for lymphocyte subpopulations and viability analysis (Navios cytometer; Beckman Coulter®, conjugated Monoclonal antibodies; Miltenyi Biotec®). The final product was infused intravenously to the patient on days +8 and +15 if manufacturing conditions were met (range of 0.5-100x106 NK/Kg, purity ≥ 80%, viability≥ 70% and < 1x104 CD3+ cells/Kg). If not, it was discarded. NK cell activation in the product was measured by the expression of CD25 and CD69.
Results: Between November 2017 and April 2018, 3 patients were included in this ongoing trial. Two products were manufactured for 2 of the patients, and only one for the first patient, due to transplant complications between first and second infusion. One product did not meet minimum viability criteria and was discarded. In the infused final products mean and SEM of NK cell purity, recovery and viability were 83.7%±4.4, 30.9%±4 and 76.3%±17.4, respectively. Log CD3+ depletion ranged between -5.48 and -6.03. Median infused doses of NK cells and CD3+ cells per kg were 3.78x106(2.8x106-4.57x106) and 114 (87-532). Complete manufacturing data of all 5 procedures are shown in Table 1. Mean expression of activation markers was: CD69 (basal 15.6%± 2.6, after IL-15 69%±12.7), CD25 (basal 0.1%±0.04, IL-15 33%±7.75). No patient had immediate adverse effects with product infusion.
Conclusions: We demostrate the feasibility of the manufacturing process of IL-15 estimulated NK cells from haploidentical donors and early post-transplant infusion in adult AML patients in the setting of unmanipulated Haplo-HSCT. Achieved doses of NK cells for adult patients are promising, with safe content of contaminant T lymphocytes less than 1x104 /Kg. More procedures need to be analyzed in order to confirm this observations.
Clinical Trial Registry: NCT03669172
Disclosure: This study is funded by Instituto de Salud Carlos III (PI 15/00879). None of the authors have something to declare.
P079 Improving clinical manufacturing of cytokine-induced killer (CIK) cells
Melanie Bremm1, Eva Rettinger1, Claudia Cappel1, Verena Katzki1, Stephanie Erben1, Sibille Betz1, Andrea Quaiser2, Halvard Bonig3, Michael Schmidt3, Lisa-Marie Pfeffermann1, Thomas Klingebiel1, Peter Bader1, Sabine Huenecke1
1 University Hospital Frankfurt/Clinic for Children and Adolescents, Frankfurt am Main, Germany, 2 University Hospital Leipzig, Institute for Clinical Immunology, Leipzig, Germany, 3 Institute for Transfusion Medicine and Immunohematology, Frankfurt am Main, Germany
Background: Cytokine-induced killer (CIK) cells are a promising immunotherapeutic approach to combat relapse following allogeneic hematopoietic stem cell transplantation (HSCT) for acute leukemia or myelodysplastic syndrome. To show safety and efficacy, a multicenter clinical study with 20 pediatric and 20 adult patients including up to eight CIK cell applications with escalating doses is ongoing.
Methods: We favor single large scale CIK cell generation with the aim to apply fresh CIK cells and cryopreserve ready-for-use doses according to the study protocol in contrast to recurrent manufacturing. Therefore cryopreserved CIK cells were tested against freshly generated CIK cells to approve equivalence. Furthermore, an alternative medium supplement for CIK cell culturing was investigated to avoid supply bottlenecks in AB-Serum.
Results: Fresh Frozen Plasma (FFP), platelet lysate (PL) and AB-serum in CIK cell culture showed median expansion rates of 10-fold, whereas cultivation without medium additive resulted in significantly lower proliferation (p< 0.01). CIK cell composition including T cells, NK like T cells and a minor part of NK cells was not significantly influenced by changing the medium additive. Moreover, neither cytotoxicity against THP-1 cells nor CD25 expression on NK like T cells were significantly influenced by the different medium additives. For CIK cell generation either ficollized peripheral blood (PB) or unstimulated leukapheresis (LP) products were utilized. With regard to repeated manufacturing within the clinical study, also cryopreserved LP and PBSC as starting material came into the focus of interest. Comparing CIK cell expansion rates, no significant differences for the entire CIK cells and the subgroup of T cells were detected between the four starting materials. Cryopreservation of CIK cells had no significant effect on CIK cell composition, cytotoxicity and CD25 expression on NK like T cells. A small, albeit not significant effect of cryopreservation on viability was detected, which was 86.1% before and 79.4% after freezing and thawing.
Conclusions: The challenge was an efficient time-, personal- and cost saving production of CIK cells within the clinical study. Introducing FFP enabled CIK cell manufacturing for an increased patient cohort by avoiding supply bottlenecks in AB-serum. Furthermore, cryopreservation allows the storage of ready-for-use CIK cell doses fulfilling the demands of the clinical study.
Clinical Trial Registry: EudraCT Number 2013-005446-11
Disclosure: Nothing to declare.
P080 Automated generation of CD45RA depleted donor lymphocyte infusion (DLI) with the clinimacs prodigy® CD45RA system
Joanna Justyna Stenzel1, Stephanie Soltenborn1, Carina Thießen1, Felix Hebbeker1, Kirsten Langeveld1, René Meißner1, Michaela Malchow1, Eleni Papanikolaou1, Andreas Bosio1, Mario Assenmacher1, Julia Dzionek1
1 Miltenyi Biotec GmbH, Bergisch Gladbach, Germany
Background: Donor-derived CD45RO+ memory T cells have been described to provide defense against pathogens threatening immunocompromised patients after allogeneic hematopoietic stem cell transplantation (HSCT) while bearing a reduced GvHD risk; thus, in the recent years, DLIs depleted of naïve CD45RA+ T cells by CliniMACS® technology have been infused posttransplant to prevent infections in haploidentical HSCT1, 2
Methods: The current CliniMACS CD45RA System was developed for graft engineering. Up to 20x10e9 magnetically labeled CD45RA+ cells from leukapheresis products can be depleted from up to 50x10e9 white blood cells (WBC). We developed a new CliniMACS Prodigy® process in order to ease the procedure for routine-use, to reduce the specifications according to reported cell numbers for DLI applications, and to enable the use of peripheral blood products with high amounts of red blood cells (RBC). The new system was tested by performance runs. An new fluorescent flow analysis protocol was developed.
Results: The resulting CliniMACS Prodigy PB-45RA System is an automated procedure with integrated labeling and washing steps. The new application software PB-45RA Depletion enables to deplete up to 1.8x10e9 CD45RA+ cells from up to 5x10e9 total WBC from peripheral blood products. A major difference of this process is the RBC removal option based on an integrated camera for cell pellet detection. The final cell product is provided in physiologic saline. Verification runs with peripheral blood products (n=6 in total, n=3 with whole blood, n=3 with leukapheresis products) resulted in a mean depletion of 5.0 log (range 3.9 - 5.7) for CD45RA+ T cells in the CD45RA depleted product. Viability of the target products was always above 96%, and mean WBC recovery was 66%. The mean process time was 3h23min (range 3h to 3h50min) without including the manual steps, i.e. tubing set installation and downstream analysis of blood products by flow cytometry. This data were in line with preceding evaluation runs (n=6), and results obtained in cooperation with an external beta test site.3 The performance results were furthermore in line with results obtained on CliniMACS Plus instrument runs. For quality control of CD45RA depleted products we developed a flow cytometric analysis strategy for fast, accurate, and convenient analysis of even rare counts of remaining unwanted cells. It allows to determine naïve T cells at two different levels of subset staining. The minimum requirement for the flow cytometric analysis includes 4 colors to define viable CD3+CD45RA+ cells. For further evaluation of the naïve T cell subsets 3 additional colors are used to define viable CD3+CD45RO-CD95-CD62L+CD197+ cells.
Conclusions: The automated CliniMACS Prodigy PB-45RA System process is capable to deplete CD45RA+ cells efficiently from peripheral blood products within 4 hours. The new process is a fast, convenient, and regulatory compliant method for the preparation of ready-to-use CD45RA-depleted cell products for clinical applications. The submission to an European notified body for CE certification is an important next step.
1 Maschan, M et al. (2017) Bone Marrow Transplant. 53:264.
2 Triplett, BM et al. (2018) Transpl Infect Dis. 20:e12823.
3 Mueller, N et al. (2018) Cytotherapy 4:532
Disclosure: All authors are employees of Miltenyi Biotec GmbH, Germany
P081 Extracorporeal photopheresis treatment for steroid resistant graft versus host disease in pediatrics: Single center experience
Başak Adaklı Aksoy1, Yunus Emre Savcı2, Azize Mergen2, Selime Aydoğdu2, Gürcan Dikme2, Ceyhun Bozkurt1, Tunç Fışgın3
1 Istinye University, Medical Park Hospitals, Bahçelievler, Istanbul, Turkey, 2 Medical Park Hospitals, Bahçelievler, Istanbul, Turkey, 3 Altinbas University, Medical Park Hospitals, Bahçelievler, Istanbul, Turkey
Background: Steroid resistant graft vs host disease (GVHD) is defined as unresolved or worsened symptomatology of GVHD at day 14 despite effective immunosuppression with steroid therapy. Second line immunosuppressive agents, extracorporeal photopheresis (ECP) and/or mesenchymal stem cell therapies are being tried as salvage therapy.
Methods: We performed a retrospective single center trial between February 2016 - September 2018 with 25 out of 173 stem cell transplanted patients diagnosed with steroid resistant GVHD and treated with ECP.
Results: 25 patients diagnosed with steroid resistant GVHD, age between 2-17 years, 15 male and 10 female with diagnosis of AML, ALL, thalassemia major, aplastic anemia, NHL, MDS, HLH and CGD before transplant. Transplant characteristics were given on.
|Donor (MFD:84, MUD: 77, Haploidentical: 12)||MFD:8(%32) MUD:15(%60) Haploidentical: 2 (%8)|
|HLA match||10/10: 10 (%40) 9/10: 13 (%52) Haploidentical: 2 (%8)|
|Stem cell source||BM: 3 (%12) PSC: 20 (%80) BM + PSC: 2 (%8)|
|CD34 + cells(x10e6/ kg)||Median: 5,8 (3,9-19)|
|Neutrophil engraftment (days)||Median: 13 (10-29)|
|Platelet engraftment (days)||Median: 17 (10-38)|
|Chimerism (Full blood)||Full donor: 21(%84) Mixed: 4 (%16)|
[ [P081 Table] 1 . Transplant Characteristics]
Myeloablative conditioning regimen was preferred for 24 patients out of 25. GVHD prophylaxis regimens are CSA+MTX: 20(%80), CSA+MMF: 2(%8), CSA only: 1(%4). ATG was given 20 patients. Despite been given GVHD prophylaxis 47(%27,1) patients out of 173 transplanted patients had GVHD features. Of 47 patients, 25 had experienced steroid resistant GVHD after transplantation, including 17 (%68) grade 3 and 8 (%32) grade 4. ECP treatment was started mean 11 days after diagnosis of steroid resistant GVHD and 2 (%8) patients had complete response while 12 (%48) patients had partial and 11 (%44) patients had no response to ECP treatment on day 28. Sixteen out of 25 patients had also received mesenchymal stem cell therapy as salvage therapy. Only one patient had experienced hypocalcemic tetany, a complication of ECP procedure. Thirteen patients had died and 12 were directly related with steroid resistant GVHD. Other conditions like relapse of primary disease or PRES syndrome also played role in death.
Conclusions: Extracorporeal photopheresis is a reliable and effective second line treatment modality in steroid resistant GVHD. Starting ECP sessions as soon as GVHD symptoms occur increases its effectivity. Mesenchymal stem cell administration with ECP for 16 (%64) patients limits our study to reach o conclusion for efficacy of ECP itself. Need for hemodialysis catheters, the prolonged sessions while adequate flow is not possible and catheter related infections are the lmitations for feasibility of ECP.
Disclosure: nothing to declare
P082 Donor lymphocyte infusion administrations after allogeneic stem cell transplantations in pediatrics: A single center experience
Selime Aydoğdu1, Azize Mergen1, Başak Aksoy2, Hazal Ş. Akbay3, Funda Çipe1, Gürcan Dikme1, Tunç Fışgın3, Ceyhun Bozkurt2
1 Medical Park Hospitals, Bahçelievler, Istanbul, Turkey, 2 Istinye University, Medical Park Hospitals,Bahçelievler, Istanbul, Turkey, 3 Altinbas University, Medical Park Hospitals, Bahçelievler, Istanbul, Turkey
Background: Loss of chimerism is one of the major problems after allogeneic stem cell transplantation(SCT). Donor- lymphocyte infusions(DLI) are used as a treatment after taper or stopping immunosuppression. In this study, DLI experience in 20 patients with loss of chimerism after SCT due to various benign and malign hematological diseases was presented.
Methods: Between July 2015- August 2018, twenty patients, detected chimerism loss and received DLI after SCT were evaluated retrospectively. Patients received myeloablative or reduced intensity conditioning, ATG, cyclosporine A and methotrexate for GVHD prophylaxis. Chimerism analyses were performed with short tandem repeat(STR) method from peripheral blood. Results below 95% were considered as mixed chimeric and below %5 were nonchimeric. When patients considered as mixed chimeric, immunosuppression therapy was ceased immediately and treated with DLI. Donor lymphocyte infusions were performed at two-week intervals with chimerism follow-up. Student T, Mann Whitney U, Ki Kare tests and Kaplan-Meier analysis were used.
Results: Between 1-16 ages (median 4), 7 female, 13 male patients were evaluated. The initial diagnoses were thalassemia major(10), aplastic anemia(3),ALL(4), AML(3). DLI initiation time was 119.65+-92.71 days after SCT, total number of DLI administrations were 3.5+-2.19. Dose of DLI was 1X105-63.6x106/kg (mean 20.5x106/kg). Nine patients' chimerism out of 20, fell below 95% at first month after transplant; 4 patients were nonchimeric, 2 of them were complet chimeric and 3 were mixed chimeric. Eleven patients´ chimerism were below 95% between 1-6 months after SCT, 5 patients were nonchimeric and 6 were mixed chimeric. Early mixed chimerism was found relevant with graft rejections (p=0.04). Patients were followed up for 91-645 days. Eight patients' chimerism increased after DLI infusion and continued to decrease in 12 patients. After DLI, acute GVHD has been seen in both group.The group with decreased chimerism after DLI, dose was mean 12x106±23x106/kg while the group with increased chimerism had DLI dose mean 22x106±19x106/kg. Although the difference was not statistically significant, numerical value revealed significantly different. Eventually10 patients out of 20 were mixed chimeric, 6 patients were complete chimeric and 4 were none. In thalassemic patients, 7 patients with thalassemia-trait donor were mixed chimeric, In 3 patients whose donors were normal, 2 of them were complete chimeric and one of them was nonchimeric.The difference was significant (p=0.02). The CD34 infusion doses revealed mean 6.61 ±5.06x106/kg in mixed chimeric patients, 7.16±3.31x106/kg in complete chimeric patients and 6.625±1.37x106/kg in the patients with loss of chimerism. CD34 amount was seen high as numerical value in complete chimerics but no statistical significance was found. Overall survival was 85%, disease-free survival was 25%.
Conclusions: We evaluated the efficacy of DL for patients with mixed chimerism in our patient group. We concluded that chimerism loss in patients with early decreased chimerism is similar to those in literature in spite if DLI practices. Dose and application frequency were greater in patients with increased chimerism. The small number and the heterogeneity of the patients limited our study. In this regard, studies with larger series and homogeneous groups are acquired.
Disclosure: Nothing to declare
P083 Phase I clinical trial of repeated administrations of bone-marrow derived mesenchymal stem cells in steroid-refractory chronic graft-versus-host disease patients
Nayoun Kim1, Young-Woo Jeon2, Jae-Deog Jang1, Keon-Il Im1, Nak-Gyun Chung2, Young-Sun Nam1, Yunejin Song1, Jun-Seok Lee1, Seok-Goo Cho1,2
1 The Catholic University of Korea, Seoul, Korea, Republic of, 2 Seoul St. Mary's Hospital, The Catholic University of Korea, Catholic Blood and Marrow Transplantation Center, Seoul, Korea, Republic of
Background: Chronic graft-versus-host disease (cGHVD) is the most common long-term complication of allogenic hematopoietic stem cell transplantation which is associated with poor quality of life and increased risk of morbidity and mortality. Currently, there is no standardized treatment available for patients who do not respond to steroids. As an alternative to immunosuppressive drugs, mesenchymal stem cells (MSCs) have been used to treat and prevent steroid-refractory acute GVHD patients. These studies and reports have also provided a basis for using MSCs in steroid refractory cGVHD patients.
Methods: To evaluate the safety and efficacy of repeatedinfusions of MSCs, we enrolled ten severe steroid-refractory cGVHDs patients. Steroid refractory was defined as either no response to steroids lasting at least 4 weeks or progression of disease during treatment or tapering lasting at least 2 weeks. Patients were intravenously administered with MSCs produced from third-party bone marrow donors at a 2-week interval for a total of four doses. Each dose contained 1x106 cells per kg body weight and all four doses consisted of MSCs from the same donor and same passage.
Results: We enrolled ten patients (3 female/ 7 male, with a median age of 41.5(range 17-68). Median of cGVHD affected organs was 3 (range 2-4) including the skin (n=4), eyes (n=8), oral cavity (n=9), lung (n=1), liver (n=2) and joints (n=6). All ten patients received their planned four doses of MSCs, administering a total of 40 infusions. Median time from initial cGVHD diagnosis to first MSC treatment was 709 days (range 222-4413). MSC infusions were well tolerated with no immediate or delayed toxicities. After 8 weeks of the first MSC infusion, all ten patients showed partial response showing alleviation in clinical symptoms and increased quality of life. Organ responses were seen in skin (n=2), eyes (n=5), oral cavity (n=8), liver (n=1), and joint(n=5). However, one patient died of progressive GVHD and one patient relapsed from primary disease.
Conclusions: Repeated infusions of MSCs was feasible and safe and may be an effective salvage therapy in patients with steroid-refractory cGVHD. Further large-scale clinical studies with long-term follow up is needed in the future to determine the role of MSCs in cGVHD.
Clinical Trial Registry: This study was registered and approved by Clinical Research Information Service, Republic of Korea, in the WHO Registry Network (KCT0001894).
Disclosure: Authors have nothing to declare
P084 Therapeutic use of umbilical cord blood stored in the polish stem cell bank for standard and experimental therapy
Izabela Zdolińska-Malinowska1, Maciej Rojek1, Dariusz Boruczkowski1
1The Polish Stem Cell Bank, Warsaw, Poland
Background: The majority of pregnant Polish women (84%) have heard of cord blood banking. However, most doctors do not have sufficient knowledge about the possibility of using cord blood in order to respond to their potential concerns. Only 16.5% of healthcare professionals were aware that cord blood could be used to treat haematological diseases. In order to make doctors aware of this issue and provide patients with the information they expect, we would like to present data on the use of cord blood stored in our blood bank for haematological and non-haematological therapies.
Methods:The table presented below has been created using data from the general database of the Polish Stem Cell Bank, Warsaw, Poland. No data regarding umbilical cord blood data have been excluded. All patients were planned to be assessed on day 1, day 28, on discharge, 100 days after transplantation and 1, 2, 3, 4, and 5 years after transplantation, but in some cases, patients were lost from follow-up due to a persistent lack of reports from transplantation centres.
Results: In 32 cases, the therapeutic use of CB was transplantation (replacement of patients' own tissue); in 13 cases it was administration (infusion without destruction of patients' own tissue). Thirty-three were administered as standard therapy and 13 as experimental therapy.
Conclusions:The survey study cited above, indicated low awareness of cord blood use among healthcare professionals. On the other hand, one study indicated that the expectations placed in cord blood banking may be unreasonable. As a private cord blood bank, we support recommendations which underline the importance of patient education. In Poland, cord blood has been approved as standard therapy in approx. 80 diseases; most of them are rare, but Polish law allows the use of cord blood for the siblings, parents and grandparents of a donor. Additionally, 168 active and planned clinical trials throughout the world evaluate the therapeutic efficacy of cord blood in such areas as haematology, neurology, cardiology, diabetology, congenital paediatric disorders, ophthalmology, dermatology, gastroenterology, HIV infection, and the quality of life during aging. Therefore, further indications may be expected in the future.
|Indication||Number of allogeneic transplantations/administrations for related recipients||Number of allogeneic transplantations/administrations for unrelated recipients (public bank)||Number of autologous transplantations/administrations||Only cord blood||Cord blood + bone marrow/ placental blood||Complete remission||Partial remission/improvement||Lack of improvement/Relapse without death||Death|
|Cerebral palsy / ischemia||0||0||5||5||0||0||5||0||0|
|More than one indication||2||0||0||0||2||2||0||1||0|
[ [P084 Table] 1 . Therapeutic use of umbilical cord blood in particular diseases]
Disclosure: All authors are employees of the Polish Stem Cell Bank
P085 Cytokine release syndrome treatment and management flowchart
Jaydine Carr1, Sonia Berzosa1
1Bristol Oncology and Haematology Centre, Ward D703, Bristol, United Kingdom
Background: Cytokine release syndrome (CRS) has been identified as a clinically significant, on target, off tumour side effect of the chimeric antigen receptor (CAR) T-Cell therapies. It is clinically increased in interkeukin 6 and elevations in other cytokines, lactate dehydrogenase (LDH), C-reactive protein (CRP), and ferritin. These side effects can include fever, fatigue, headache, encephalopathy, hypertension, tachycardia, coagulopathy, nausea, capillary leak and multi organ dysfunction. CRS symptoms can appear as early as one day after infusion and can resolve quickly or last for weeks. It´s severity to be related to the disease burden prior to CAR T-Cell therapy.
Methods:The Bristol Oncology and Haematology centre will be providing CAR T-Cell therapy to patients in early 2019. On collating from the leading consultant on the ward and fellow nursing team members it was apparent that an effective way at managing patients post CAR T-Cell therapy side effects is to provide an educational and informative poster depicting a flow chart that will aid the practitioner to recognise and effectively treat/manage a patient with CRS symptoms.
Results: None as of yet as this is a prospective tool ready for our first patient in early 2019
Conclusions: Through continuing reading and study days prior to the ward receiving its first CAR T-Cell patient it is increasingly important that the entire multi disciplinary team recognise CRS and understand the importance of early detection, careful monitoring and early intervention.
Clinical Trial Registry: N/A
Disclosure: Nothing to declare
Chronic leukaemia and other myeloproliferative disorders
P086 Reduced intensity allogeneic stem cell transplantation for younger patients with myelofibrosis
Daniele Mannina1,2, Christine Wolschke1, Tatjana Zabelina1, Gaby Zeck1, Ute-Marie von Pein1, Francis Ayuk1, Nicolaus Kröger1
1 Hamburg University Hospital, Hamburg, Germany, 2 Ospedale San Raffaele, Milano, Italy
Background: Allogeneic stem cell transplantation (alloSCT) is the only curative procedure for primary and secondary myelofibrosis (PMF, SMF). Elderly people are mainly affected, limiting the feasibility of intensive myeloablative chemotherapy regimens. The introduction of reduced-intensity conditioning (RIC) made alloSCT feasible and effective for old patients. Nevertheless, the incidence of PMF and SMF is not negligible in young patients, theoretically able to tolerate also high-intensity therapy. Very few data are available about the efficacy of RIC-alloSCT in the particular setting of young-aged MF patients.
Methods:This study includes 56 Myelofibrosis young patients (age < 55y) who received alloSCT between 2002 and 2016 at the University Hospital Hamburg/Germany. Four patients were previously splenectomized. Patients mostly fall into intermediate risk groups according to DIPSS. Four patients belonged to the high-risk triple-negative category (JAK2/CALR/MPL-). ASXL1-mut was tested in 50 patients (pos: 17). In 96% graft source was PBSC, 2 patients received BMSC. Only 30% of patients had a 10/10 HLA-matched sibling, the others were transplanted from fully-matched (36%) or partially-matched (34%) unrelated donor. All transplants were conditioned according the EBMT protocol with Busulfan (10 mg/Kg PO or 8 mg/Kg IV), Fludarabine (150 mg/m2), ATLG (Grafalon® Neovii, Germany) administered in 3 days at a dose of 20 mg/Kg die for MUD, 10 mg/Kg die for MRD transplants, followed by CylosporinA, and Mycophenolate in the first 28 days.
Results: Engraftment rate was 98%, median neutrophil engraftment time 15 days. Platelet engraftment was reached by 51 patients (91%, median 19 days). Four patients (7%) developed poor graft function, successfully treated with CD34+ selected PBSC-boost. After a median follow up of 8.6 years, estimated 5y-PFS and OS were 68% and 82% respectively. DIPSS-risk and donor HLA-matching resulted the only significant impacting factors on OS. Neither cytogenetic nor molecular abnormalities were significantly related to OS. Twenty-five patients (44%) experienced aGVHD grade >1. C-GVHD was observed in 34 patients (65%), mostly (82%) beginning in the first 300 days after transplantation. Cumulative incidence of TRM was 7% at 1 year, with a plateau after the first year (5y TRM = 12%). TRM was observed only in patients with maximal grade (3) of marrow fibrosis. Furthermore, TRM never occurred in previously splenectomized patients (p=0.00), but no significant impact from splenectomy on OS was observed (p=0.32). After transplant, 11 patients (20%) relapsed: 1 died without any treatment because of infection, 9 received DLI (3 durable CR), 7 patients (6 after DLI) underwent a second alloSCT, with long-term survival in 5 cases.
Conclusions: RIC followed by allogeneic SCT is a curative treatment approach for younger patients with myelofibrosis with a low NRM. The most important outcome-determining factor is donor HLA-matching. Interestingly, marrow high grade fibrosis showed to significantly impact TRM. Biological markers such as ASXL1 mutation and cytogenetics, largely known as highly predictive for poor prognosis in the disease natural course, did not show any impact on survival, suggesting that patients harboring these abnormalities could get the greatest benefit from alloSCT. Further data collection, and a prospective randomized trial are needed to confirm our conclusion.
Disclosure: Nothing to declare
Abstract already published.
P088 Splenectomy as a risk factor for relapse after allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis - retrospective cohort study
Rashit Bogdanov1, Markus Ditschkowski1, Nina-Kristin Steckel1, Vesna Klisanin1, Michael Koldehoff1, Lambros Kordelas1, Tobias Liebregts1, Nikolaos Tsachakis-Mueck1, Rudolf Trenschel1, Dietrich W. Beelen1
1 University Hospital Essen, West-German Cancer Center, Essen, Germany
Background: Splenectomy is a common procedure in patients (pts) with myelofibrosis (MF) performed to achieve improvement in blood cell counts and reduce B-symptoms. However, it has also been shown that splenectomy may adversely predispose to leukemic transformation in this setting.
Aim: To evaluate in a single-center retrospective analysis the long-term impact of pre- or post-transplant splenectomy on transplant outcome regarding overall survival and relapse risk.
Methods: This retrospective analysis comprises the data of 163 pts (93 male and 70 female) with primary (n=108) or secondary (n=55) MF after allo-HSCT from HLA-matched sibling (n=48) or unrelated (n=115) donors in our center between 1994 and 2018. The median age was 56 years (range, 22 to 75 years). A myeloablative conditioning regimen was performed in 142 pts, while 21 pts where treated with a reduced intensity conditioning. Peripheral blood stem cells (n=154) or bone marrow (n=9) with a median of 7.0 x 106 CD34+ cells/kg bodyweight (BW) (range, 1.0 to 30) were transplanted. Splenectomy was performed in 41 of 163 pts: 21 pts were splenectomized prior to and 20 pts after allo-HSCT. Relapse was diagnosed in 22 (14%) of 163 pts. The median duration to relapse after transplantion was 13 months (range, 3-99 months).
Results: The median duration of follow-up of this cohort was 28 months (range, 2-120 months), the 10-year overall survival (OS) was 46%. 74 pts died, including 7 pts who relapsed and 67 pts who died of treatment related causes. The observed probability of relapse was significantly higher in splenectomized pts than in non-splenectomized pts: 37% versus 10% (relative risk (RR) 3.7, 95% CI, 1.5-9.4, p=0.007). At 10 years, the OS was 50% in non-splenectomised and 39% in splenectomised pts (p=0.35) (Fig.1). The relapse rate in splenectomised pts was independent of pre- (5 of 21 pts, 24%) or post-transplant (6 of 20 pts, 30%) treatment (RR 1.3, 95% CI, 0.34-5.5, p=0.73).
Conclusions: On the basis of our cohort, we could assert that pre- and post-allo-HSCT splenectomy was equally and significantly associated with an increased relapse ratio in patients with MF, which also tends to negatively affect overall survival.
[ [P088 Image] 1 . Figure 1: The overall survival after allo-HSCT in patients with myelofibrosis.]
Clinical Trial Registry: no
Disclosure: Nothing to declare
P089 Three consecutive cases illustrating that Rituximab can induce deep responses in ibrutinib-resistant B-cell prolymphocytic leukemia for bridging to allogeneic stem cell transplantation
Nora Liebers1,2, Sascha Dietrich1,2,3, Michael Hundemer1, Susanne-Annegret Hain4, Martin Schiller1, Eckhart Weidmann5, Tobias Roider1, Monika Brüggemann6, Carsten Müller-Tidow1, Peter Dreger1
1 University of Heidelberg, Heidelberg, Germany, 2 National Center for Tumor Diseases and German Cancer Research Centre, Heidelberg, Germany, 3 European Molecular Biology Laboratory (EMBL), Heidelberg, Germany, 4 St. Marien-Krankenhaus, Medizinische Klinik III, Siegen, Germany, 5 Krankenhaus Nordwest, Klinik für Onkologie und Hämatologie, Frankfurt, Germany, 6 Universitätsklinikum Schleswig-Holstein, Klinik für Innere Medizin II, Kiel, Germany
Background: B-cell prolymphocytic leukemia (B-PLL) is a very rare lymphoproliferative disorder. Although allogeneic stem cell transplantation (alloSCT) could be a curative option, patients often do not qualify for this consolidation treatment due to an aggressive course of disease. In this case study, we report on three patients who failed ibrutinib therapy but achieved complete remission and even MRD negativity after treatment with the chimeric CD20-antibody Rituximab, enabling them to undergo alloSCT.
Methods: Clinical data and follow-up data were collected by chart review.
Results: All three patients (pt#1: male, 42 years; pt#2: female, 66 years; pt#3: female, 64 years) were referred with B-PLL harboring highly complex aberrant karyotypes, including 17p abnormalities in pt#1 and pt#2. A TP53 mutation could be detected in pt#2 and pt#3. All three patients had symptomatic disease with rapidly increasing hyperleukocytosis and massive splenomegaly. Two of them were treatment-naive and one relapsed after chemoimmunotherapy. All patients were put on ibrutinib 420mg. Despite initial response to treatment, two patients developed progressive disease after 4 (pt#1) and 9 months (pt#2) on ibrutinib, whereas pt#3 remained in partial remission with persisting leukocytosis, precluding consolidating alloSCT as originally intended. In pt#1, ibrutinib was replaced by venetoclax, but without response. In order to control rapid lymphoproliferation, rituximab was added to venetoclax. Grade 4 infusion reaction / tumor lysis syndrome (TLS) (fever, tachycardia and hypotonia requiring intravenous vasopressors) followed each rituximab administration despite fractionating rituximab to small doses. However, continuation of rituximab (100mg/d over 10d) led to complete and durable clearance of hyperleukocytosis (from 250/nl to MRD negativity) despite venetoclax cessation. A similar pattern was observed in pt#2, who received rituximab while showing rapidly increasing leukocytosis upon ibrutinib. Again, complete clearance of B-PLL cells in the peripheral blood (from 148/nl to MRD negativity) occurred after initial grade 4 TLS despite only modest CD20 expression on tumor cells in this patient. Also, pt#3 achieved profound B-PLL cell depletion (from 38/nl to a MRD rate of 1.1%) upon addition of rituximab to ibrutinib (without TLS in this case). Subsequently, all three patients were able to undergo alloSCT after conditioning with fludarabine and total body irradiation with 8 Gy. Pt#1 received stem cells from a HLA-ident sibling donor, whereas Pt#2 and Pt#3 had unrelated donors (HLA-ident and HLA-matched respectively). With follow-up times of 17 and 11 months post-transplant, pt#1 and pt#2 are currently in ongoing MRD-negative remission. Pt#1 developed an acute graft-versus-host disease (GvHD) of the liver (grade 3), nevertheless the clinical course was well controlled by immunosuppression. In pt#2 a chronic GvHD of the skin occurred. Pt#3, who achieved MRD negativity after alloSCT, developed acute and chronic steroid-refractory GvHD of the skin and gastrointestinal tract. Nine months post-transplant, GvHD deteriorated and after further complications the patient died of pneumonia 11 months post-transplant.
Conclusions: Supplementary treatment with rituximab can induce deep remissions in patients with ibrutinib-resistant, genetically poor-risk B-PLL, thereby enabling them to undergo successful consolidation with alloSCT. A high risk of life-threatening infusion reactions / TLS associated with the addition of rituximab has to be taken into account.
Disclosure: Nora Liebers: consultant for Takeda
Peter Dreger: consultant for AbbVie und Janssen
All other authors: no conflicts of interest
P090 Safety and efficacy of the BCR inhibitors after allogeneic stem cell transplantation for CLL
Lucrecia Yáñez1, Christelle Ferra2, Miguel Alcoceba3, Marcos Gonzalez3, Rafael Andreu4, Ildefonso Espigado5, Javier Loscertales6, Jose Antonio Garcia Marco7, Maria José Terol8, Carlos Solano8, Francesc Bosch9
1 Hospital Universitario Marqués de Valdecilla, Santander, Spain, 2 Trias i Pujol, Institut Català d’Oncologia (ICO), Badalona, Spain, 3 Hospital Universitario de Salamanca, Salamanca, Spain, 4 Hospital Universitari i Politècnic La Fe, Valencia, Spain, 5 Hospital Universitario Virgen del Rocio, Sevilla, Spain, 6 Hospital de La Princesa, Madrid, Spain, 7 Hospital Puerta de Hierro, Madrid, Spain, 8 Hospital Clinic de Valencia, Valencia, Spain, 9 Hospital Vall d´Hebron, Barcelona, Spain
Background: There is little experience on the use of the newer targeted therapies in CLL patients relapsed after allogeneic stem cell transplantation (allo-SCT). Against this background, we evaluate the safety and efficacy of the BCR inhibitors (BCRi), ibrutinib and idelalisib, administered after allo-SCT for the purpose of treating the CLL relapse.
Methods: Data from 11 CLL pts who relapsed after SCT,and were subsequently treated with ibrutinib (n=6), idelalisib (n=3) or both (n=2),were retrospectively collected in collaboration with the Spanish group of CLL (GELLC) and the Spanish group of Stem Cell Transplantation (GETH).
Results: Transplant characteristics are summarized in table 1.
Eight patients received the BCRi as the first salvage treatment after SCT relapse, whereas 3 patients had received ≥2 prior lines of treatment. At the time of the onset of the BCRi, 7 patients had Rai 4 stage and 6 patients had a lymph node size ≥5 cm. Del17p was present in 4 patients and del11q and complex karyotype in 2 patients, respectively. TP53 gene mutation was detected in 3 patients (all with del17p13). Median time from SCT to BCRi therapy was 53.9 months, being shorter in patients treated with ibrutinib (n=8, median 51 months) than in those treated with idealisib (n=3, median 111 months).
Median time on ibrutinib and on idelalisib was 7.3 months (4.1-18.8) and 6 months (3.0-23.4), respectively. The best overall response rate (ORR) obtained with ibrutinib was 75% (1 CR, 4 PR, 1 PR+L) whereas it was of 40% for patients receiving idelalisib (1 CR, 1 PR+L).
Among the 8 patients treated with ibrutinib, 7 (87.5%) presented an adverse event (AE), being diarrhea (n=3), asthenia (n=2) and infections (n=5) the most frequent. Hypertension was seen in 1 patient and none patient developed atrial fibrillation. Five patients stopped ibrutinib treatment, due to toxicity (n=4) or progression (n=1). After ibrutinib discontinuation, 4 patients were newly treated with idelalisib (n=2) or venetoclax (n=2). All patients treated with idelalisib developed at least one AE, being diarrhea (n=3), pneumonitis (n=2) and neutropenia (n=2) the most common. Four patients discontinued idelalisib because progression (n=3) or toxicity (n=1). Venetoclax was given after idelalisib in 3 patients.
Although acute and/or chronic GVHD before BCRi was documented in 7 (63.6%) and 5 (45.5%) patients, respectively, only one patient (treated with idelalisib) reactivated a mild chronic GVHD. None patient received infusion lymphocyte from donor after BCRi and one patient underwent a second SCT.
With a median follow-up of 14.3 months (5.9-33.9) after the onset of the BCRi treatment, 4 patients had died, all of them due to CLL progression (3 Richter´s transformation), whereas 5 patients remained in response (3 CR, 2 PR). The overall survival probability of the whole series at 12 months was 77.8% ±13.9%.
Conclusions: In our study, ibrutinib and idelalisib, administered in CLL patients relapsed after SCT did not increase the risk of GVHD reactivation but they show high incidence of adverse events. Nevertheless, BCRi offers a possibility of disease control in these patients with poor prognosis. Further studies are needed to confirm these data.
|Gender (male)||7 (63.6)|
|Age at transplant, years, median (range)||52 (45-60)|
|≥2 prior lines of treatment||7 (63.6)|
|BCRi prio SCT||2 (18.2)|
|Stem cell source, peripheral blood||9 (81.8)|
|Matched related donor||6 (54.5)|
|Matched unrelated donor||3 (27.7)|
|Reduced intensity conditioning||10 (90.9)|
[ [P090 Table] 1 . Patients and transplant characteristics, N=11.]
Disclosure: Dr. Yañez reports travel grants and conferences with Janssen, Roche, Gilead, Merck and Pfizer.
Dr. Ferra reports travel grants and conferences with Gilead, Jansen and Abbvie.
Dr. González reports travel grants and conferences with Gilead, Jansen, Roche and Abbvie. The rest of authors declare no conflicts of interest.
P091 Long-term survival of CML patients who received autologous HCT before and after the tyrosine kinase inhibitors ERA. Study on behalf of the EBMT CMWP
Mauricette Michallet1, Mohamad Sobh1, Sheree Hazelaar2, Jane Apperley3, Noel Milpied4, Hélène Labussière-Wallet5, Didier Blaise6, Roberto Foa7, Jorge Sierra8, Eric Deconinck9, Emanuele Angelucci10, Kristina Carlson11, Rocio Parody Porras12, Arnold Ganser13, Jaime Sanz14, Mohamad Mohty15, Rizzoli Vittorio16, Richard E Clark17, Amit Patel17, Martin Mistrik18, Grant McQuaker19, Patrice Chevallier20, Tsila Zuckerman21, Achilles Anagnostopoulos22, Franck E Nicolini1, Yves Chalandon23, Ibrahim Yakoub-Agha24
1 Centre Leon Berard, Hematology, Lyon, France, 2 EBMT data office Leiden, Leiden, Netherlands, 3 Imperial College London, London, United Kingdom, 4 CHU Bordeaux, Pessac, France, 5 Centre Hospitalier Lyon Sud, Pierre Benite, France, 6 Institut Paoli-Calmettes, Marseille, France, 7 University 'La Sapienza', Roma, Italy, 8 Hospital Santa Creu i Sant Pau, Barcelona, Spain, 9 Hopital Jean Minjoz, Besancon, France, 10 Ospedale San Martino, Genova, Italy, 11 University Hospital Uppsala, Uppsala, Sweden, 12 ICO - Hospital Duran i Reynals, Barcelona, Spain, 13 Hannover Medical School, Hannover, Germany, 14 Hospital Universitari i politècnic La Fe, Valencia, Spain, 15 Hospital Saint Antoine, Paris, France, 16 Centro Trapianti Unico Di CSE Adulti e Pediatrico A. O Brotzu, Parma, Italy, 17 Royal Liverpool University Hospital, Liverpool, United Kingdom, 18 University Hospital Bratislava, Bratislava, Slovakia, 19 Beatson, West of Scotland Cancer Centre, Glasgow, United Kingdom, 20 CHU Nantes, Nantes, France, 21 Rambam Medical Center, Haifa, Israel, 22 George Papanicolaou General Hospital, Thessaloniki, Greece, 23 Hôpitaux Universitaires de Genève and Faculty of Medicine, University of Geneva, Geneva, Switzerland, 24 CHRU de Lille, Lille, France
Background: Prior to the introduction of tyrosine kinase inhibitors (TKI), median survival of chronic phase chronic myeloid leukemia (CP-CML) patients was approximately 60 months and the standard treatment with interferon-alpha resulted in complete cytogenetic responses in about 30% of the patients. Autologous stem cell transplantation (auto-SCT) was first attempted for patients in transformation in order to restore a second CP and was introduced secondarily in CP to try to prolong the response. The main rational for autografting in CP resides on the reduction of the tumor burden and the number of leukemic cells at risk of developing blastic transformation. Nevertheless, auto-SCT alone was not able to maintain a long-term remission. Nowadays, TKIs represent the state-of-the-art therapy for CML and the concept of Auto-SCT has only little interest while long-term follow-up and outcome in this setting are currently unknown.
The aim of our study is to evaluate at a first time the long-term outcome of CML patients who received auto-SCT in chronic phase, and to evaluate at a second time in a subgroup analysis, the outcome of those who received TKI after having been auto-transplanted, mainly for disease progression/loss of response and/or to enhance disease response.
Methods: We found a total of 969 patients who received auto-SCT for CP-CML in Europe between years 1989 and 2004, 578 (60%) were males, median age at auto-SCT was 47 years (range: 19-67), the median time between diagnosis and auto-SCT was 19 months, stem cells source was peripheral blood in 84% of patients, most frequent conditioning regimen was busulfan 4mg/Kg/day 4 days + 1 day of melphalan 140 mg/m² one day prior to the cells reinfusion. Information about receiving TKI post auto-SCT was available only for 103 patients, first TKI was imatinib for 89 (86%) patients, dasatinib for 8 (8%), nilotinib for 6 (5%) and ponatinib for one (1%) patient.
Results: After a median follow-up of 9.5 years (range: 1-27) from time of auto-SCT for the whole population, the probability of overall survival (OS) at 10 years was 50% (95% CI: 46-53); there was 540 (56%) patients who relapsed after a median time of 16 months after auto-SCT. There was a total of 530 patients transplanted before the TKI era and survived until the availability of TKIs. When we performed a landmark analysis evaluating the outcome of patients who received auto-SCT, survived until the TKI era and received TKI (N=103), the 10 years OS probability of these patients from TKI treatment was 70% (95% CI: 58-78). Additional data requests will be sent to centers querying about prognosis, molecular responses, treatment and disease details.
Conclusions: We demonstrate here with these preliminary results that the introduction of TKI has improved survival of CML patients. In addition, patients who received auto-SCT, survived until the TKI era and also received TKI, had encouraging rates of long-term survival. An extensive analysis will be performed when additional data will be available and the study will be updated with more results.
Disclosure: Nothing to declare
P092 A 35 year single center transplant experience in chronic myeloid leukemia
Antonella Bruzzese1, Walter Barberi1, Isabella Sperduti2, Roberto Latagliata1, Massimo Breccia1, Luisa Quattrocchi1, Ursula La Rocca1, Michela Ansuinelli1, Sara Pepe1, Robin Foà1, Anna Paola Iori1
1 Sapienza University, Roma, Italy, 2 Istituto Nazionale dei Tumori, Roma, Italy
Background: Allogeneic hematopoietic stem cell transplantation (HSCT) has been considered for decades the only curative approach for patients with chronic myeloid leukemia (CML). In the tyrosine kinase inhibitors (TKIs) era, HSCT for CML has been reserved only to patients not achieving a cytogenetic remission or showing progressive disease after multiple TKI treatment lines. However, a progressive improvement in the long-term survival has been obtained in the overall HSCT population. The present study aimed at evaluating whether in CML patients transplanted at our Center over a long time period - from 1983 to 2018 - the outcome improved over time.
Methods: 136 consecutive patients who underwent a transplant between 1983 and 1999 were compared to 43 patients who received the transplant between 2000 and 2018. Overall survival (OS), leukemia-free survival (LFS) and graft-leukemia-free survival (GLFS) were estimated using the Kaplan-Meier method and the log-rank test was used to compare risk factors categories.
Results: Of the 179 patients [median age 35 years (range7-66)], 148 (82.7%) were in 1st or 2nd chronic phase, 25 (13.9%) in accelerated phase and six (3.4%) in blast crisis. Matched related donors and alternative donors (matched unrelated donors, cord blood or mismatched related donors) were used in 156 and 23 cases, respectively. As stem cell source, bone marrow was used in 142 patients, peripheral blood in 33 and umbilical cord blood in 4. TBI-based conditioning regimens were used in 89 patients, while in the other 90 cases irradiation-free conditioning regimens were used.
Both in univariate and multivariate analysis, irradiation-free conditioning regimens (HR 1.8; 95%CI 1.1-3.0, p=.0014) and transplants performed in 1st chronic phase (accelerate phase HR 2.1; 95%CI 1.2-3.8, p=.008 - 2nd chronic phase HR 4.9; 95%CI 2.3-10.3, p=.0001 - blast crisis HR 2.5; 95%CI 1.0-6.4, p< .05) were associated with a better OS. Patients transplanted before 2000 had a worse OS (HR 6.5; 95%CI 2.7-15.5, p < .0001) and DFS (HR 2.2; 95%CI 1.0-4.8, p=.045). A trend for a worse GLFS was observed in univariate analysis (HR 1.6; 95%CI 1.0-2.7, p=0.05), in the first period of observation.
Conclusions: Our single center experience confirms that higher OS, DFS and GLFS are observed in CML patients allografted in more recent years. Improvement of conditioning regimens, use of TBI-free conditioning regimens and supportive therapy, have presumably contributed to these results, together with the more recent strategy of close monitoring of minimal residual disease, and prompt use of TKI or donor lymphocyte infusion in case of relapse. HSCT is nowadays a safer therapeutic procedure in CML patients that should be considered timely in TKI-resistant patients to avoid progression into a more advanced disease phase.
Disclosure: The authors declare no conflict of interest.
P093 Reduced-intensity transplantation (RIT) in patients with high-risk or advanced chronic lymphocytic leukemia in last 5 years: Improvement of transplant outcomes - single centre experience
Michal Karas1, Katerina Steinerova1, Marcela Hrabetova1, Daniel Lysak1, Jiri Sramek1, Alexandra Jungova1, Pavel Jindra1
1 University Hospital Pilsen, Pilsen, Czech Republic
Background: Allogeneic hematopoietic stem cell transplantation is the only documented curative treatment of chronic lymphocytic leukemia (CLL) however with reported higher transplant-related morbidity and mortality. New targeted drugs dramatically improved the results of high-risk CLL treatment, leading to a decrease in the number of CLL transplanted patients (pts). In recent years outcome of RIT has also improved, but actual published results in CLL patients are limited. To evaluate the current results of RIT for CLL we retrospectively analysed the results of pts with CLL transplanted in our centre during last 5 years and we also tried to compare these results with our historical results and published EBMT results in period 2000-2010 (van Gelder, 2017).
Methods: From 6/2013 to 6/2018 20 consecutive pts with median of age 61 years (range: 36-68 years) with high-risk or advanced CLL (17p-/p53 mutation, chemoresistant CLL including 3 pts resistant to BCRi, relapse ≤ 24 moths, ≥ 3 treatment lines) underwent RIT (25% HLA identical related, 60% HLA matched unrelated, 25% HLA mismatched unrelated). HCT-CI ≥ 3 was in 20% of pts. Source of stem cells was peripheral blood in 80% and bone marrow in 20% of pts. The median of infused CD 34+ cells was 5,4x10^6/kg. The conditioning regimen consisted of fludarabine and melphalan (+ATG in unrelated donor). GVHD prophylaxis were cyclosporine and methotrexate.
Results: All pts engrafted. None of 3 pts in CR before RIT progressed at day +30 after RIT and among 17 pts beyond CR before RIT all of them achieved at least PR at day +30 after RIT. 13 pts (65%) developed acute GVHD (2 pts grade III-IV) and among 19 evaluable pts 10 (53%) of them developed chronic GVHD (6 mild, 2 moderate, 2 severe). With median follow-up 50 months (range 6-63 months) 15 pts (75%) are alive in CR. 3 pts (15%) relapsed or progressed 5, 19 and 21 months after RIT and 2 of them died. Last relapsed patient achieved next CR after ibrutinib. 3 pts (15%) died due to NRM. NRM till day +100 after RIT was 5%. The estimated probabilities of 2-years CGRFS, PFS and OS are 55%, 73% and 83%.
Conclusions: In spite of relatively small number of evaluated pts and retrospective type of analysis our data show that RIT in pts with high-risk or advanced CLL has achieved promising results (2- and 5- years PFS and OS 73% and 55% resp. 83 and 57%) in recent years and these results are better than outcomes of our historical patient cohort from period 2010-2012 (2- and 5-years PFS 41% and 26% resp. OS 56% and 35%, p=0.009) or EBMT published data of pts transplanted for CLL in period 2000-2010 (2- and 5-years PFS 46% and 35% resp. OS 62% and 45%). Current results of transplantation should be taken into account in our future decision-making process on indications for transplantation in pts with high-risk CLL, of course also in the context of new or updated results of targeted CLL treatment and its complications.
Disclosure: No conflict of interest and funding
Abstract already published.
P095 Childhood chronic myeloid leukemia in Singapore: Is there a role for hematopoietic stem cell transplantation in the TKI era?
Ah Moy Tan1, Mya Soe Nwe1, Vijayakumari K1, Met Yoke Chan1, Vinod Gunasekaran2, Prasad Iyer1, Poh Lin Tan2
1 KK Women's and Children's Hospital, Singapore, Singapore, 2 National University Hospital, Singapore, Singapore
Background: Chronic Myeloid Leukemia (CML) in children is rare. It constitutes < 1% of all paediatric leukemia's. The availability of Tyrosine Kinase Inhibitors (TKI) from the early 2000's has revolutionized the care as well as quality of life for children with CML. TKI became available for children in Singapore from 2004. The role of upfront HSCT for CML in the TKI-era is controversial.
Methods: Retrospective data and treatment outcomes were collected from the Singapore Childhood Cancer Registry (SCCR). Most children with cancer in Singapore receive therapy at one of the two public paediatric cancer centers (KKH or NUH). A total of thirty two cases were diagnosed with CML and received treatment in either of these centers over a twenty year period (1997-2016).
Results: The age at diagnosis of the thirty two children ranged from 4 to 17 years (median 12.5years). Six patients in the pre-TKI era were treated with an upfront HSCT. The remainder twenty six patients were initially started on a TKI. Of these 12/26 (46%) had a HSCT at a median period of 22.5 months from diagnosis (range 5-43 months). The reason for HSCT in ten out of the twelve children was due to high risk features i.e. accelerated/blastic phase/ no CCR/no CMR. The remaining two patients had a HSCT due to parent and patient preference for attempt at upfront cure rather than the use of life-long and expensive TKI therapy. Non-compliance to TKI therapy was a major finding in our teenage cohort.
Eleven of the eighteen transplants used a matched sibling donor. Three patients had cord blood as their stem cell source. One patient had a single antigen mismatched related donor and three patients had a mismatched unrelated donor for their HSCT.
All patients except one had myeloablative conditioning with Busulfan and Cyclophosphamide. ATG was added according to physician preference. One patient had Cy/TBI conditioning because of pre-transplant lymphoid blast crisis. Anti GvHD medications included cyclosporine/methotrexate or tacrolimus and methylprednisolone in the cord transplant patients.
Six of the eighteen (33%) patients who had a HSCT died. Four died due to treatment related mortality (2 infections, 1 Acute GvHD and 1 pulmonary fibrosis). One patient died due to an early relapse and one had a late relapse related mortality. For the pre-TKI era, HSCT related 5 and 10 year OS was 83% and 67% respectively. Post-TKI era 5 and 10 year OS was 75%. For the entire cohort, the 10 year OS was 70%.
Conclusions: The post-TKI era transplant outcomes from our two centers is comparable to leading centers in the world. Outcomes for patients with mismatched unrelated donors was poor in our cohort. We recommend a haploidentical related donor transplant or an unrelated cord blood stem cell source for patients when a matched sibling or unrelated donor is not available.
Clinical Trial Registry: NA
Disclosure: We have nothing to disclose.
P096 Fludarabine, busulfan, and thiotepa may be a promising conditioning regimen for myelofibrosis patients undergoing allogeneic stem cell transplantation
Roni Shouval1, Yakov Vega1, Joshua A Fein1, Ivetta Danylesko1, Noga Shem Tov1, Ronit Yerushalmi1, Arnon Nagler1, Avichai Shimoni1
1 Chaim Sheba Medical Center, Tel Aviv University, Hematology and Bone Marrow Transplantation, Ramat Gan, Israel
Background: Allogeneic stem-cell transplantation (SCT) is a curative therapy for patients with myelofibrosis. However, recurrent disease and non-relapse mortality (NRM) are frequent causes of treatment failure. The optimal conditioning regimen for SCT in this disease has not been defined.
Methods: We retrospectively analyzed transplantation outcomes of all adult patients given SCT for myelofibrosis between 2003 and 2018 at a single large academic medical center. Patients (n=59) were treated with several conditioning regimens that were grouped according to conditioning intensity. Myeloablative conditioning (MAC) included busulfan 12.8 mg/kg and cyclophosphamide 120 mg/kg (BuCy, n=10), fludarabine and busulfan 12.8 mg/kg (Flu/Bu4, n=9) and fludarabine and treosulfan 30-36 g/m2 (Flu/Treo, n=6). Reduced-intensity conditioning included fludarabine and busulfan 6.4-8.0 mg/kg (Flu/Bu2, n=22). More recently we adopted the TBF regimen including fludarabine, busulfan 6.4-9.6 mg/kg and thiotepa 5-10 mg/m2 (n=12). All patients were also given anti-thymocyte globulin during conditioning, irrespective of donor source.
Results: The median age was 59 years (interquartile range [IQR] 52-63). The majority of patients had documented splenomegaly (81%) and were not previously exposed to ruxolitinib (71%). Donor type was an HLA-matched sibling (41%), 10/10 (51%) or 9/10 (8%) matched unrelated donor. The DIPPS+ score distribution was intermediate-1 (16%), intermediate-2 (45%), or high (n=39%). The median follow-up was 3.2 years (IQR 1.7-5.5). At 3 years the probability for overall survival (OS), NRM, and relapse were 56% [95%CI: 42-70], 32.9% [19.8-46.1] and 21.0% [10.4-31.6]), respectively. In a univariate analysis, conditioning type was strongly associated with OS; at 1-year, the probability of OS was highest with TBF (92% [77-100]) compared with Bu/Cy (80% [59-100]), FB4 (68% [51-91%]), Flu/Treo (33% [11-100]), and FB2 (68% [51-91]), P=0.001. TBF benefit was maintained in a multivariable Cox model when compared to MAC (hazard ratio [HR] 0.10 [0.01-0.93], P=0.043). Relapse rates at 1-year were lowest with TBF (8% [1-54], P=0.33) with a trend to a lower risk in the multivariable analysis (HR 0.14 [0.01-1.41], P=0.096). In a univariate and multivariable analysis, NRM risk was not increased with TBF (P=0.234 and P=0.642, respectively). Other variables associated with inferior 1-year OS included hypoalbuminemia at SCT (p=0.05), a high DIPSS+ score (p=0.01), and an HLA mismatched unrelated donors (p=0.001). Age, the degree of splenomegaly and prior ruxolitinib were not significant prognostic factors.
Conclusions: Outcomes following Allogeneic SCT are strongly dependent on the conditioning regimen. TBF may be an ideal regimen for myelofibrosis patients, providing promising rates of survival and disease control, without excessive NRM. This regimen should be further explored in prospective comparative studies.
Disclosure: Nothing to declare
P097 Outcome of patients with chronic myeloid leukemia transplanted with HLA-identical sibling donor and partial T-cell depletion. a single center experience with a very long follow-up
Stavroula Masouridi Levrat1, Sarah Morin1, Federica Giannotti1, Carole Dantin1, Amandine Pradier1, Thien-An Tran1, Thomas Longval1, Maria Anastasiou1, Laura Bounaix1, Caroline Stephan1, Olga Tsopra, Yan Beauverd1, Mitja Nabergoj1, Carmen de Ramon Ortiz1, Anne-Claire Mamez1, Yves Chalandon1
1 Geneva University Hospitals, Geneva, Switzerland
Background: Since the success of tyrosine kinase inhibitors (TKIs), transplant-related mortality is considered too high to justify allogeneic hematopoietic stem cell transplantation (alloHSCT) as first-line treatment for chronic myeloid leukemia (CML) patients in chronic phase (CP). AlloHSCT is currently considered for patients failing to at least 2 TKIs or with disease in advanced phase. Nevertheless, the optimal timing for transplant referral is still not well defined.
Methods: We performed a retrospective analysis on 23 consecutive patients with CML in CP receiving first transplants from an HLA-identical sibling donor with partially T-cell depleted grafts from 1998 to 2016 at our center. Partial T-cell depletion (pTD) consisted of in vitro alemtuzumab incubation of a part of the graft for infusion at day 0 while the rest, containing 100x106 CD3+ cells/kg was given as a T-cell add-back at day 1. Donor lymphocyte infusions (DLIs) were provided, in the absence of GvHD, in case of disease relapse or mixed chimerism. Molecular monitoring was performed by 3-month BCR-ABL1 RT-qPCR testing in peripheral blood during at least a 5-year period after HSCT. Thereafter, 3-month testing schedule was maintained where possible, or followed by a 6-month one. Kaplan-Meier method was employed to determine the probability of overall survival (OS) and leukemia free survival (LFS) since alloHSCT.
Results: Median age at HSCT was 36 years (range, 18-58). All patients were in first CP but one who was in second CP. Twelve patients were TKI-naïve at HSCT (1998-2001 period), 4 patients had presented suboptimal response or/and intolerance to imatinib (2002-2004 period), while the last seven patients had presented suboptimal response or/and intolerance to imatinib, dasatinib and nilotinib (2005-2016 period). The time interval from diagnosis to transplant was < 12 months in 11/23 (48%) patients. 15 (65%) patients had an EBMT risk score of 0-2, while 8 (35%) patients of 3-4. The conditioning regimen was myeloablative for all but one patients. The stem cell source was PBSC for 22 patients and bone marrow for one. All patients engrafted. 14 patients presented molecular relapse and one patient hematological relapse with a median interval from transplant to relapse of 9 months (range, 5-70). 17 patients received DLIs (15 for relapse and 2 for mixed chimerism), while 3 patients in relapse also received TKI. Without prior administration of DLI, 3(13%) patients presented grade II aGvHD and 2 patients moderate cGvHD. After DLI, aGvHD occurred in 3 and cGvHD in 4 patients. One patient died of disease progression 3 years after HSCT and one of myocardial infarction 19 years after HSCT. With a median follow-up of 14.4 years (range 2.3-20.6), 15-year OS and LFS were 95%. At the time of the analysis 21/23 patients were alive and in major molecular response.
Conclusions: These results of excellent long-term survival and no transplant-related mortality suggest that pTCD improves the outcome of CP-CML patients transplanted from an identical sibling donor and they can be useful for deciding risk-adapted strategies. We believe that pTCD could allow earlier transplant referral of patients failing TKIs and having an identical sibling donor.
Disclosure: Nothing to declare
P098 Single tertiary centre experience in allogeneic haematopoietic stem cell transplantation (allo-HSCT) for primary and secondary myelofibrosis (MF)
Anna Tsoulkani1, Sarah Louise Wharin1, Mamta Garg2, Katherine Hodgson1, Ann E. Hunter1, Alexander Murray Martin1
1 University Hospitals of Leicester, Leicester, United Kingdom, 2 University Hospitals of Leicester, Haematology, Leicester, United Kingdom
Background: Myelofibrosis (MF) is a category of myeloproliferative neoplasms (MPN) according to the WHO 2016 classification which is divided into primary MF (PMF) and secondary MF incorporating post-essential thrombocythaemia (post-ET) and post-polycythaemia vera (post-PV) MF. Secondary MF occurs in up to 10% and 20% of patients diagnosed with ET and PV respectively. Overall survival in overt PMF across all risk groups is variable at 3-7 years. The only curative option for fit patients is allo-HSCT. Novel therapy is emerging but current recommendation is that eligible patients with life expectancy less than 5 years should be considered for allografting.
Methods: We retrospectively looked at the clinical features and outcomes of all allo-HSCT for MF performed in our centre since 2010.
Results: 12 patients (10 male, 2 female) aged between 29-68 years old (median age 60) with intermediate-2 or high-risk MF as per the International Prognostic Scoring System (IPSS) or Dynamic IPPS (DIPPS) were transplanted in our centre since 2010. 6 of them (50%) were diagnosed with PMF and the remaining 50% with secondary MF; 4 post-ET and 2 post-PV MF. 2/12 of our patient group received a sibling allograft and 10/12 a matched unrelated donor allograft (70% received a 10/10 Human Leukocyte Antigen (HLA)-matched transplant, 20% a 9/10 HLA-matched and 10% a 8/10 HLA-matched graft). All patients received a reduced intensity conditioning (RIC); 3/12 patients with Fludarabine/ Melphalan/ Campath (FMC), 8/12 Fludarabine/ Busulphan/ ATG (FBATG) and 1 Fludarabine/ Ara-C/ Campath (FLAG/ Campath); all received peripheral blood as source of HSC. Engraftment occurred between day 13-48, with a median of D+17. One late graft rejection occurred. All patients were alive at D+100. 9 patients are currently alive; Overall survival (OS) is 75%. Transplant related mortality (TRM) was 16.6% at 1 year, 25% at 3 years. 1 patient died of graft versus host disease (GvHD) and 2 patients of septicaemia leading to multi-organ failure. Acute GvHD grade II skin occurred in 5 patients, grade III and above in 2 patients. 5 patients have limited chronic GvHD. 2/12 patients received Donor Lymphocyte Infusion (DLI) for mixed chimerism (one of which had 2nd graft failure). Out of these 2 patients 1 developed acute grade 4 GvHD and died.
Response rate: 6/9 alive patients i.e 66.6% exhibit no fibrosis in trephine biopsies, 1/9 alive patients had residual fibrosis but 100% donor chimerism, 1/9 alive patients had residual fibrosis with mixed donor chimerism, other patient non-assessable.
Conclusions: Allo-HSCT remains the only potentially curable option for myelofibrosis. In our centre which serves 1.1 million population, with 12 new cases per year, 12 patients were transplanted since 2010. Our data suggest that close collaboration between MPN-treating haematologists and transplant physicians is required so that all suitable patients have a transplant assessment early in their disease course. Novel molecular prognostic systems are likely to identify those best placed to benefit in future but this series currently supports allo-HSCT survival and cure.
Clinical Trial Registry: N/A
Disclosure: Nothing to declare
P099 Hematopoietic cell transplantation in myelofibrosis patients: A single centre experience
Annalisa Natale1, Stella Santarone1, Gabriele Papalinetti1, Paola Olioso1, Mauro Di Ianni1, Paolo Di Bartolomeo1
1 Ospedale Civile Dipartimento di Ematologia, Medicina Trasfusionale e Biotecnologie, Pescara, Italy
Background: Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy available for myelofibrosis (MF) patients. The aim of this study is to evaluate the outcome of MF patients after HCT performed in our Centre.
Methods: We retrospectively analyzed 21 consecutive MF patients transplanted in our Center between November 1986 and January 2018.
Results: Median age at time of HCT was 53 years (range, 33-67). 15 patients were male. 13 patients had primary MF, 6 secondary MF (6 post Essential Thrombocytemia, 2 post Polycythemia Vera). Median time from diagnosis to HCT was 413 days (range, 105-4624). Dynamic international prognostic scoring system (DIPSS) score at the time of HCT was intermediate-2 or high risk in 20 patients (95%), intermedate-1 in 1 patient. Molecular evaluation was available in 14 out of 21: JAK2 V617F mutation was detectable in 8 patients, MPL-W515K in 1 patient, CARL in 1 patient. 4 patients were “triple negative” for driver mutations. Cytogenetics information was available for 6 out of 21; among which 3 patients had complex karyotype, 1 trisomy 8 and 1 trisomy 9. 3 patients underwent splenectomy before HCT. Ruxolitinib was administered in 4 patients before HCT. 10 (48%) patients received stem cells from an HLA identical sibling, 9 (42%) from a matched unrelated donor and 2 (10%) from an haploidentical sibling. Graft source was bone marrow in 7 patients (34%) and peripheral blood in 14 (66%). Conditioning was myeloablative in 16 patients (76%), reduced intensity in 5 (24%). All patients engrafted. Acute graft versus host disease was absent in 12 patients (57%), grade I-II in 7 (34%), grade III-IV in 2 (9%). In 18 evaluable patients chronic graft versus host disease was limited in 3 (17%), extensive in 4 (22%) and absent in 11 (61%). Transplant-related mortality at 180 days was 24%. Main causes of death were: acute GvHD in 2 patients, chronic GvHD in 1, pancreatitis in 1, pulmonary aspergillosis in 1. Relapse occurred in 7 patients and was the main cause of death in 4 of them. Notably, 2 patients experienced late relapse after 6.6 and 17.6 years after HCT. Both of them are living while receiving Ruxolitinib therapy. After a median follow up of 581 days (range, 38-11660), 10 out of 21 patients are alive. 7 of them (33%) are disease-free and 3 are living. The Kaplan-Meyer overall survival and disease-free survival at 10 years was 40% and 35%, respectively.
Conclusions: Our experience confirms that HCT is a valid option to achieve cure in one third of MF patients. Two patients experienced very late (> 5 years) recurrence of MF. The rarity of this condition limits the amount of data and cases available for evaluation and study. Life-long follow-up of all MF transplanted patients is warranted to better understand this rare event.
Disclosure: Nothing to declare
P100 Allogeneic stem cell transplantation results of patients with myelofibrosis:Single center experience
Elif Birtas Atesoglu1, Meral Sengezer1, İmran Dora1, Cigdem Eren1, Suat Celik1, Demet Cekdemir1, Zafer Gulbas1
1 Anadolu Medical Center, Hematology, Kocaeli, Turkey
Background: With existing treatment strategies high risk myelofibrosis patients have short survival rates. In fact allogeneic stem cell transplantation is the only treatment modality which has a curative potential. Therefore, we decided to analyze the results of patients who had undergone allogeneic stem cell transplantation with diagnosis of myelofibrosis in our center.
Methods: We collected and analyzed the data of myelofibrosis patients who had undergone allogeneic stem cell transplantation with a conditioning regimen consisting of Fludarabine-Busulfan-ATG between March 2015 and May 2018.
|Age, median (range)||59(42-65)|
|Donor type of Allogeneic Stem Cell Transplantation HLA-matched sibling Matched Unrelated Haploidentical||7 5 1|
|Neutrophil engraftment time, day;median(range)||21(14-26)|
|Platelet engraftment time, day;median(range)||21(14-37)|
|100 day mortality||2(15,4%)|
|1 year OS||57%|
[ [P100 Table] 1 . Table1: Characteristics of the patients]
[ [P100 Image] 1 . Figure 1:Overall Survival]
Results: There were 13 patients. The characteristics of the patients are summarized in Table 1. While, 7 out of 13 patients were transplanted from HLA-matched siblings, in 5 of the patients the donors were matched unrelated and 1 patient were transplanted from a haploidentical donor. 100 day mortality rate was 15,4% and 1 year Overall Survival was 57% (Table 1 and Fıgure 1).
Conclusions: Allogeneic stem cell transplantation with a conditioning regimen of Fludarabine-Busulfan-ATG has an acceptable toxicity profile and survival rate in myelofibrosis patients and should be considered in high risk myelofibrosis patients.
Disclosure: Nothing to declare
P101 Allogeneic haematopoietic stem cell transplantation in patient with primary myelofibrosis and splanchnic vein thrombosis
Maria Barabanshikova1, Elena Morozova1, Julia Vlasova1, Ivan Moiseev1, Olga Pirogova1, Vadim Baikov1, Alexander Shvetsov1, Alexander Smirnov1, Elena Darskaya1, Boris Afanasyev1
1 Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russian Federation
Background: Primary myelofibrosis (PMF) is BCR-ABL-negative myeloproliferative neoplasm with progressive clinical course and usually poor prognosis. Allogeneic stem cell transplantation (alloHSCT) is currently the only treatment option with curative potential in patients with PMF. Thrombotic episodes are frequent events in MF, especially thrombosis of splanchnic veins. Usually it leads to portal hypertension, esophageal variceal bleeding (EVB) and may complicate alloHSCT. To our knowledge there are no data about the feasibility of alloHSCT in myelofibrosis complicated by splanchnic vein thrombosis. Here we report the outcome of alloHSCT in PMF patient with subacute Budd-Chiari syndrome and portal vein thrombosis.
Methods: А 37-years old female was diagnosed with JAK2V617F-positive PMF, 46XX, IPSS low risk, DIPSSplus intermediate -2 risk, subacute Budd-Chiari syndrome and portal vein thrombosis four years before alloHSCT. To reduce the splenomegaly and constitutional symptoms we performed pre-transplant ruxolitinib therapy 30 mg daily. After three months of therapy the patient achieved clinical improvement (ELN criteria). Contrast-enhanced computer tomography and magnetic resonance imaging showed enlarged intrahepatic collateral vessels and signs of portal vein thrombosis with cavernous transformation and multiple dilated collateral veins. Gastroscopy documented enlarged esophageal veins. Allogeneic stem cell transplantation was performed from 10/10 -HLA matched unrelated donor with peripheral stem cells (6.1 x 109 СD34+ cells/kg). Conditioning regimen consisted of fludarabine (180 mg/m2), busulfan (10 mg/kg p.o.). Post-transplant cyclophosphamide was administered at 100 mg/kg at day +3, +4, and ruxolitinib 15 mg was used from D+5 till D+100 as graft versus host disease prophylaxis.
Results: Starting D+1 the patient experienced eight episodes of EBV some of them with severe blood loss. To treat the bleeding episodes Blackmore tube was placed six times with temporary effect. To place Blackmore tube the patient was two times intubated and required mechanical ventilation. At D+18 leukocyte and neutrophil engraftment, full donor chimerism and molecular remission were achieved. Platelet engraftment was documented only at D+42 and poor graft function was present due to cytomegalovirus reactivation (D+41) and parvovirus B19 reactivation (D+62). EVB was stopped at D+95 only after two esophageal veins ligations, and two procedures of gastric veins sclerotherapy. Soon (D+111) the patient achieved complete platelet recovery (more than 50x109/l) and became red blood cells transfusion independent.
At day + 180 complete remission was confirmed by splenomegaly resolution, regression of bone marrow fibrosis, full donor chimerism, JAK2V617F-negative molecular status. CBC showed Hb 130 g/l, platelets 73x109/l, leucocytes 3,8x109/l. Ultrasound examination after transplant documented portal vein thrombosis recanalization. At day + 180 she developed mild (NIH) chronic graft versus host disease with eyes and mouth involvement, which was managed with topical steroids. At D+958 after transplant the patient is alive in complete remission and has no recurrent bleedings.
Conclusions: Splanchnic vein thrombosis can significantly complicate the course of alloHSCT in PMF. Easy access to surgical, intensive care unit and endoscopic teams is required to make alloHSCT more feasible in this group of patients.
Disclosure: authors declare no conflict of interest
P102 Treosulfan-based conditioning regimens for allogeneic haematopoietic stem cell transplantation in paediatric non-malignant diseases
Samar Elbahy1,2, Denise Bonney1, Helen Campbell1, Tasneem Khaled1, David Deambrosis1, Robert Wynn1
1 Royal Manchester Children's Hospital, Manchester, United Kingdom, 2 Benha University, Benha, Egypt
Background: Haematopoietic stem cell transplantation(HSCT) represents the definitive treatment for many non-malignant diseases. Treosulfan is considered a safe and effective conditioning drug compared to other conventional myeloablative conditioning(MAC) regimens, especially in patients with comorbidities.
Methods: We present the results of 94 transplants in 92 Patients(62% males and 38% females) transplanted for various non-malignant conditions at a median age of four years(Range, 1 month-18 years).
All patients received Treosulfan-based MAC regimens, Treosulfan(Total dose, 36-42gms/m2) was given in combination with different conditioning drugs. The most commonly used regimen was Treosulfan, Fludarabine(150mgs/m2) and Thiotepa(10mgs/kg) referred to as FTT that was used in 59%(n=55). Serotherapy was given in 93% of patients(n=87), as either Alemtuzumab or Anti-thymocyte globulin in 82%(n=77) and 11%(n=10), respectively. post-transplant Graft-versus-Host disease(GVHD) prophylaxis was given in all patients, based mostly on ciclosporin.
46 patients(49%) received the transplant from identical-related donors, 46 patients(49%) received the transplant from matched-unrelated donors, and two patients(2%) had haploidentical transplants. 90% of the patients(n=85) were fully HLA-matched. All stem cell sources were used as bone marrow in 59%(n=55), peripheral blood stem cells in 33%(n=31), and umbilical cord blood in 8%(n=8).
This Treosulfan-based conditioning was given as the 1st transplant in 92%(n=85), and as the 2nd transplant after the failure of a first procedure in 8%(n=9). Two patients received Treosulfan-based conditioned transplant twice.
Results: Neutrophil engraftment and platelet engraftment occurred at a median of 13 days and 18 days respectively. Chimerism was full donor in 55%(n=52), high donor in 18%(n=17), and mixed donor in 9%(n=8).
GVHD developed in 43% of patients(n=40), with acute GVHD grade I/II and grade III/IV developed in 29%(n=27) and 2%(n=2), respectively. Chronic GVHD grade I/II and grade III/IV developed in 13%(n=12) and 2%(n=2), respectively.
All chronic GVHD were mild, limited, non-extensive, and resolved completely. None of our patients had persistent GVHD necessitating long-term systemic immunosuppression.
Mild VOD occurred in 13%(n=12), and severe VOD occurred in 2%(n=2). One of them died but was believed to be related to the underlying disease (Wolman Syndrome).
Viral reactivation occurred in 55% of patients(n=52), with CMV, EBV, and Adenovirus reactivation was found in 34%, 21%, and 14%, respectively. Five patients had invasive adenoviraemia that contributed to death in two of them.
Primary graft failure happened in two patients(2%) due to adenoviraemia. Seven patients(7%) had secondary graft failure with autologous reconstitution. Graft failure was significantly lower (P0.045) in the FTT group than other conditioning groups.
At a median follow-up of 35 months (Range, two-174 months), eleven patients(11.9%) died, with Overall survival of 88.1%, and event-free survival of 80.9%. Five patients died due to complications related to their original disease, while six patients died due to transplant-related causes (transplant-related mortality 6.5%).
Immune reconstitution in alive patients was achieved at a median of eight months. This time was significantly longer (P0.034) in FTT group.
Conclusions: This study demonstrates that Treosulfan is a safe and effective conditioning drug that can achieve engraftment, with low rates of graft failure, transplant-related mortality and morbidity, even if it is used twice in the same patient.
Disclosure: Nothing to declare
Abstract already published.
Abstract already published.
Abstract already published.
P106 Busulfan, etoposide, cytarabine and melphalan (BUEAM) as a conditioning regimen for autologous stem cell transplantation in patients with non-hodgkin lymphoma (NHL)
Jae-Cheol Jo1, Jin-Seok Kim2, Je-Hwan Lee3, Jung-Hee Lee3, Seong Nam Im4, Won-Sik Lee5, Sang-Min Lee5, Sung-Soo Yoon6, In-Ho Kim6, Yun Suk Choi1, Seong Hwa Bae7
1 Ulsan University Hospital, University of Ulsan College of Medicine, Hematology and Oncology, Ulsan, Korea, Republic of, 2 Severance Hospital, Yeonsei University College of Medicine2, Seoul, Korea, Republic of, 3 Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, Republic of, 4 Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea, Republic of, 5 Busan Paik Hospital, Inje University College of Medicine, Busan, Korea, Republic of, 6 Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea, Republic of, 7 Daegu Catholic University Medical Center, Daegu Catholic University College of Medicine, Daegu, Korea, Republic of
Background: High-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) is the treatment of choice for the patients with relapsed or high risk NHL. Although the high-dose conditioning regimens commonly used in patients with non-Hodgkin lymphoma (NHL) are BEAM (BCNU, etoposide, cytarabine, and melphalan), BEAC (BCNU, etoposide, cytarabine, and cyclophosphamide), survival of patients with NHL received above high-dose chemotherapy followed by ASCT was still unsatisfactory.
Methods: We prospectively evaluated the efficacy and toxicity of busulfan, etoposide, cytarabine and melphalan (BuEAM) including iv busulfan instead of BCNU of standard BEAM as a conditioning for ASCT in patients with NHL. The high-dose chemotherapy consisted of Bu (3.2 mg/kg i.v. q.d. from day -6 to day -5), E (200 mg/m2 i.v. b.i.d. on day -4 and day -3) A (1 g/m2 i.v. q.d. on day -4 and day -3) and M (140 mg/m2 i.v. q.d. on day -2) at 7 centers in Korea.
Results: Two hundred five patients were enrolled onto the study. Main subgroup was diffuse large B cell lymphoma (n=104, 50.7%), T cell lymphomas (n=59, 29.8%), and NK/T cell lymphoma (n=22, 10.7%). Upfront ASCT was performed in 160 patients (78.0%), and salvage ASCT in 45 patients (22.0%). The disease status of the patients before HDT/ASCT consisted of 133 patients (64.8%) with complete response and 72 patients (35.2%) with partial response. Treatment related toxicities included nausea in 149 patients (72.7%), diarrhea in 127 patients (62.0%), anorexia in 107 patients (52.2%) and stomatitis in 97 patients (47.3%), which were grade I or II in the majority of cases. The common grade III toxicities were stomatitis (6.9%), diarrhea (5.9%), and anorexia (5.4%). There were no VOD, and transplant-related mortality occurred in 4 patients (1.95 %), due to infection. One hundred fifty three patients (74.6%) achieved a complete response and 13 patients (6.3%) after ASCT, while 28 patients (13.7%) showed progressive disease. At a median follow-up duration of 38.6 months, the estimated 3-year overall survival and progression free survival for all patients was 74.5% and 56.6%, respectively.
Conclusions: The conditioning regimen of BuEAM for ASCT was well tolerated and seemed to be effective in patients with relapsed or high risk NHL.
Disclosure: None of declare
P107 Post-transplant cyclophosphamide combined with ATG as GVHD prophylaxis for allogeneic HCT in high risk AML and MDS
Wael Alanazi1, Jeffrey H Lipton1, Dennis D Kim1, Auro Viswabandya1, Santhosh Thyagu1, Rajat Kumar1, Wilson Lam1, Arjun D. Law1, Fotios V Michelis1
1 Hans Messner Allogeneic Transplant Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada
Background: Allogeneic hematopoietic cell transplantation (HCT) is potentially curative for high risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), however both GvHD and disease relapse remain major challenges. We recently introduced a combination of post-transplant cyclophosphamide (PTCy) and ATG (4.5 mg/kg) as graft-versus-host disease (GvHD) prophylaxis. The purpose of our study was to compare outcomes between PTCy/ATG and other GvHD prophylaxis regimens for high risk AML and MDS.
Methods: We retrospectively investigated outcomes of 159 patients that underwent allogeneic HCT between January 2014 and July 2017 for high risk AML (n=120, 75%) and MDS (n=39, 25%). GvHD prophylaxis regimens were compared for overall survival (OS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) in univariate and multivariable analysis. High risk AML was defined as secondary AML, therapy related AML, high risk cytogenetics (ELN criteria) in CR1, good/intermediate cytogenetic risk AML in CR2 and primary induction failure; high risk MDS was defined as high/very high risk WPSS score.
Results: Median age of patients was 56 years (range 22-73 years). Donors were matched related in 52 (33%) patients, matched unrelated in 89 (56%) patients and haploidentical in 18 (11%) patients. Graft source was peripheral blood stem cells in 158 patients (99%). Myeloablative conditioning was used in 54 patients (34%), reduced intensity regimens in 105 (66%) patients. PTCy combined with ATG was used in 69 (43%) patients, other GvHD prophylaxis regimens were used in 90 (57%) patients. Both donor and recipient were CMV negative in 18 (11%) patients.
Median follow-up of survivors was 29 months (range 14-56 months). Univariate analysis demonstrated OS of the entire cohort at 2 years was 49% (95%CI 41-57%), CIR at 2 years was 22% (95%CI 16-29%) and NRM at 2 years was 32% (95%CI 25-39%). Concerning GvHD prophylaxis regimen, 2-year OS for PTCy/ATG versus others was 46% (95%CI 33-58%) versus 51% (95%CI 40-61%) (p=0.87, Figure), 2-year CIR for PTCy/ATG versus other was 31% (95%CI 20-43%) versus 16% (95%CI 9-24%) (p=0.02) and 2-year NRM for PTCy versus other was 28% (95%CI 18-39%) versus 34% (95%CI 25-44%) (p=0.35). Grade II-IV acute GvHD was seen in 23% of PTCy/ATG patients versus 59% using other regimens (p< 0.0001). Chronic GvHD was observed in 20% of PTCy/ATG patients versus 42% using other regimens (p=0.004).
Multivariable analysis for OS confirmed that the GvHD prophylaxis regimen has no influence (p=0.19), while the predominant predictor of survival was age at HCT (HR 1.03, 95%CI 1.01-1.05, p=0.01). For CIR, the PTCy/ATG combination had no influence compared to other GvHD prophylaxis regimens (p=0.6), while RIC conditioning was the predominant predictor of relapse (HR 3.05 for RIC, 95%CI 1.26-7.37, p=0.01). For NRM, the ATG with PTCy combination demonstrated no significant difference (p=0.12), while age at HCT was the predominant predictor (HR=1.04, 95%CI 1.01-1.07, p=0.02).
Conclusions: The PTCy/ATG combination for GvHD prophylaxis has demonstrated on multivariable analysis similar OS, CIR and NRM with other previously used regimens at our center. A decrease in ATG dose may potentially decrease the relapse rate while retaining the advantage of decreased GvHD.
[ [P107 Image] 1 . Overall survival]
Disclosure: No disclosures
P108 Frequency and impact of early mixed chimerism after myloablative conditioning regimen with fludarabine and busulfan (FB4) and ATG for allogeneic transplantation in myeloid malignancies
Anna Grassi1, Chiara Pavoni1, Caterina Micò1, Alessandra Algarotti1, Maria Chiara Finazzi1, Marta Bellini1, Federico Lussana1, Federica Delaini1, Elena Oldani1, Anna Salvi1, Orietta Spinelli1, Alessandro Rambaldi1
1 ASST Papa Giovanni XXIII, Italy
Background: The combination of fludarabine with myeloablative doses of busulfan (FB4) represents a standard of care conditioning regimen before allogeneic transplantation in patients with myeloid malignancies (Giralt, S.: The Lancet Oncology 2015). FB4 has potent antileukemic activity and is associated with low transplant-related mortality and acute GvHD. However, early after transplantation (days 30-90), a proportion of patients may not convert to a full donor haemopoietic chimerism, particularly if anti-T lymphocyte globulin (ATG) is used as GvHD prophylaxis (Rambaldi A, et al.: The Lancet Oncology 2015)
Methods:We retrospective analyzed 104 patients who underwent an allogeneic stem cell transplantation after FB4 conditioning regimen at our hospital, from November 2007 to August 2018. The median age was 51 years (range 22-67) and diagnoses were AML 76%, MDS 18% CML 5% MFI 1%). The disease status at transplantation was: CR1 in 59%, CR2 in 5% and active disease in 36% of patients. The stem cell source was represented by PBSC in more than 95% of cases and anti-T lymphocyte globulin (ATG) was part of the conditioning regimen in more than 95% of cases at a dose of 5 mg/Kg. The donor was a HLA identical sibling (26%), a matched unrelated (65%) or mismatched (one allele or one antigen mismatched) unrelated, 9%. Hematopoietic chimerism was molecularly evaluated by Variable Number of Tandem Repeats (VNTR) on bone marrow (BM) mononuclear cells or peripheral blood (PB) T lymphocytes, purified by immunomagnetic positive selection (Miltenyi, Biotec). The analysis was performed at day 30, 60, 90, 180 and 360 after transplantation
Results: After 30, 60 and 90 days from transplantation, the proportion of patients with a full BM chimerism was 94%, 87% and 83%, respectively. At the same time points, the PB T cell chimerism was 47%, 65% and 69%. Before day 100, 10 patients required the infusion of DLI to treat a pending or overt hematologic relapse and 12 patients to convert the lymphoid chimerism from mixed (median 44%, range 0-76), to complete (successfully in 7 cases). After day 100, 13 additional patients required DLI to treat disease relapse or progression and 8 patients to improve the chimeric status or the immune reconstitution. At 5 years, the Overall Survival is 64%, with a relapse and non-relapse mortality of 21 % and 11%, respectively (Figure 1). By uni and multivariable analysis, AML diagnosis and a mixed BM chimerism before day 100 were associated with Relapse and Overall Survival while age > 50 was the only factor significantly associated with NRM. A mixed PB T-lymphoid chimerism before day 100 does not adversely impact on non-relapse mortality, cumulative incidence of relapse, leukemia-free and overall survival.
Conclusions: After FB4 and ATG, a progressive increase of PB lymphoid donor chimerism develops gradually after transplantation, in most of cases without the need of DLI. Early mixed lymphoid chimerism does not compromise the main long-term clinical outcomes and may at least partially explain the low non-relapse mortality. An incomplete BM chimerism within the first 3 months strongly correlates with early disease progression or relapse.
[ [P108 Image] 1 . Fig.1]
Disclosure: Nothing to declare
P109 Busulfan/sulfolane metabolic ratio on day three of conditioning may predict the event-free survival in children receiving busulfan based conditioning prior to allogeneic hematopoietic stem-cell transplantation
Chakradhara Rao S Uppugunduri1,2, Aziz Rezgui3, Patricia Huezo-Diaz Curtis1,2, Tiago Nava1,2, Simona Mlakar1,2, Yves Theoret3, Henrique Bittencourt3, Maja Krajinovic3, Marc Ansari1,2
1 University Hospitals of Geneva, Geneva, Switzerland, 2 CANSEARCH Research Laboratory, Faculty of Medicine, University of Geneva, Geneva, Switzerland, 3 Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Canada,
Background: Busulfan (Bu) is widely used as a component of myeloablative conditioning regimen before hematopoietic stem cell transplantation (HSCT) in children. Bu has a narrow cumulative exposure window. The relation of Bu exposure with toxicity is well established, but the link between the exposure and EFS is not clear due to conflicting reports especially in pediatric patients. Obtaining the ratio of Bu to its metabolite i.e. metabolic ratio (MR) may serve as an indicator of Bu GSH conjugating capacity of an individual, thus cumulative exposure of Bu for a particular day that could be used along with AUC as a marker to predict EFS. The present investigation is aimed at evaluating the utility of Bu MR to predict EFS in children undergoing allogeneic HSCT.
Methods: Two different cohorts with children receiving Bu in four times daily (QID, n=44) and once daily doses (QD, n=13) at St. Justine's Hospital, Montreal were studied. Bu and Su levels were measured on day 3 of the conditioning regimen at the end of infusion (dose 9 in QID or dose 3 in QD dosing). EFS was defined from the time of transplant until death, relapse, or rejection, whichever occurred first. A receiver-operator characteristic curve (ROC) for Bu MRs measured was plotted to show the trade-off in sensitivity vs. 1- specificity rates for EFS, as the cut-off of the test was shifted from low to high. Cutoff values were defined based on the Youden´s J statistic (i.e. sensitivity+specificty-1).
Results: Twenty-two males and 22 females aged from 0.1 to 19.9 years (mean±SD: 7.2 ± 5.7) from Bu QID cohort had the mean MR of 5.9 (SD: 3.2). A cut off value of 4.9 in MR was chosen in ROC analysis in this cohort, with better sensitivity (71 %) and specificity (70 %) for EFS prediction (p=0.01, AUC= 0.7 (95 % CI= 0.6-0.8). In QD cohort nine females, and four males aged between 0.4 and 15.8 years (6.7±5.1) had the mean MR of 29.3 (SD: 16.6). In ROC analysis, a cut off value of 25.06 was chosen with better sensitivity (100 %) and specificity (100 %) for EFS prediction (p=0.003; AUC=1.0).
Conclusions: The Bu MR on day 3 above 4.973 and 25.06 were associated with worse EFS in children undergoing HSCT and received Bu in QID and QD dosing schedules, respectively.
Clinical Trial Registry: NCT01257854
Disclosure: Nothing to declare
P110 Population pharmacokinetics of treosulfan in pediatric patients undergoing hematopoietic stem cell transplantation
Eileen van der Stoep1, Juliette Zwaveling1, Alice Bertaina2, Franco Locatelli2, Henk-Jan Guchelaar1, Arjan Lankester3, Dirk Jan Moes1
1 Leiden University Medical Center, Clinical Pharmacy and Toxicology, Leiden, Netherlands, 2 Bambino Gesù Childrens Hospital IRCCS, Rome, Italy, 3 Leiden University Medical Center, Leiden, Netherlands
Background: Treosulfan is an alkylating agent increasingly used prior to hematopoietic stem cell transplantation (HSCT). The main objective of this study was to develop a population pharmacokinetic model of treosulfan in pediatric HSCT recipients and to explore the effect of different covariates on treosulfan pharmacokinetics (PK). Also, a limited sampling model (LSM) was developed.
Methods: In this multicentre study, 91 patients, receiving a dose of 10, 12 or 14 g/m2 treosulfan a day, administered during 3 consecutive days, were enrolled. A population pharmacokinetic model was developed using nonlinear mixed effect modelling (NONMEM version 7.3.0, using PsN toolkit 4.7.0 and Piraña version 2.9.7 as modelling environment). Demographic factors, as well as laboratory parameters, were included as covariates.
Results: Treosulfan PK was best described by a two-compartment model. A bodyweight-based allometric model improved the model more than a model incorporating body surface area (BSA). Clearance (CL) and intercompartmental clearance parameters were 6.07 L/h/15.6kg (95%CI 5.46-6.68) and 2.15 L/h (95%CI 1.39-2.91). Typical volumes of distribution of the central and peripheral compartments were 8.00 L/15.6kg (95%CI 6.88-9.12) and 2.05 L (95%CI 1.52-2.58). A model-based dosing table based on bodyweight is created to achieve a target exposure of 1540 mg*hr/L (Table 1), which was the median exposure of our population. Estimated glomerular filtration rate (eGFR) was shown to be the only parameter that significantly reduced interpatient variability in CL from 36.5% to 34.8%. A limited sampling model with 3 samples (taken at 1.5, 4 and 7 hours after start of infusion) accurately estimated pharmacokinetic parameters of treosulfan.
Conclusions: To the best of our knowledge, this is the largest cohort of pediatric patients treated with treosulfan used for a population pharmacokinetic study. We developed a two-compartment model with weight and eGFR as covariates influencing treosulfan PK. Recently we showed a relationship between treosulfan exposure and early toxicity. Patients with an exposure >1650 mg*hr/L have an increased risk of developing grade 2 or higher mucositis and skin toxicity. Another study in 87 pediatric patients with thalassemia major reported an association between treosulfan clearance (< 7.97 L/h/m2) and poor overall survival. Our model, together with the limited sampling strategy, can be used to adjust the dose, prior to or during treosulfan administration. Ongoing studies conducted in different disease settings will determine if treosulfan exposure can influence patient outcome. Subsequently, the optimal target exposure can then be established.
|Weight (kg)||Treosulfan dose (mg) per day|
[ [P110 Table] 1 . Table 1: Recommended treosulfan dose for different weight categories]
Disclosure: This study was supported by a grant (no. 213) from the Dutch Foundation Kinderen Kankervrij (KiKa). An unrestricted research grant by Medac GmbH was provided to AL. All other authors declare no conflict of interest.
P111 Phase II study for safety and efficacy of BEB (bendamustine, etoposide, busulfan) conditioning regimen for ASCT in non-hodgkin lymphoma
1Pusan National University Hospital, Busan, Korea, Republic of
Background: Autologous stem cell transplant (ASCT) is an effective treatment method for non-Hodgkin lymphoma (NHL). Until recently, carmustine, etoposide, cytarabine and melphalan (BEAM) was the most commonly used conditioning regimen. Despite acceptable efficacy with BEAM, carmustine is associated with major pulmonary toxicity. For this reason, the aim of this study was to investigate the safety and efficacy of BEB conditioning regimen for ASCT in NHL.
Methods: We conducted a prospective, multicenter, phase II study for BEB conditioning regimen for ASCT in NHL patients. A total of 33 patients were enrolled from 3 centers. They underwent ASCT with BEB conditioning regimen (Busulfan 3.2mg/kg for 3days, Etoposide 400mg/m2 for 2days, Bendamustine 200mg/m2 for 2days) between 2016 and 2018.
[ [P111 Image] 1 . Two year progression-free survival and overall survival.]
Results: The median age was 52 years (range 21-66) and 16 patients (48.5%) were men. The most common type was diffuse large B cell lymphoma (n=23, 69.7%) and more than half of patients (n=19, 57.6%) were classified as IPI score 3 or 4. Eight patients (27.3%) had a history of relapse and 19 patients (57.6%) received more than 2 lines of chemotherapy before ASCT. Most patients (n=27, 81.8%) were complete remission (CR) state at ASCT. A median number of 5.85x106/kg CD34 cells were infused (range 2.0-18.6). All patients engrafted after a median time of 11 days (range 10-14). Twelve patients (36.4%) experienced neutropenic fever and 16 patients (48.5%) had grade 3 toxicities during ASCT. However, no one had a documented infection, veno-occlusive disease, or treatment-related death. Three months CR rate was 81.8%. During a median follow-up period of 10.2 month, 7 patients (21.2%) exhibited relapse or progression, while 1 patient (3.0%) died of the disease. The estimated 2-year PFS and OS rate were 73.0% and 89.8%, respectively (Figure 1).
Conclusions: The BEB conditioning regimens for ASCT is a feasible with tolerable toxicity in patients with NHL.
Disclosure: Nothing to declare
P112 Long-term report of total marrow or total lymphoid IMRT in advanced leukemia, myeloma and lymphoma
Stefano Vagge1, Alida Dominietto1, Fabio Guolo1, Roberto Lemoli1, Andrea Bacigalupo2, Emanuele Angelucci1, Renzo Corvò1
1 IRCCS Ospedale Policlinico San Martino, Genova, Italy, 2 Università Cattolica del Sacro Cuore; Fondazione Policlinico Universitario 'A.Gemelli'-IRCCS, Haematology, Roma, Italy
Background: During the last three decades, total body irradiation (TBI) continues to play an important role in the conditioning regimens for patients undergoing stem-cell transplant (SCT) for a wide variety of advanced hematological malignancies. However, TBI showed boundaries in dose limits for toxicity in allogenic and moreover in autologous stem cell transplantation. Currently, the choice of conditioning regimen is based on the use of the least-toxic regimen to achieve the optimal therapeutic result. This report aims to assess the feasibility of a conditioning strategy based on high dose chemotherapy and whole-body radiotherapy focused on selective extensive tumor burden irradiation, both in allogeneic and autologous stem cell transplantation.
Methods:Since December 2009, sixty-two patients (pts) have been irradiated by helical tomotherapy (HT) to extensive target before allogeneic or autologous transplantation. Selected total marrow irradiation (TMI) schedules were planned to treat patients with high risk acute leukemia (ALL or AML) or multiple myeloma (MM) as a part of conditioning regimen. Total lymphoid irradiation (TLI) was planned for patients with refractory or relapsed (R/R) Hodgkin (HD) or Non-Hodgkin lymphomas (NHL).
Results: TMI and TLI allowed delivering therapeutic dose over extensive selected targets with wide reduction of toxicity to all the organs at risk (OARs). The higher radiation doses rate to the OARs is reduced from 30% to 70%. Allogenic conditioning regimen was TLI (4Gy x 3fx) than fludarabine + endoxan for patients with HD (4 pts). TMI (4Gy x 3fx) + fludarabine + melphalan for patients with MM (4 pts). TMI (4Gy x 2 fx) + thiotepa + fludarabine + busulfan for advanced LAM patients (4 pts). TMI as the boost (2-3Gy) after conventional TBI was (12 Gy in 6 bi-fractionated doses) by cyclophosphamide (18 pts). Autologous preparation to SCT consisted of TLI (4Gyx 3fx) followed by high-dose bendamustine and melphalan for patients older than 40 years and conventional FEAM (Fotemustine, Etoposide, Cytarabine, and Melphalan) for younger patients, in HD e NHL (20 pts). While TMI (4Gy x 3 fx) plus melphalan was delivered for autologous SCT in MM and LAM (12 pts). No unexpected acute toxicity was found. In the allogenic setting, all the patients' engraftment was achieved in all patients. No acute graft versus host disease increasing was detected. Within the autologous setting, only 33% developed grade 3/4 mucositis. None experienced grade 3/4 extra-hematological toxicity. Outcomes of the specific disease will be reported.
Conclusions: The current report describes the clinical feasibility of using HT to deliver TMI or TLI in the setting of autologous transplantation or during allogenic stem cell conditioning regimen, to allow all patients (old, fragile or with high tumor burden) to achieve an ablative regimen before SCT. To our knowledge, this single institution experience describes data from one of the largest cohort of patients treated in Europe since the development of this irradiation techniques.
Disclosure: Nothing to declare
P113 Intravenous busulphan plus melphalan versus melphalan alone as conditioning regimen for newly diagnosed patients with multiple myeloma: Long-term follow-up of a matched case-controlled study
Margarita Blanes1, Jose Ignacio Lorenzo2, Paz Ribas3, Ana Jiménez4, José David González5, María José Cejalvo3, Carlos Solano6, Adrian Alegre7, Javier de la Rubia3
1 University Hospital General de Elda, Hematology, Elda, Spain, 2 University Hospital La Fe, Hematology, Valencia, Spain, 3 University Hospital Doctor Peset, Hematology, Valencia, Spain, 4 University Hospital 12 de Octubre, Hematology, Madrid, Spain, 5 University Hospital Insular de Canarias, Hematology, Las Palmas de Gran Canaria, Spain, 6 University Hospital Clínico, Hematology, Valencia, Spain, 7 University Hospital La Princesa, Hematology, Madrid, Spain
Background: Autologous stem cell transplantation (ASCT) is considered the standard consolidation therapy for younger patients with newly diagnosed multiple myeloma (MM). We have previously reported the results of a matched case-control study comparing the outcome of a series of patients with newly diagnosed MM undergoing ASCT after intravenous (iv) busulfan (BU) and melphalan (BUMEL) or melphalan 200 mg/m2 (MEL200) as preparative regimen (Blanes et al, BBMT 2013). Here we update the progression free survival (PFS) and overall survival (OS) data from this case-control study.
Methods:Between June 2005 and September 2009, 51 patients with newly diagnosed MM underwent ASCT after BUMEL in five Spanish centers. These patients were compared with a control group of 102 pair mates included in the study of Grupo Español de Mieloma GEM2000. Induction therapy in both groups of patients was based in polychemotherapy without the use of new drugs. Case matching was performed according to age, clinical stage at diagnosis, and response to induction therapy. Conditioning regimen consisted of iv BU at a dose of 3.2 mg/kg once a day on days -5 to -3 followed by MEL at a dose of -140 mg/m2 on day -2 in the BUMEL group versus MEL200 in the control group. Maintenance therapy after transplant consisted of interferon and steroids in the majority of patients.
Results: The cut-off date for this update was June 30, 2018. After a median follow-up of 56 and 63 months in the BUMEL and MEL200 groups respectively, 35 patients had relapsed in the BUMEL group and 82 patients in the control group. Median PFS was 33 (95% CI, 25.4-48.3) months in the BUMEL and 24 (95% CI, 20.1-32.7) months in the MEL200 group (P = 0.04) (Figure 1). In this update, 12 patients in the BUMEL group are in maintained response and 7 of them are in continuous CR (two with negative status for minimal residual disease) between 9 and 12 years after transplantation. Ten-year OS was not significantly different between both groups, being 41 (95% CI 30-58) months in the BUMEL and 29 (95% CI 18-47) months in the control group.Transplant-related mortality was similar in both groups of patients (4% in the BUMEL and 2% in the MEL200 group). Regarding toxicity, BUMEL was associated with a higher incidence of mucositis and liver toxicity than the melphalan-only approach but no patient in our series developed sinusoidal occlusive syndrome and the hepatic toxicity observed was only grade I/II. Finally, no long-term side effects have been reported among BUMEL recipients.
Conclusions:This long-term follow-up analysis confirms that a therapeutic strategy including BUMEL as conditioning regimen beforeASCT in patients with newly diagnosed MM is highly active and safe in these patients.
[ [P113 Image] 1 . Figure 1. Progression free survival in the BUMEL (____) and control group (……).]
Clinical Trial Registry: The GEM2000 protocol and BUMEL clinical trial were registered at ClinicalTrials.gov as NCT00560053 and NCT00804947
Disclosure: None of the authors has anything to disclose.
P114 A phase I trial evaluating carfilzomib, bendamustine, and melphalan (CBM) conditioning prior to autologous hematopoietic stem cell transplantation for multiple myeloma- final results
Muneer Abidi1,2, Kelli Cole3, Marlee Muilenburg1, Jessica Parker1, Stephanie Williams1,2, Samer Al-Homsi3
1 Spectrum Health Cancer Center, Grand Rapids, MI, United States, 2 Michigan State University College of Human Medicine, Internal Medicine, Grand Rapids, MI, United States, 3 NYU Langone Health, Internal Medicine, Hematology, New York, NY, United States,
Background: Autologous hematopoietic cell transplantation (AHCT) & high-dose melphalan (M) based conditioning remains the standard of care for transplant eligible patients with multiple myeloma (MM). Efforts to combine radiation & other chemotherapeutic drugs with M have resulted in increased toxicity. We hypothesized that integrating a Proteasome inhibitor, another alkylating agent and M in the conditioning is safe & may improve complete remission (CR) & overall survival (OS) rates.
Methods:We enrolled MM patients (pts), eligible to receive AHCT in this phase I dose escalation study from 05/2014 to 10/2017. Carfilzomib (C) was added to bendamustine (B) & M. All patients received a fixed dose (20 mg/m2) of C on days (d) -29, -28, -22, -21, -15, & -14. C was done in dose escalation, per table I, on d -2, -1, +5 and +6. Dose limiting toxicity (DLT) was defined as: lack of neutrophil & platelet engraftment by d +22 and +35 respectively, & any G 4 GI toxicity or any ≥ G 3 non-hematologic toxicity as probably related to the study protocol. Due to DLT in cohort 2, the study was amended after first 6 pts & the M was reduced to 140 mg/m2 & the d +6 dose of C was omitted.
Results:Eighteen pts were enrolled, 11 males & 7 females. Median age was 58 years (39-68). Performance status was ≥ 70% (KPS) in all pts. Per the International Staging System (ISS), 3 pts had stage I disease, 6 had stage II, & 7 had stage III. Staging was indeterminate in 2 pts. Five pts had undergone a prior AHCT. Disease status at enrollment was stable disease (SD) (n=3), partial response (PR) (n=9), very good partial response (VGPR) (n=5), & one pt had progressive disease (PD). Median CD34+ cell dose infused was 3.24x106/kg (2.23-8.42x106). Median follow-up was 25.1 months (1.4-44.4). Median time to neutrophil engraftment was 12 d (11-15). and platelet engraftment was 16 d(12-20). One pt died (cohort 2) on d +44 before achieving platelet engraftment. Ten pts received maintenance therapy. Post-transplant disease status was assessed per protocol by SPEP, SPIF, serum free light chains & ratio. Seventeen pts were evaluable for response assessment at d +100, d+180 & d+ 365. At d+100: 4 pts had CR, 8 had VGPR, 1 pt had PR & 4 pts had SD. At d+365: 4 pts had CR, 5 had VGPR, 3 pts had PR and 5 pts had PD. OS probability at last follow up was 60.3% (95% CI 27.6 -82%) and progression free survival 66.3% (95% CI 29.8-87%).
Conclusions: The combination of CBM (cohort 3B) for AHCT appears feasible, with manageable toxicities. Longer follow-up & a phase II study are warranted to determine response rates and long-term outcomes.
|Cohort||Pts (n)||C (mg/m2) days||B (mg/m2) days||M (mg/m2) days|
|1||3||(15) d -2, -1, +5, & +6||(120) d -2 & (100) d -1||(100) d -2 & -1|
|2||3||(20) d -2, -1, +5, & d +6||(120) d -2 & (100) d -1||(100) d -2 & -1|
|2B||3||(20) d -2, -1, & +5||(120) d -2 & (100) d -1||(140) d -1|
|3B||9||(27) d -2, -1, & +5||(120) d -2 & (100) d -1||(140) d -1|
[ [P114 Table] 1 . Table I]
Disclosure: Muneer Abidi: Research funding/honorarium from following pharmaceutical companies: Amgen, Celgene, Onyx, Millennium, Sobi. Other authors have Nothing to declare.
P115 The effect of TGFB1 polymorphism after allogeneic hematopoietic stem cell transplantation
Hajnalka Andrikovics1, Petra Kovy1, Nora Meggyesi1, Livia Varga1, Katalin Balassa1, Andras Bors1, Laszlo Gopcsa1, Melinda Paksi1, Aniko Barta1, Eszter Vad1, Arpad Batai1, Attila Tordai2, Tamas Masszi2, Janos Sinko1, Peter Remenyi1
1 Central Hospital of Southern Pest (DPC), Budapest, Hungary, 2 Semmelweis University, Budapest, Hungary
Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapeutic option for malignant hematopoietic diseases. Cytokines including transforming growth factor β1 (TGFB1) play a pivotal role in immune reconstruction, and the development of graft versus host disease (GvHD) or infections.
Methods: The role of TGFB1 gene -1347C>T variant was investigated in a cohort of 409 adult recipient-donor pairs [178 female and 231 male, median age: 43 years (range 19-73)]. The majority of the patients suffered from acute myeloid leukaemia (155/409, 38%) and 254 patients from other malignant hematopoietic disorders. During transplantation 210 (52%) patients received graft from their siblings, 199 (48%) from matched unrelated donors (MUD). Myeloablative conditioning (MAC) was applied in 261 (64%) and reduced intensity conditioning (RIC) in 148 (36%) cases. For GvHD prevention tacrolimus plus sirolimus (TAC&SIR) were most commonly applied in 238 (58%), cyclosporine (CSA) in 95 (23%) and TAC as single agent in 76 (19%) cases. TGFB1 variant was analysed from genomic DNA with LightCycler hybridisation probe method.
Results: We did not find any association of recipient TGFB1 -1347C>T with HSCT outcome parameters (acute and chronic GvHD, cytomegalovirus infection [CMV], transplant associated thrombotic microangiopathy [TA-TMA]) and survival (transplant related mortality, [TRM]; overall survival, [OS]) neither in the whole HSCT cohort nor in any subgroups. In the whole cohort donor -1347C>T genotype did not impair survival (p= 0.4). Diagnosis, donor type, conditioning and GvHD prophylaxis were tested for interaction with donor TGFB1 genotype. Although donor TGFB1 -1347C> genotype influenced OS in the subgroups of patients with acute leukaemia, or treated with MAC conditioning or with TAC-based GvHD prophylaxis in multivariate analyses, test for interaction indicated the differential effect of TGFB1 genotypes in MAC versus RIC subgroups (p=0.035). In the MAC cohort, patients transplanted with -1347TT genotype donor had unfavourable outcome (60-month OS CC: 62.1%±4.8%, TC: 46.8%±4.8% and TT: 35.6%±9.3%, p=0.032; which was independent from age, donor type and GvHD prophylaxis, p= 0.003, HR: 2.35, 95% CI: 1.35-4.10). In case of myeloablative conditioning, relapse rate (CC: 18% vs. CT 28% vs. TT 18%) was not different in subgroups stratified by donor TGFB1 genotype. Frequency of acute GvHD grade III-IV [CC: 11%; CT: 17%; TT: 24%, p=0.057], and transplant-related mortality was higher in TT-carriers (CC:26%; CT:28%; TT:46%, p=0.02 CC&CT vs TT). TA-TMA, CMV infection/reactivation and cGvHD were also not different according to donor genotypes. Fungal infections occurred more frequently as causes of death in carriers (CC: 9.7% vs. CT: 38.1% vs TT: 33.3%, p=0.022).
Conclusions: Our results suggest that donor TGFB1 -1347C>T may exert an adverse influence on the outcome of myeloablative conditioning. Our finding might be explained by the combination therapy of calcineurin and mTOR inhibition in GvHD prophylaxis in myeloablative conditioning.
Disclosure: Nothing to declare.
P116 Treosulfan-based reduced intensity conditioning in HLA-haploidentical transplantation using PTCY as GVHD prophylaxis in high-risk MDS /AML of the elderly
Alessia Fraccaroli1, Dusan Prevalsek1, Sarah Haebe1, Veit Bücklein1, Christoph Schulz1, Heidrun Drolle1, Susanne Fritsch1, Georg Ledderose1, Johanna Tischer1
1 University Hospital of Munich, LMU, München, Germany
Background: Standard conditioning regimens prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) are often associated with a considerable risk of severe adverse events, especially in elderly patients suffering from high-risk (HR) MDS/AML. Previous clinical studies have demonstrated feasibility of treosulfan-based reduced-intensity conditioning (RIC) by stable engraftment, low non-relapse mortality (NRM), and favorable survival in elderly patients undergoing HLA-matched related or unrelated allo-HSCT (Beelen et al, ASH 2017 #0521). However, data for treosulfan-based conditioning in the T-cell-replete HLA-haploidentical (haplo-HSCT) setting in high-risk AML/MDS patients are rare. Here we report on the outcome of eleven patients treated with a treosulfan-based conditioning undergoing haplo-HSCT using exclusively post-transplantation cyclophosphamide (PTCY) as GvHD prophylaxis.
Methods: Eleven patients with high-risk (HR) AML (n=9)/MDS (n=2) who underwent haplo-HSCT using treosulfan for reduced intensity conditioning (RIC) and PTCY as GvHD prophylaxis were retrospectively analyzed with respect to outcome and toxicity. All patients were >55 years old and transplanted between January 2016 and February 2018 at our institution. The majority of the patients (9/11) suffered from active disease at time of treatment initiation, only two patients presented in CR. All but one received sequential conditioning with cytoreductive chemotherapy using FLAMSA applied shortly prior to treosulfan-based RIC (10g/m2over 3 days). A bone marrow graft was used in 9/11 patients. Post-grafting immunosuppression consisted of cyclophosphamide, tacrolimus and MMF. National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 were used for non-hematologic toxicity assessment starting from sequential therapy initiation or conditioning until day +30.
Results: Median age of the entire cohort was 63 years (range: 58-71). The HCT-CI was ≥2 in eight pts (median HCT-CI=2, range: 0-5). No graft rejection occurred. Neutrophil and platelet engraftment were achieved in 100% and 91% of the patients at a median of 20 (16-23) and 26.5 (13-30) days, respectively. Acute GvHD grade II-IV occurred in 18% of the patients, exclusively involving the skin. No one developed severe (°III-IV) acute GvHD. No patient died prior to haplo-HSCT. Severe non-hematologic regimen-related toxicities (°III-IV) occurred in 2/11 patients, predominately affecting the gastrointestinal tract. No patient suffered from ≥two III-IV° toxicities. All patients developed fever during treatment course, four with positive blood cultures. CMV reactivated in 6/7 patients at risk. No EBV reactivation or PTLD occurred. Six patients had clinical and radiological signs of pneumonia (probable invasive aspergillosis) without detection of aspergillus/-antigen in the bronchoalveolar lavage. CI of NRM at day +180 was 0%. Four patients relapsed within the first year after haplo-HSCT, with two of them dying due to relapse. At last follow-up (Dec 2018) 9/11 patients were alive. With a median follow-up of 5 months (2-31) estimated 1-year OS and DFS were 80% and 59%, respectively.
Conclusions: Treosulfan-based unmanipulated HLA-haploidentical allo-grafting using PTCY as GvHD prophylaxis in HR MDS and AML patients aged over 55 years is safe and well tolerated resulting in stable engraftment and a favorable toxicity profile. Our preliminary data further show promising outcome with low NRM, no severe acute GvHD and favorable survival offering an attractive alternative in RIC for haplo-HSCT of the elderly.
Disclosure: nothing to declare
P117 Comparison of outcomes of total body irradiation (TBI) vs non-TBI conditioning regimens in acute lymphoblastic leukemia for allogeneic transplantation
Huseyin Saffet Bekoz1, Omur Gokmen Sevindik1, Tulay Ozcelik2, Mutlu Arat2, Ipek Yonal Hindilerden3, Sevgi Kalayoglu Besisik3, Meliha Nalcaci3, Ant Uzay4, Suleyman Sami Kartı4, Demet Kivanc1, Deniz Sargin1
1 Medipol University, Istanbul, Turkey, 2 Istanbul Bilim University Medical Faculty, Hematology and Adult BMT, Istanbul, Turkey, 3 Istanbul University Medical Faculty, Istanbul, Turkey, 4 Acibadem University, Hematology and Adult BMT, Istanbul, Turkey
Background: In adult patients diagnosed acute lymphoblastic leukemia (ALL) long-term results are poor with intensive chemotherapy.
Allogeneic stem stem cell transplantation is the potential treatment that provides cure for these patients. Myeloablative preparation regimens include total body irradiation (TBİ)+ cyclophosphamide(Cy) and busulfan + cyclophosphamide.In adult ALL patients WBI/Cy widely used, but the toxicity rate is higher. The aim of this study is to compare the result and effect of the TBI/Cy and busulfan/Cy regimens in Allogenic bone marrow transplantation in ALL patients.
Methods: Between 1993 -2018 there were 137 ALL patients who underwent transplantation using myeloablative preparation regimen with or without addition TBI in the adult bone marrow transplantation units of Medipol Medical Faculty, Istanbul University Istanbul Medical Faculty, Sisli Florence Nightingale Hospital, Atakent Acıbadem Hospital adult bone marrow units . We analyzed overall survival(OS), progression free survival (PFS), veno occlusive disease, acute and chronic graft versus disease development rates in these patients.
Results: Demographic characteristics of patients summarized in table -1
There was no significant difference between groups in donor age, gender, stem cell source.
It was observed that the relapse rate was not statistically significant in both group.There was no statistically significant difference between the patients who underwent myeloablative regimen and myeloablative regimen with TBI in relaps,death, OS, PFS.
[ [P117 Image] 1 . Figure 1]
In terms of transplant complications there was also no respectable difference in development of VOD and acute and chronic graft versus disease but VOD was more common in the group that did not use TBI (P: 0.068) (table-1)
|total (n:137)||MA regimen||TBI+MA regimen||P value|
|transplant timing (TR1/TR2/primary refractory||75/50/12||39/28/5||36/22/7||0.286|
|Median follow up(month)||8(1-140)||8(1-161)||10(1-91)||0.412|
[ [P117 Table] 1 . Table -1]
Conclusions: Although there are contradictory data in the literature, in our multicentre study, it was revealed that the addition of TBI in the myeloablative preparation regimen compared with myeloablative preparation regimen alone did not have a positive or negative effect on overall survival.We think that if we can prepare a good VOD prophylaxis approches, we can give up TBI in future.
Disclosure: Nothing to declare
P118 Fludarabine-based reduced intensity conditioning for fanconi anemia - A single center experience
Ehud Even-Or1, Hodaya Cohen1, Adeeb NaserEddin1, Bella Shadur1, Batia Avni1, Sigal Grisariu1, Irina Zaidman1, Polina Stepensky1
1 Hadassah Hebrew University Medical Center, Bone Marrow Transplantation, Jerusalem, Israel,
Background: Fanconi anemia (FA) is a rare genetic disease characterized by chromosomal fragility, somatic abnormalities, bone marrow failure and a tendency to develop malignancies. Hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment in FA patients who develop bone marrow failure or AML/MDS. HSCT for patients with FA is challenging as these patients are exquisitely sensitive to genotoxic chemotherapy agents and ionizing radiation, and to the inflammatory side effects of graft versus host disease. Since the mid-1990´s Fludarabine based reduced intensity conditioning regimens are used at our center for HSCT of patients with FA.
Methods: In this retrospective study we collected data from all HSCT done at Hadassah Medical Center for patients with FA using fludarabine based conditioning regimens. The collected data included patient's clinical data and transplant data. The study was approved by the institutional Helsinki committee.
Results: Since June 1996 until August 2018, 35 patients with FA underwent 39 HSCT at Hadassah Medical Center with fludarabine based conditioning regimens. The median age of the patients at transplant was 9.1 years (range 3.2 - 30.8). All patients had bone marrow failure with severe aplastic anemia, 16 of which were transfusion dependent at the time of transplant and eight of the patients developed MDS. The conditioning regimen consisted fludarabine 180 mg/m2 cyclophosphamide (20 to 40 mg/kg) and anti-thymocyte globulin. Patients with unrelated donors received additional low dose busulfan (n=7) or additional TBI (n=3). For GVHD prophylaxis, cyclosporine A was given either alone (n=21), with MMF (n=13) or with methotrexate (n=1). The graft source was bone marrow (BM) in most cases (n=31), PBSC in seven cases, matched sibling cord+BM in two cases and one matched related cord. Twenty-five of the donors were family donors and ten were unrelated. Twenty-nine of the donors were 10/10 HLA matched, six were 9/10 mismatched and one haploidentical. Four patients had engraftment failure and required a second transplant, two of them were re-transplanted with cyclophosphamide and TBI, one with fludarabine, busulfan and campath, and one with no conditioning. Thirty of the 35 patients are alive (86%). Four patients died of transplant complications and one died of metastatic squamous cell carcinoma. Eight survivors are mixed chimeras (81%-94% donor) and are all doing well, none of them developed any GVHD. Nine patients developed acute GVHD, four of them with grade 3-4. Seven of these patients later developed chronic GVHD, two of them have extensive disease.
Conclusions:Our results show a high survival rate of 86%, with a low rate of engraftment failure and reasonable rates of GVHD. Only one of our patients died of late effects of HSCT for FA. Mixed chimerism does not seem to present a problem. We conclude that reduced intensity fludarabine based conditioning regimens are a good treatment option for patients with Fanconi anemia undergoing HSCT.
Disclosure: Nothing to declare
P119 Total marrow irradiation + bendamustine as reduced-toxicity myeloablative conditioning prior to allohsct for younger patients with multiple myeloma
Malgorzata Sobczyk-Kruszelnicka1, Tomasz Czerw1, Wlodzimierz Mendrek1, Jacek Najda1, Maria Sadus-Wojciechowska1, Malgorzata Ociepa-Wasilkowska1, Andrzej Frankiewicz1, Katarzyna Michalak1, Anastazja Szlauer-Stefanska1, Malgorzata Krawczyk-Kulis1, Lukasz Dolla1, Grzegorz Wozniak1, Lukasz Kleszyk1, Bozena Jochymek1, Jerzy Holowiecki1, Krzysztof Slosarek1, Leszek Miszczyk1, Sebastian Giebel1
1 Maria Sklodowska-Curie Institute - Cancer Center, Gliwice Branch, Gliwice, Poland
Background: The prognosis of patients with multiple myeloma (MM) has improved markedly over the last two decades. Despite that, alloHSCT remains the only treatment option with curative potential. However, its use is limited due to high incidence of non-relapse mortality (NRM) after myeloablative conditioning while insufficient efficacy of reduced-intensity regimens. We developed a new protocol characterized by reduced toxicity while preserved myeloablative potential, based on the use of total marrow irradiation (TMI) in combination with bendamustine. The aim of this study was to evaluate its safety and efficacy in a single-center experience.
Methods: Between years 2013-2018, MM patients below 55 years old were offered tandem auto-alloHSCT as part of first-line therapy. The decision was based on individual patient preferences after detailed description of potential risks. AutoHSCT was preceded by melphalan 200 mg/m2 iv. The conditioning prior to alloHSCT consisted of TMI performed using helical tomotherapy at the dose of 4 Gy/d on days -3, -2, -1 (total 12 Gy) and bendamustine 140-220 mg/m2/d iv. on days -5, -4 (total 280-440 mg/m2). The immunosuppressive therapy consisted of cyclosporine + methotrexate +/- ATG. Peripheral blood was used as a source of stem cells.
Results: The analysis included 18 patients (women - 9, men - 9). The median follow-up was 28 (4-68) months. The median age at alloHSCT was 44 (26 - 53) years. The disease stage before alloHSCT was as follows: CR-6, VGPR-4, PR-6. Patients were treated with HSCT from either HLA-matched siblings (n=7) or unrelated donors (n=11). The interval between autoHSCT and alloHSCT was 5 (4-23) months.
All patients engrafted after alloHSCT with median time of neutrophil and platelet recovery of 14 and 12 days, respectively. One patient (6%) experienced grade 2 acute GvHD, while there were no cases of grade 3-4 acute GvHD. The incidence of mild, moderate and severe chronic GvHD was 17%, 0% and 6%, respectively. The rate of grade 3 non-hematological toxicities was 11%. One patient died of late bacterial infection. The incidence of TRM was 5%. Grade 4 adverse events were not reported. Disease status 3 months after alloHSCT was: CR-10, VGPR-5, PR-3. The probability of OS and PFS after 30 months was 94% (+/- 6%) and 77% (+/- 12%), respectively. The incidence of progression and TRM was 17% and 6%, respectively.
Conclusions: AlloHSCT using TMI 12Gy + bendamustine conditioning protocol is characterized by good tolerance and low risk of GvHD. It may be used for younger patients with MM as part of tandem auto-alloHSCT strategy. Encouraging results reported in this study should be confirmed in prospective clinical trials.
Disclosure: Nothing to declare
P120 Comparison between two reduced intensity conditioning regimens in patients with a myeloid malignancy: A single center experience comparing FB2 with flumel
Mitja Nabergoj1, Anne-Claire Mamez1, Sarah Morin1, Carmen de Ramon Ortiz1, Carole Dantin1, Amandine Pradier1, Thien-An Tran1, Thomas Longval1, Maria Anastasiou1, Laura Bounaix1, Caroline Stephan1, Yan Beauverd1, Federica Giannotti1, Stavroula Masouridi-Levrat1, Yves Chalandon1
1 Geneva University Hospitals, Geneva, Switzerland
Background: Hematopoietic Stem cell transplantation (HSCT) remains the only curative option for high-risk myeloid neoplasms. The optimal reduced-intensity conditioning (RIC) is still debated.
Methods: A single-center retrospective analysis was conducted at our institution to compare two different RIC regimens in adult patients transplanted for myeloid malignancy from 2001 to 2018. A total of 137 patients were analysed, 74 of them treated with Busulfan-based (Fludarabine 150 mg/m2, Busulfan 6.4 mg/kg, FB2) and 63 with Melphalan-based conditioning regimen (Fludarabine 150 mg/m2,Melphalan 140 mg/m2, FluMel). Antithymocyte globulin (ATG) was administered in all patients while no one received TBI. Partial in vitro T-cell depletion was performed using alemtuzumab for low risk patients.
Results: The two groups were well balanced with a median age of 61 and 62 years in the FB2 and FluMel group, respectively, and a median follow up of 46 months. The most frequent indication for transplant in both groups was AML (59.5 and 69.8% for FB2 group and FluMel group, respectively) and the stem cell source was peripheral blood in 94.6 and 96.8% of patients. More patients in the first group had near to significant worst Karnosfky status (< 90) at transplant compared to second (35.1 vs 19%, p=0.057) and more patients received a T-partial depleted graft (54.1 vs 33.3%, p= .028). The neutrophil engraftment was significantly shorter after FluMel (15 vs 18 days, p < .01). The 3-year overall survival (OS) and disease-free survival (DFS) were of 43.0 and 36.5%, respectively, after FB2 and 54.9 and 52.0% after FluMel, respectively, and were not significantly different (p=.41 for OS and .15 for DFS), with a Karnofsky >= 90 being the only factor significantly associated in univariate analysis with better OS and DFS (p=.02 for both). The cumulative incidence (CI) of grade 2 to 4 acute graft-versus-host disease (aGVHD) was 16.2% after FB2 and 38.3% after FluMel (p< .001) and was associated in multivariate analysis with both T depletion and RIC type (p< .001 and .005, respectively). The CI of chronic GVHD at 3 years was 13.9% in FB2 and 22.1% in FluMel group (p=.24). The CI of Non-relapse mortality at 3 years was 18.7% after FB2 and 29.6% after FluMel (p=.11). The CI of relapse at 3 years was 44.8% for the first and 18.4% for the second group (p< .001) and was associated with conditioning regimen in multivariate analysis (p=.02). No difference in 3-years GVHD-free/relapse-free survival (GRFS) was observed between the two group (25.5% for FB2 and 37.6% for FluMel, p=.48).
Conclusions: When comparing two RIC regimens for myeloid neoplasms, we observed a higher incidence of aGVHD after FluMel whereas no statistical difference was noted for the cGVHD occurrence. While the toxicity appears to be higher after FluMel, this result is counterbalanced by a higher proportion of relapse after FB2, accounting for no difference in OS, DFS and GRFS between the two groups. These findings could be partially explained by a larger proportion of patients receiving a partial T-depletion after FB2 RIC, but a larger trial is needed to clarify this issue.
Disclosure: Nothing to declare.
P121 Once-daily vs 4-times daily intravenous busilvex in conditioning regimen before allogeneic stem cell transplantation for patients with myeloid malignancies: Safety and efficacy
Nour Ben Abdeljelil1, Ons Hrizi1, Maroua Ben Hmida1, Amel Lakhal1, Rym El Fatmi1, Lamia Torjemane1, Dorra Belloumi1, Saloua Ladeb1, Tarek Ben Othman1
1 Centre National de Greffe de Moelle Osseuse, Tunis, Tunisia
Background: Busilvex (Bu) is part of standard conditioning regimen before allogeneic stem cell transplantation (ASCT) for patients with myeloid malignancies and usually administered as an intravenous (iv) infusion 4-times daily. This study aimed to compare the saftey and efficacy of this schedule to a once-daily iv Bu.
Methods: We conducted a retrospective study in adult patients (≥18 years) with myeloid malignancies who received ASCT from HLA-identical sibling donors between January 2011 and June 2018 following iv Bu-based preparative regimens. Graft-versus host disease (GVHD) prophylaxis consited of cyclosporine and short course of methotrexate. Intravenous Bu was administered 4-times daily (0.8 mg/kg every 6 hours x12 to 16 doses) or once-daily in a 3-hour infusion (3.2 mg/kg x 3 to 4 days) since June 2015.
Results: Ninty-nine patients were enrolled (54 men and 45 women). Median age was 35 years (range, 18-50 y). The median time from diagnosis to ASCT was 5 months (range, 51days -7 years). Diagnosis were acute myeloid leukemia (n=79, 80%), chronic myeloid leukemia (n=8, 8%), myelodysplasic syndrome (n=6, 6%), primitive myelofibrosis (n=4, 4%) and chronic myelomonocytic leukemia (n=2, 2%). Thirty-seven (37.3%) patients had EBMT-score ≥2. Sixty-five (65.6%) patients were transplanted in CR1, 5 (5%) beyond CR1 and 24 (24.2%) had active disease. Conditioning regimens consisted of Bu/cyclophosphamide in 86 patients (86.8%), Bu/fludarabine in 13 patients (13.1%). Four-times daily Bu was given to 58 patients (58.5%, groupe1) and once-daily Bu to 41 patients (41.5%, groupe 2). Stem cell source were BM in 46 patients (46.5%) and PBSC in 53 patients (53.5%). Globally, patients characteristics were well balanced between the two groups. The rates of severe complications were similar between the two groups with no statistically significant differences except oral mucositis (table1).
|4-times daily Bu (n=58)||Once-daily Bu (n=41)||p|
|Severe infections||22 (37.9%)||11 (26.8%)||0.25|
|Hepatic cytolysis||33 (56.9%)||26 (63.4%)||0.51|
|Hepatic cholestasis||19 (32.8%)||20 (48.8%)||0.11|
|Sinusoidal occlusion syndrome||3 (5.2%)||0||0.27|
|Oral mucositis grade III-IV||38 (65.5%)||35 (85.4%)||0.03|
|Median time to engraftemnt (days)||16 (range, 11-55)||14 (range, 11-25)||0.18|
|Acute GVHD grade II-IV (n=97)||19 (33.3%)||14 (35%)||0.87|
|CMV reactivation/infection (n=97)||15 (26.3%)||13 (32.5)||0.51|
|Chronic GVHD (n=91)||29 (54.7%)||16 (42.1%)||0.24|
[ [P121 Table] 1 . Table1. Complications post ASCT]
Non-relapse mortality (NRM) was comparable in the two groups (21% and 17% in groups 1 and 2, respectively, p=0.65). The relapse rate was 24% and 32%, respectively (p=0.4). After a median follow-up of 2 years (range, 5days - 7years), the OS was not significantly different between groups 1 and 2 : 64% vs 56% (p=0.09). However, the RFS was significantly better in the groupe 1 : 62% vs 56% (p=0.03).
Conclusions: Once-daily iv Bu regimen seems to be an efficient and safe alternative to the 4-times daily protocol. However, results should be interpreted with caution because the historical comparison and lack of Bu pharmacokinetics studies.
Disclosure: No conflict of interest
P122 Long-term follow-up of children with JMML underwent allogenic HSCT with busulfan or treosulfan-based conditionin
Veronika Konstantinova1, Elena Machneva1, Yulia Skvortsova2, Kirill Kirgizov2, Alexandra Burya1, Ekaterina Prinstanskova1, Natalia Sidorova1, Olga Filina1, Elena Skorobogatova1
1 The Russian Children's Research Hospital, Moscow, Russian Federation, 2 Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
Background: Standard therapy of the most patients with juvenile myelomonocytic leukemia (JMML) is allogeneic hematopoietic stem cell transplantation (aHSCT). The choice of optimal conditioning regimen for patients with JMML is crucial as well as long-term observation. We aimed to estimate the long-term follow-up and survival rates of patients with JMML after aHSCT with the help of Busulfan or Treosulfan-based conditioning regimens.
Methods: Thirty eight patients with JMML underwent aHSCT in 2002-2018. We compared equal groups of patients received Busulfan (n=19) and Treosulfan-based (n=19) conditioning regimen. M:F=28:11. Median of age at HSCT was 2.5 (0.6-5). Donor type: HLA-related 10/10 - 29% (n=11), HLA-related 9/10 - 2.6% (n=1), HLA-unrelated 10/10 - 39.4% (n=15), HLA-unrelated 9/10 - 15.8% (n=6), and haploidentical - 13.2% (n=5). Stem cell source: BM - 55.3% (n=21), PBSC - 26.3% (n=10), UCB - 10,5% (n=4), and UCB+BM - 7.9% (n=3). Disease status on HSCT: CR - 73.7% (n=28), Refractory - 26.3% (n=10).
Results: Median follow-up 15.5 months (1-129 months). The estimated 10-year overall survival (OS) probability in patients received Busulfan-based conditioning was 48,8±13,4% in comparison with 68,0±10,8% in patients with Treosulfan-based regimen (р=0,458). Event-free survival (EFS) was 42,1±11,3% in group with Busulfan-based regimen and 57,0±11,5% in patients with Treosulfan-based conditioning (р=0,224).
[ [P122 Image] 1 . EFS of patients with JMML after aHSCT]
Relapse-free survival (RFS) in patient's group with Busulfan-based regimen was 72,7±12,0%, with Treosulfan-based conditioning - 81,5±9,8% (р=0,505). No statistical difference shown.
Conclusions: Long-term follow-up of patients with JMML underwent aHSCT showed satisfactory OS, EFS and RFS. There we no statistical difference shown between Busulfan and Treosulfan-based conditioning regimens.
Disclosure: Nothing to declare
P123 High dose sequential conditioning regimen followed by allogeneic hematopoietic transplantation for high-risk acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative neoplasia patients: A multicenter study in Singapore
Elson Neo1,2, Michelle Poon1, Yeh Ching Linn3, William Hwang3, Aloysius Ho3, Lip Kun Tan1, Davanaliz R. Del Rosario1, Liang Piu Koh1,2
1 National University Cancer Institute, Singapore, Singapore, 2 National University of Singapore, Yong Loo Lin School of Medicine, Singapore, Singapore, 3 Singapore General Hospital, Singapore, Singapore
Background: Post-transplant relapse remains the leading cause of treatment failure in high risk (HR) acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasia (MPNs) receiving allogeneic hematopoietic cell transplantation (allo-HCT), especially for patients with relapsed or refractory AML. Recently, a sequential transplant approach, as developed by the Munich group, comprising of intensive cytoreductive chemotherapy FLAMSA (Fludarabine/Amsacrine/cytarabine) to decrease leukemia cell burden shortly prior to conditioning regimen, has been successfully used for high-risk (HR) AML/MDS with promising results.
Methods: We studied 48 patients (median age 53 years, range 26 - 68) with HR AML (n=38), as defined by refractory, relapsed disease, secondary leukemia, or high/very risk disease risk index risk, and HR MDS (n=10) according to IPSS-R, undergoing allo-HCT using the sequential transplant approach in 2 institutions between January 2009 and October 2018. The sequential transplant approach combined a cytoreductive chemotherapy, which consisted of either FLAMSA (n=17), FLAG +/- Ida (fludarabine/cytarabine/Granulocyte colony stimulating factor /Idarubicin) (n=23), or Clo-AraC (Clofarabine/Cytarabine) (n=8), followed by reduced (RIC) (N=43) or myeloablative (MAC) (N=5) conditioning regimen. All patients received peripheral blood stem cell from matched related donors (N=27) matched unrelated donors (N=14), or mismatched unrelated donors (N=7). Post-grafting immunosuppression consisted of calcineurin inhibitor and mycophenolate mofetil in all patients. Thymoglobulin was added for GVHD prophylaxis for unrelated donor transplant.
Results: The median time to neutrophil > 1000/µL was 10 days (range, 9-25). With a median follow-up of 28.2 months (range, 1.4 to 103.1 months), the Kaplan-Meier estimate of leukemia-free (LFS) and overall survival (OS) at 5 years were 45 % (95% CI, 8-30), 46% (95% CI, 8-30), respectively. Patients receiving FLAG or Clo-AraC based sequential regimen showed a trend towards more favourable overall survival (OS) as compared to patients given FLAMSA (5 year OS: 53% vs 31%; p=0.236). At 2 years, the cumulative incidences of relapse and non-relapse mortality (NRM) were 46 % (95% CI, 31-60 %) and 15 % (95% CI, 7- 21 %), respectively. In multivariate analysis, the type of sequential conditioning regimen did not show any significant impact on LFS, OS, NRM or relapse.
Conclusions: Sequential transplant conditioning with FLAMSA, FLAG or Clo-AraC followed by allo-HCT is an effective strategy in overcoming the dismal prognosis of HR AML and MDS, and enabling long-term disease free survival. More studies on effective strategies such as post-transplant maintenance therapy of prophylactic donor lymphocyte infusion, are needed to further eliminate the risk of relapse, without increasing risk of treatment related toxicity.
Disclosure: Nothing to declare
P124 Optimization of the blood sampling procedure for busulfan therapeutic drug monitoring (TDM)
Vera Domingos1, Paulo Paixão2, Nuno Miranda1, Margarida Pereira2, Vera Pires1, Ana Sofia Jorge1, Elsa Oliveira1, António Melo Gouveia1, Manuel Abecasis1
1 Instituto Português de Oncologia de Lisboa, Lisbon, Portugal, 2 Faculdade Farmácia da Universidade de Lisboa, Lisbon, Portugal
Background: We implemented the busulfan TDM program in 2014 and in January 2017 we switched from the multiple daily dosing (MDD) to the once daily dosing (ODD) regimen .
To optimize our sampling scheme (15 minutes, 1, 2, 3, 4, 6, 8 and 10 hours after the end of a 3-hour infusion), we reduced the number of blood samples collected, reducing nursing and laboratory staff time and increasing patient convenience.
This study aims to show the performance of a simplified sampling protocol which includes the first 5 samples from the original protocol.
Methods: Individual PK parameters were retrospectively estimated using 5 samples (simplified protocol) and were compared with those obtained after 8 samples (original protocol).
Individual PK parameter values for a one compartment model were estimated using a maximum likelihood estimation modelling algorithm (ADAPT 5.0) and the statistical analysis of the results was performed (Statgraphics Centurion XV).
Results: 43 patients [18 females, 25 males, 18 children and 25 adults, mean age 30.1 (10 months-62 years)] were included. 38 patients had malignant disease and 5 non-malignant disease.
BU Clearance (CL) and AUCs values obtained for both protocols are summarized in table 1.
|Original Protocol - Mean (SD)||Simplified Protocol - Mean (SD)|
|CL D1 (L/h)||8.07 (3.10)||8.12 (3.14)|
|CL D2 (L/h)||8.17 (2.98)||8.23 (3.03)|
|CL D3 (L/h)||6.51 (2.54)||6.53 (2.56)|
|AUC D1 (mg*h/L)||21.2 (5.3)||21.1 (5.1)|
|AUC D2 (mg*h/L)||19.7 (3.8)||19.6 (3.8)|
|AUC D3 (mg*h/L)||23.6 (6.5)||23.5 (6.5)|
[ [P124 Table] 1 . Busulfan CL and AUC values]
Based on the approved dosage recommendations, mean (SD) initial dose was 171.1(69.3) mg. After TDM, mean (SD) calculated dose at day 1 for the remaining days (to achieve the defined target cumulative AUC) was 158,5(72,6) mg obtained from the original protocol. According to the simplified protocol the result would be 159,8(73,7) mg. The median and the mean variation of the calculated dose were 0% and 1% (0-8%) between protocols.
A strong relationship between the CL of the day 1- 3 obtained from the original protocol and the simplified protocol is observed (R2=0.9985).
This high correlation is also observed for patients with busulfan t1/2 >3h (R2=0.9936), a population were the reduction of sampling could be more problematic.
ANOVA test for the log CL with the factors: patient, day of busulfan and type of sampling protocol was performed. Sampling protocol was determined as non-statistically significant (p = 0.7248).
Conclusions: Results suggest that both protocols are equivalent concerning to the busulfan CL estimation and calculated AUC. Variation between protocols regarding the calculated dose at day 1 for the remaining days to achieve the defined target cumulative AUC is considered acceptable.
We verified a strong relationship between busulfan CL obtained from both protocols and sampling protocol doesn't influence CL statistically.
A reduced sampling collection of 5 determinations until 4 h after the end of the infusion is shown to be sufficient for the TDM of busulfan, so this was implemented in our centre in line with published data.
Disclosure: Nothing to declare
P125 Impact of anti-thymocyte globulin doses in unrelated hematopoietic stem cell transplantation for patients with myeloid neoplasm
Sung Hwa Bae1, Jun Yeb Nam1, Min Kyoung Kim2, Myung Soo Hyun2, Joon Ho Moon3, Yoo Jin Lee3, Sang Kyun Sohn3
1 Daegu Catholic University Hospital, Daegu, Korea, Republic of, 2 Yeungnam University Hospital, Daegu, Korea, Republic of, 3 Kyungpook National University Hospital, Daegu, Korea, Republic of
Background: Anti-thymocyte globulin (ATG) is widely used for the prophylaxis of graft-versus-host disease (GVHD) in hematopoietic stem cell transplantation (HSCT). However, there is still controversy regarding the optimal dose of ATG. Therefore, we analyzed the impact of ATG doses in unrelated HSCT for patients with myeloid neoplasm.
Methods: This was a retrospective multi-center study that assessed the impact of ATG doses on clinical outcomes in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing an unrelated HSCT. The patients who received peripheral blood stem cells (PBSC) transplantation after conditioning regimens containing i.v. busulfan (BU), fludarabine and rabbit ATG between 2010 and 2017 were included in this study.
Results: A total of 96 patents, median age 45 years, with AML (n=74) or MDS (n=22) were included in our analyses. 66 patients (69%) received a myeloablative regimen (i.v. BU>6.4 mg/kg). High-ATG (ATG 9 mg/kg), intermediate-ATG (ATG 4.5-5 mg/kg) and low-ATG (ATG 3 mg/kg) were given in 11, 49 and 36 patients, respectively. After a median follow-up of 23 months, the cumulative incidence of extensive chronic GVHD was 9.1% in the high-ATG group, 13.8% in the intermediate-ATG group and 29.7% in the low-ATG group (p=0.31). The rate of 2-year relapse-free survival was significantly higher in the intermediate-ATG group than other groups (30% in the high-ATG group vs. 73.2% in the intermediate-ATG group vs. 53.8% in the low-ATG group, p=0.048). The rate of 2-year overall survival was similar (45.5%, 68.5% and 44.8%, respectively; p=0.09). The rate of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the intermediate-ATG group (18.2% in the high-ATG group vs. 53.8% in the intermediate-ATG group vs. 18.8% in the low-ATG group, p=0.0086).
Conclusions:Our study shows that the incidence of extensive chronic GVHD was similar regardless of the doses of ATG after transplantation of PBSC from unrelated donor for patients with AML or MDS. However, the rate of relapse-free survival and the rate of a composite end point chronic GVHD-free and relapse-free survival were significantly higher in the intermediate dose (4.5-5 mg/kg) of ATG group.
Disclosure: Nothing to declare
P126 Autologous stem cell transplantation with reduced-dose beam/beac is feasible for patients ≥70 years old and yields similar results as full-dose conditioning in patients aged 65-69
Israel Henig1, Dana Yehudai-Ofir1, Ronit Leiba1, Noa Lavi1, Shimrit Ringelstein-Harlev1, Tsila Zuckerman1,2
1 Rambam Health Care Campus, Haifa, Israel, 2 Technion, Rappaport Faculty of Medicine, Haifa, Israel
Background: Autologous hematopoietic stem cell transplantation (ASCT) with BEAM/ BEAC conditioning is widely used in patients with lymphoma. There are no clear guidelines for dose adjustment in frail patients aged 65 and older. We aimed to study the feasibility of reduced-dose conditioning in this patient population.
Methods: We retrospectively retrieved data from the electronic medical records for consecutive patients aged 65 and older, who underwent an ASCT for lymphoma over the last 10 years at our institution.
Results: Forty four patients ≥ 65 years old underwent ASCT between 1 Aug 2008 and 31 Aug 2018. Twenty eight of them received a reduced-dose conditioning (median 25%, range 20%-33% dose reduction). The dose was reduced for 92% of patients ≥ 70 years old and for 53% of patients aged 65-69. The outcomes of the following three groups of patients were compared: A) age ≥ 65; without dose reduction, B) age 65-69; with dose reduction and C) age ≥ 70; with dose reduction (table 1). Only one patient aged 70 received full-dose conditioning. There was no significant difference between the groups in the number of previous chemotherapy cycles (median 2, range 1-3). However, significantly more patients at the age of 65-69 were in complete remission (CR) pre-transplant in both full and reduced-dose conditioning groups (A and B). No significant intergroup differences were observed in the occurrence of complications (mucositis and infections), day 30 transplant-related mortality (TRM) or engraftment day. Similarly, no significant differences were found either in the 1-year progression-free survival (PFS), which was 50%, 64% and 50%, or 1-year non-relapse mortality (NRM), which was 17%, 7% and 10%, respectively for groups A, B and C. The 1-year overall survival (OS) tended to be higher in group B (85%), compared to groups A (66%) and C (70%).
Conclusions:BEAM/BEAC conditioning dose reduction was not found to adversely affect 1-year PFS and OS rates. Despite the fact that 2/3 of the patients in the age group ≥ 70 underwent ASCT in partial remission and had dose reduction, theier achieved TRM, PFS and OS rates were similar to those of patients aged 65-69. BEAM/BEAC conditioning at a 75%-dose may be a suitable option for patients in their seventh decade requiring ASCT. This strategy should be further evaluated in prospective clinical trials.
|Group||A) age≥65, 100% dose (n=16)||B) age 65-69, 75% dose (n=17)||C) age ≥ 70, 75% dose (n=11)||P-value|
|CR pre-ASCT||80%||65%||27%||P<0.001* (A vs. C)|
|Day 30 TRM||6%||6%||9%||ns*|
|CD34 (*106/kg) dose||6.6 (range 2.9-25.5)||5.75 (range 2.5-30)||5.9 (range 5.1-11.8)||ns‡|
|Engraftment day||10 (range 9-12)||11 (range 8-16)||11 (range 9-21)||ns‡|
[ [P126 Table] 1 . Patient information; NRM - Non-relapse mortality; * Chi-square test, ‡ One way ANOVA]
Clinical Trial Registry: N/A
Disclosure: Nothing to declare
P127 Reduction in autologous transplant related mortality by modifying conditioning regimen protocol
Natasha Ali1, Kashif Shahzad1, Bakhtawar Altaf1, Ahmed Raheem1, Mohammad Usman Shaikh1, Salman Adil1
1 Aga Khan University, Karachi, Pakistan
Background: The transplant related mortality in autologous transplants for lymphoma and multiple myeloma, reported worldwide ranges from 0-5%. From 2004-2015, the TRM at our center for these two diseases was approximately 20%. We introduced changes in mobilization schedule, conditioning regimens and drug dosages to determine whether these changes affected the transplant related mortality and overall survival.
Methods: From April 2004- December 2015, we used BEAM (BCNU: 300 mg/m2 on day -6; Etoposide 200 mg/m2 on days -5 to -2, Cytarabine 200 mg/m2 on days -5 to -2 and Melphalan 140mg/m2 on day -1 as conditioning chemotherapy for patients admitted in transplant unit for autologous transplants in Hodgkin's and Non-Hodgkin's Lymphoma. In patients with multiple myeloma high dose Melphalan (200mg/m2) was used. The mobilization protocol consisted of Cyclophosphamide 1.5gm/m2 followed by GCSF 5µgm/kg twice daily till stem cell collection was completed. From January 2016, we changed the BEAM protocol to BendaEAM with dose modifications that included: bendamustine 150mg/m2 on days -5 and -4, cytarabine 150mg/m2 on days -5 to -2, etoposide 150mg/m2 on days -5 to -2 and melphalan 100mg/m2 on day -1. For multiple myeloma Melphalan was reduced to 150mg/m2. We used only GCSF for mobilization of stem cells, which was continued till stem cell harvest was complete. Response to treatment was evaluated by comparing TRM and overall survival for two time periods: 2004-2015 and from 2016 till date.
Results: From April 2004 till December 2015, n=78 autologous transplants were performed. The male:female ratio was 2.4:1. Fifty seven patients underwent transplant for lymphomas, n=16 for multiple myeloma and n=5 for other diagnosis. Median age was 23±14.6 (2-64 years). The mean MNC was 4.7 × 108 ± 1.7/kg. Engraftment was achieved in 80% of patients. The transplant related mortality was 19.5% and overall survival was 72% (follow up: 104 months). Since January 2016 till March 2018 we have performed n=18 autologous transplants of which n=17 were males. Fifteen transplants were performed for lymphomas (NHL:8, HD:7) and n=3 for multiple myeloma. Median age was 24±15 (20 - 64 years). The mean mononuclear cell count was 5.8 x 108/kg and the mean CD34 count was 3.7 x 106/kg. Engraftment was achieved in all patients. The transplant related mortality was 0% and the overall survival was 83% (follow up 22 months).
Conclusions: We were able to reduce the autologous transplant related mortality to 0% by decreasing dosages of conditioning chemotherapy and changing the mobilization protocol. Long follow-up is needed to determine late mortality and late relapse in comparison to standard chemotherapy dosages
Disclosure: Nothing to declare
P128 Risk and benefit of thiotepa based conditioning followed by autologous stem cell transplantation in high risk lymphomas
Zoltan Csukly1, Laszlo Gopcsa1, Aniko Barta2, Melinda Paksi2, Eszter Sari2, Mariann Reti2, Peter Remenyi2
1 South-Pest Hospital Centre, Haematology, Budapest, Hungary, 2 South-Pest Hospital Centre, Budapest, Hungary
Background: The purpose of this study was to assess transplantation related mortality, overall survival (OS) and disease free survival (DFS) of patients with high risk Hodgkin's (HD), primary refractory diffuse large B cell lymphoma (DLBCL) and primary central nervous system lymphoma (PCNSL) who received thiotepa based high-dose chemotherapy and autologous stem-cell transplantation (ASCT).
Methods: Data were reviewed of 15 HD, 11 DLBCL and 11 PCNSL patients who received ASCT between 2013 and 2018. Patients caracteristics was 16 men and 21 women, median age at diagnosis 36 years (16-62). Stage (Ann-Arbor) at diagnosis of HD/DLBCL/PCNSL: stage IE n=0/0/10 (0/0/91%), stage II n=7/2/0 (47/18/0%), stage III n=2/0/1 (13/0/9%), stage IV n=6/9/0 (40/82/0%). Median time from diagnosis to ASCT HD/DLBCL/PCNSL: 25/11/6 month (4-72). Induction treatment in HD patients was ABVD, in most DLBCL patients R-CHOP and in PCNSL patients high dose methotrexate and cytosin arabinoside.Tumor status at ASCT HD/DLBCL/PCNSL: complete metabolic remission (CMR) n=4/1/11 (27/9/91%) and from PCNSL patient's n=8 (73%) were in first complete remission (CR1). Type of stem cell graft was periferial blood stem cell in all case. Conditioning: thiotepa (250mg/m2 on days -9 to -7, busulphan 3,2mg/kg on days -6 to -4 and cyclophosphamide 60mg/kg on days -3 to -2 plus rituximab 500mg/m2 on day -10 in DLBCL and PCNSL. Median follow up from ASCT 711 days (31-1554). Tumor stage at ASCT was defined with computer tomography with positron emission tomography (PET-CT).
Results: Median time of engraftment was 10 days (9-14). Thiotepa caused toxicoderma appeared at 9 (24%) patients. Cytomegalovirus (CMV) reactivation was seen in 3 (8%) cases with low DNA content (284,454,5500 copies/ml) and responded completely to oral valgancyclovir therapy. Transplantation related mortality HD/DLBCL/PCNSL n= 2/3/1 (9/27/13%), in 4 cases bacterial sepsis and one systemic mycoses and one pulmonary fibrosis. Incidence of long-lasting grade III-IV thrombocytopenia and anaemia: n=15 (40,5%) and n=3 (8%), median time of duration from transplantation 71 days (31-720) and 35 days (31-85) respectively. Two-year OS of HD/DLBCL/PCNSL: 87/55/82%. Two-year DFS of HD/DLBCL/PCNSL: 73/ 27/82%.
Conclusions: Conditioning caused side effects (toxicoderma, CMV reactivation, long-lasting cytopenias) are frekvent but a managable problem. Life threatening comlications such as bacterial and fungal infections are more frekvent than after B(T)EAM conditioning. TRM was much highest in DLBCL patients (27%) wich is associated with high number of active tumor status at transplantation (91%). In contrast to DLBCL patients with poor DFS, patients with PCNSL and HD can gain benefit with this conditioning. For PCNSL patients is important to transplant in CR1 and it must be carried out as soon as possible after induction treatment.
Disclosure: Nothing to declare
P129 Busulfan and thiotepa conditioning regimen for autologous stem cell transplantation in patients with multiple myeloma
Sung-Hoon Jung1, Seo-Yeon Ahn1, Deok-Hwan Yang1, Hyeoung-Joon Kim1, Jin Seok Kim2, Kihyun Kim3, Hyeon-Seok Eom4, Ho-Young Yhim5, Yoo Jin Lee6, Shin Young Hyun7, Je-Jung Lee1
1 Chonnam National University Hwasun Hospital, Hwasun-gun, Korea, Republic of, 2 Severance Hospital, Yonsei University College of Medicine, Seoul, Korea, Republic of, 3 Samsung Medical Center, Seoul, Korea, Republic of, 4 National Cancer Center, Goyang-si, Korea, Republic of, 5 Chonbuk National University Medical School, Jeonju, Korea, Republic of, 6 Kyungpook National University Hospital, Daegu, Korea, Republic of, 7 Wonju Severance Christian Hospital, Wonju, Korea, Republic of
Background: This study evaluated the efficacy and toxicity of intravenous busulfan and thiotepa as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM).
Methods: We retrospectively analyzed the data of 68 patients with MM who received the intravenous busulfan and thiotepa conditioning for ASCT between November 2016 and April 2018 in Korea.
Results: The median time to transplant was 5.4 months, and 66 patients (97.1%) underwent ASCT within 12 months of the diagnosis. The overall response rate after ASCT was 95.6%, including 55.9% with complete response, 22.1% with very good partial response, and 17.6% with partial response. The most common severe non-hematologic toxicity (grade 3-4) was infection (44.1%). Three patients (4.4%) developed venous-occlusive disease. One patient (1.5%) died due to severe pneumonia after ASCT. After a median follow-up of 13.0 months, the median progression-free survival (PFS) and overall survival (OS) were not reached.
Conclusions: In conclusion, a conditioning regimen of intravenous busulfan and thiotepa was effective and tolerable.
Clinical Trial Registry: Not applicable
Disclosure: The authors have declared no conflicts of interest.
P130 Myeloablative haploidentical bone marrow transplantation with post-transplant cyclophosphamide in paediatric patients with haematological malignancies
Santanu Sen1, Sameer Tulpule1
1Kokilaben Dhirubhani Ambani Hospital, Mumbai, India
Background: Haploidentical transplants have been shown to be safe and effective in treating haematological malignancies in the paediatric population. We have previously reported on our experience of using reduced intensity conditioning with post Transplant Cyclophosphamide in Haploidentical patients. We herein report our experience of using a TBI based Myeloablative conditioning to treat our first 8 patients with haematological malignancies.
Methods: 8 patients were enrolled in the study, 5 with relapsed Acute Lymphoblastic Leukemia (ALL) and 3 with relapsed/resistant Acute Myeloid Leukemia (AML). All AML patients had genetic markers of high risk disease and all ALL patients had very early relapses (either on therapy or within 6 months of stopping therapy). All patients were conditioned with an identical protocol using TBI-based myeloablative preparative regimen (Fludarabine 30 mg/m2/d × 4 d and TBI 150 cGy bid on d −4 to −1 [total dose 1200 cGy]) followed by an infusion of unmanipulated peripheral blood stem cells from a Haploidentical family donor. Postgraft immunosuppression consisted of Cyclophosphamide 50 mg/kg/day on days 3 and 4, Mycophenolate Mofetil through day 35, and Tacrolimus through day 180.
Results: Median time of neutrophil and platelet engraftment was 11 and 19 days, respectively. All patients achieved sustained complete donor chimerism by day +28. Acute GVHD, grades II-IV and III-IV, was seen in 75% and 25%, respectively. Disease progression occurred in 2 patients: 8 & 10 months after transplant and there was one death due to severe fungal infection. Estimated two-year survival and relapse were 75% and 24%, respectively. 2 patients had severe BK viremia and CMV reactivation occurred in 4 patients. All patients were successfully managed with appropriate supportive and antiviral therapy.
Conclusions: We report good outcome with a myeloablative conditioning in haploidentical transplants with excellent engraftment and hopefully a longer life expectancy. With small number of patients, it is difficult to state whether using a myeloablative conditioning would lead to better long term outcomes in this cohort of patients with very haematological malignancies, but we certainly showed that it is possible to achieve excellent early results.
Disclosure: Nothing to declare
P131 Fludarabine in combination with melphalan and ATG can be the best conditioning for hematopoietic stem cell transplant of children with hemophagocytic lymphohistiocytosis
Gholamreza Bahoush Mehdiabadi1
1Iran University of Medical Sciences (IUMS), Pediatrics, Tehran, Iran, Islamic Republic of
Background: Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning for disorders associated with excessive inflammation such as hemophagocytic lymphohistiocytosis (HLH) is associated with early mortality. The superior overall survival rate of HCT using reduced intensity conditioning (RIC) regimen for HLH patients compared to myeloablative conditioning were reported by various group since 2006.
Methods: In this prospective study, we analyzed the outcome of two pediatric patients with HLH who had received HSCT, using reduced-intensity conditioning (RIC) regimen. They received the same RIC regimen based on the use of Fludarabine (30 mg/m2/day for 5 days) in combination with melphalan (70 mg/m2/day for 2 days) and horse antithymocyte globulin (ATG 10 mg/kg/d for 4 days). Cyclosporine and Methotrexate were used as graft-vs.-host disease (GvHD) prophylaxis.
Results: A 2 months boy with primary HLH (FHL2) was transplanted from his mother and a 4 years girl with secondary HLH was transplanted from her brother. Both of donors were HLA match with their recipients. They were received 6 x 106/kg and 10 x 106/kg CD34+cells from the harvested peripheral blood stem cells, respectively. They achieved full neutrophil and platelet recovery. The time to neutrophil recovery was 13 and 11 days, respectively. Full chimerism was achieved for both of them. In addition, they was developed grade 3 and 2 of acute GvHD, respectively. GvHD was completely controlled with prednisolone. They are alive and in complete remission without any significant complications after 36 and 14 months, respectively.
Conclusions: It appears that Fludarabine in combination with Melphalan and ATG may be the best conditioning regimen for hematopoietic stem cell transplant of children with HLH. Due to a few number cases of this study, a study with sufficient sample size is required.
Disclosure: "Nothing to declare"
Early complications / late effects & quality of life / fertility
P132 Associations among depression, antidepressant use, survival, and quality of life in hematopoietic cell transplant recipients
Anna Barata1, Brian D. González2, Jun-Min Zhou3, Jongphil Kim3, Hailey Bulls2, Areej El-Jawarhi4, Heather Jim2
1 Hospital de la Santa Creu i Sant Pau and Josep Carreras Leukemia Research Institute, Barcelona, Spain, 2 Moffitt Cancer Center, Tampa, FL, United States, 3 Moffitt Cancer Center, Tampa, FL, United States, 4 Massachusetts General Hospital, Boston, MA, United States
Background: Hematopoietic cell transplant (HCT) recipients often report depression and impaired quality of life (QOL) before transplant. Mixed evidence suggests depression may be a risk factor for greater mortality and worse QoL. Inconsistent findings may be due to the fact that previous studies have not evaluated antidepressant use. The aim of the study was to compare pre-transplant patient-reported physical functioning and post-transplant overall survival (OS) between four groups of HCT recipients: 1) non-depressed/taking antidepressant (treated depression), 2) depressed/taking antidepressant (undertreated depression), 3) depressed/not taking an antidepressant (untreated depression), and 4) not depressed/not taking an antidepressant (control). It was hypothesized that physical functioning and OS would be worse among patients with untreated and undertreated depression relative to those with treated depression and controls.
Methods:This retrospective case-control study included patients completing depression (PHQ-8) and quality of life (SF-12) questionnaires at pre-transplant. Analyses were conducted separately for allogeneic and autologous recipients.
Results:Participants (N=1,797) were 58% men, mean age 57 years (19-79), 39% allogeneic recipients. Regarding depression and antidepressant use, 146 (21%) allogeneic patients were characterized as having treated depression, 47 (7%) as untreated depression, 49 (7%) as undertreated depression, and 461 (65%) as controls. Hierarchical linear regression models indicated that after adjusting for significant univariate factors (performance status, disease status, and regimen intensity), allogeneic patients with treated depression (B=-2.58, 95% CI=-4.63, -0.54) reported better physical functioning than patients with undertreated depression (B=-6.06, 95% CI=-9.43, -2.70) and untreated depression (B=-7.48, 95% CI=-10.70, -4.25) but worse physical functioning than controls (p values <0.05). Cox regression models indicated depression/antidepressant usage was not associated with OS among allogeneic patients (p values>0.10).Among autologous patients, 195 (17.82%) were characterized as having treated depression, 83 (7.59%) as untreated depression, 77 (7.04%) as undertreated depression, and 739 (67.55%) as controls. Hierarchical linear regression models indicated that after controlling for significant univariate factors (gender, performance status, diagnosis, and disease status), autologous patients with treated depression (B=-2.97, 95% CI=-4.71, -1.23) reported better physical functioning than patients with undertreated depression (B=-8.63, 95% CI=-11.23, -6.03) and untreated depression (B=-8.62, 95% CI=11.15, -6.08), but worse physical functioning than controls (p values <0.05). Cox regression models showed depression/antidepressant usage was associated with OS (p values <0.05), with patients with treated depression demonstrating significantly worse OS than other groups (p=0.05), but this association was no longer significant in multivariate analyses controlling for diagnosis and disease status (p=0.09).
Conclusions: Patients with untreated or undertreated depression pre-transplant may benefit from depression screening and treatment to improve physical functioning.
Disclosure: HSLJ: Consultant for RedHill Biopharma and Janssen Scientific Affairs
P133 Eltrombopag (EPAG) induces a high percentage of responses in patients WITH post allo-HSCT poor graft function (PGF) and no active GVHD
Lourdes Aguirre1, Aitziber Lizardi1, Pilar Bachiller1, Brigida Esteban1, Carmen González1, Nagore Argoitia1, María Araiz1, Aranzazu Aguirre1, Anunciación Urquía1, Carlos Vallejo1
1 University Hospital Donostia, San Sebastián, Spain
Background: Persistent cytopenia is a life-threating complication after HSCT. Several causes can lead to this situation (viruses, GVHD, drugs, etc). A specific entity is the one called “poor graft function (PGF)”, which is diagnosed in pts with ≥2 cytopenias after day +30, in the presence of donor chimerism and the absence of GVHD or relapse. PGF is more frequent after alternative allo-HSCTs, such a haplo-identical, mismatched, or UCB. Several therapeutic approaches for PGF, with poor results, have been tested. Recently, EPAG has been shown to improve platelet counts in the post-allo-HSCT setting. In this study, we analysed the efficacy of EPAG in pts with post-transplant persistent cytopenias.
Methods:The population analyzed includes all 175 pts who underwent allo-HSCT from June 2015 through May 2018 in our Unit. Median age was 52 years (12-69). 102 were male (58.3%) and 73 female (41.7%). Baseline diseases were: 69 AML, 39 LPD, 20 ALL, 18 MDS, 15 MPD, 9 MM, and 5 BMF. Donor was unrelated in 101 (54.3%) and was family in 74 (42.3%) (including 25 haplo-identical). Conditioning was RIC in 95 (54.3%) and intensive in 80 (45.7%). SC source was PB in 164 (93.7%) and BM in 11 (6.3%). Median follow-up was 24 months (6-41). EPAG was initiated at some point during the first 6-month post-HSCT period in 12 pts (6.9% of the series) due to thrombocytopenia (< 20000/mcL) plus, at least, one other cytopenia. Patients characteristics shown in table 1. EPAG was started at 50 mg/day and escalated each 2 weeks to 75, 125 and 150 mg/day if platelet count was < 20000/mcL. Global response was considered when, after EPAG, the patient needed no transfusions and reached the three of the following: platelets >50000/mcL, Hgb >10 g/dL, and ANC >1000/mcL. EPAG was tapered off in responders and discontinued if no response was reached after 16 weeks.
Results: At EPAG initiation, all the 12 pts had thrombocytopenia (< 20000/mcL), 10 had anemia (Hgb < 10 g/dL), and 5 had neutropenia (ANC < 1000/mcL). Counts pre and post and response to EPAG are shown in table 2. Among the 8 responders, all but one (who relapsed from thrombocytopenia and died from bleeding) were alive at analysis close (87.5%). Among the 4 non-responders, three pts had GVHD-associated cytopenias, and finally died from infectious complications; the other patient relapsed from her AML, reached a new CR after treatment, and is alive and well 27 months afterwards. EPAG was tapered off and discontinued in 6/8 pts who responded; 2/8 responders are still on EPAG. EPAG was discontinued in the 4/4 pts who did not respond. Rest of treatment details shown in table 2.
1) EPAG worked striking well in subjects with PGF, an otherwise a life-threatening situation for patients.
2) EPAG induced impressive responses in platelets, but strong bilinear and trilinear responses were also seen.
3) EPAG did not improve GVHD-associated cytopenias.
4) To confirm these innovative and transcendent results, we have just initiated a multicenter prospective study on the role of EPAG for treatment of post-HSCT PGF.
|EPAG after allo-HSCT (n=12)|
|Age (years) (median [range])||59 [24-69]|
|Gender (male/female)||7 (58.3%) // 5 (41.7%)|
|Baseline disease (AML // NHL // ALL // MDS // MF // AA)||3 // 4 // 2 // 1 // 1 // 1|
|Donor (URD* // Haplo** // MSD)||6 (50%) // 6 (50%) // 0 (0%)|
|Conditioning intensity (RIC // Intensive)||9 (75%) // 3 (25%)|
|SC source (PB // BM)||11 (91.7%) // 1 (8.3%)|
|Pre-HSCT transfusion load (PBRC) (median [range])||18 [0-122]|
|Pre-HSCT ferritin level (ng/mL) (median [range])||1232 [22-2149]|
* Five out of the six URDT were mismatched
** The donor was a woman in the six cases: three sisters and three daughters
[ [P133 Table] 1 . Characteristics of patients and transplants
|EPAG after allo-HSCT (n=12)|
|EPAG initiation (post-HSCT) (median [range])||Day +103 [17-178]|
|EPAG treatment duration (median [range])||19 weeks [2-84]|
|EPAG maximum dose (median [range])||150 mg/day [125-150]|
|Platelets pre-EPAG // post-EPAG* (n=8) (median [range])||13000 [1000-18000] // 104000 [39000-171000]|
|Hgb pre-EPAG // post-EPAG* (n=3) (median [range])||8.7 [7.3-9.8] // 13.3 [10.2-16.1]|
|ANC pre-EPAG // post-EPAG* (n=3) (median [range])||470 [70-660] // 3020 [1830-5200]|
|Global response to EPAG|
- Poor graft function (no GVHD) (N=9)|
- GVHD-associated cytopenia (N=3)
[ [P133 Table] 2 . EPAG treatment and response]
Disclosure: Nothing to declare
P134 Pooled safety analysis of defibrotide treatment in patients with HEPATIC veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) following hematopoietic stem cell transplantation (HSCT)
Paul Richardson1, Angela Smith2, Nancy Kernan3, Leslie Lehmann4, Robert Ryan5, William Tappe5, Stephan Grupp6
1 Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States, 2 University of Minnesota, Minneapolis, MN, United States, 3 Memorial Sloan Kettering Cancer Center, New York, NY, United States, 4 Center for Stem Cell Transplantation, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States, 5 Jazz Pharmaceuticals, Palo Alto, CA, United States, 6 The Children's Hospital of Philadelphia, Philadelphia, PA, United States
Background: Hepatic VOD/SOS with multi-organ dysfunction (MOD; typically, renal or pulmonary) may be associated with >80% mortality. Defibrotide is approved for treating severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the EU, and for hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the US. This analysis provides an overview of the safety results from 3 studies of patients with VOD/SOS, with or without MOD, who received defibrotide 25 mg/kg/day.
Methods: Safety data were pooled from patients with VOD/SOS post-HSCT treated with defibrotide in a phase 3 trial (n=102) and a phase 2, randomized dose-finding trial (n=74 receiving 25 mg/kg/day). Safety data for historical controls (HC) from the phase 3 study (n=32) also are provided. Reported separately, due to differences in patient population and data monitoring protocol, are AEs from the expanded-access program (T-IND) in patients with VOD/SOS with and without MOD (n=1000 post-HSCT). VOD/SOS was diagnosed by Baltimore criteria/biopsy for the phase 2/3 studies; diagnosis by Baltimore or modified Seattle criteria was permitted in the T-IND.
Results: Median patient age at HSCT for the phase 2/3 studies was 24.0 years, 18.0 years for the HC, and 14.0 years for the T-IND.
In the phase 2/3 studies defibrotide-treated group (n=176), 169 (96.0%) experienced AEs; most common (>10%) were hypotension (36.9%), diarrhea (24.4%), and multi-organ failure (21.6%). Treatment-related AEs were at least possibly related to defibrotide (Table). Any hemorrhage (an AE of special interest) occurred in 101 patients (57.4%); most commonly epistaxis (13.6%), gastrointestinal and pulmonary alveolar hemorrhage and hematuria (8.5% each), and conjunctival hemorrhage (6.3%).
All 32 HC experienced an AE; most common (>25%) were hypotension (50.0%), tachycardia (43.8%), diarrhea (37.5%), nausea (31.3%), and pyrexia, agitation, and petechiae (28.1% each). Any hemorrhage occurred in 24 patients (75.0%): most common (>10%) were petechiae (28.1%); hematuria, epistaxis, and pulmonary alveolar hemorrhage (15.6% each); and lip hemorrhage (12.5%).
In the T-IND (n=1000), 385/512 patients with MOD (75.2%) and 324/488 patients without MOD (66.4%) had an AE; other than VOD/SOS and MOD, most commonly (>10% in either subgroup) hypotension (15.2% and 8.4%, respectively). TRAEs occurred in 210 patients (21.0%) (Table). Any treatment-emergent hemorrhage occurred in 166 patients with MOD (32.4%) and 124 patients without MOD (25.4%); most commonly (>5% in either subgroup) pulmonary hemorrhage (8.2% and 4.7%, respectively) and gastrointestinal hemorrhage (5.5% and 4.3%, respectively).
Conclusions: The incidence and type of AEs were as expected in these critically ill patients. Of the pooled patients, 96% had AEs; 57.4% had a hemorrhage. All HCs had an AE, with 75.0% having a hemorrhage. In the T-IND, patients with MOD had higher rates of AEs.
Support: Jazz Pharmaceuticals
|Event, n(%)||Phase 2/3 studies (n=176)||
No MOD (n=488)
|Total TEAEs||169 (96.0)||385 (75.2)||324 (66.4)|
|Total TRAEs||58 (33.0)||118 (23.0)||92 (18.9)|
|Most Common by|
|PT: Pulmonary hemorrhage||10 (5.7)a||25 (4.9)||21 (4.3)|
|Hypotension||10 (5.7)||16 (3.1)||4 (0.8)|
|GI hemorrhage||7 (4.0)||16 (3.1)||14 (2.9)|
|Epistaxis||8 (4.5)||11 (2.1)||12 (2.5)|
[ [P134 Table] 1 . Table. Safety Summary]
Clinical Trial Registry: ClinicalTrials.gov: NCT00003966, NCT00358501, and NCT00628498
Disclosure: Paul G. Richardson has served on advisory committees and as a consultant, and has received research funding from Jazz Pharmaceuticals.
Angela R. Smith and Leslie Lehmann have nothing to disclose.
Nancy A. Kernan received grants from Gentium during the conduct of the study, and her research was supported by The National Cancer Institute of the National Institutes of Health under award number P30 CA008748; the content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health. She has a research grant from Jazz Pharmaceuticals.
Robert Ryan and William Tappe are employees of Jazz Pharmaceuticals and hold stock and/or stock options in Jazz Pharmaceuticals plc.
Stephan A. Grupp has served on a steering committee and as a consultant to Jazz Pharmaceuticals.
P135 Defibrotide for treatment of adults with hepatic VOD/SOS with or without multiorgan failure after hematopoietic cell transplantation: Results of a systematic review/meta-analysis
Mohamed Kharfan-Dabaja1, Tea Reljic2, Hemant Murthy3, Athanasios Tsalatsanis2, Mohamad Mohty4, Ambuj Kumar2
1 Mayo Clinic, Blood and Marrow Transplantation Program, Jacksonville, FL, United States, 2 University of South Florida, Morsani College of Medicine, Program of Comparative Effectiveness Research, Tampa, FL, United States, 3 University of Florida Health Cancer Center, Gainesville, FL, United States, 4 University Pierre & Marie Currie and Inserm UMRs 938, Paris, France
Background: Although hematopoietic cell transplantation (HCT), autologous or allogeneic, is potentially curable in various hematologic malignancies, the procedure is associated with serious and potentially life-threatening complications, among them veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) of the liver. Several studies, prospective or retrospective, have reported outcomes of defibrotide, when used as prophylaxis or treatment, in a mixed population of adult and pediatric patients. In this systematic review/meta-analysis, we analyze outcomes of defibrotide when specifically used for treatment of adult patients with hepatic VOD/SOS with or without multiorgan failure.
Methods: A comprehensive search of 3 large databases (Medline/Pubmed, Cochrane and EMBASE) on November 2, 2018 identified 642 publications. Analysis was restricted only to adult patients (defined as median age older than 16 years) who received defibrotide for treatment of VOD/SOS and were reported in prospective or retrospective (which included ≥ 5 patients) studies published in full manuscript form. There were no limitations based on language. Data were extracted in relation to benefits [complete remission (CR) rate and overall survival (OS)] and harms (hemorrhage, any site or organ-specific). A total of 15 studies (prospective=6; retrospective=9) with 1437 patients met inclusion criteria.
Results: The median year of publication of prospective studies was 2013 (2002-2018) and for retrospective ones 2016 (2000-2018). The prescribed starting dose of defibrotide varied among studies ranging from 6.25 mg/kg/day to 80 mg/kg/day, mostly for a 21-day course. The pooled CR rate was 39% (95%CI=28-49%) for prospective and 54% (95%CI=39-69%) for retrospective studies. The pooled day +100 OS rates were 43% (95%CI=37-48%) and 65% (95%CI=53-75%) for prospective and retrospective studies, respectively. The pooled rates of hemorrhage (any site) were 15% (95%CI=2-35%) for prospective and 21% (95%CI=4-43%) for retrospective studies. When analyzing organ-specific hemorrhage, 3 prospective studies (n=1091 patients) reported pooled rates of pulmonary alveolar (PA) hemorrhage of 2% (95%CI=1-3%) and of 5% (95%CI=3-7%) for gastrointestinal (GI) hemorrhage. Only one retrospective study (n=14 patients) reported an incidence of PA hemorrhage of 7% (95%CI=0-34%) and a different study (n=14 patients) reported an incidence of GI hemorrhage of 14% (95%CI=2-43%). None of the 15 studies reported cerebral hemorrhage as a complication of defibrotide therapy.
Conclusions: This systematic review/meta-analysis confirms the efficacy of defibrotide for treatment of VOD/SOS with or without multiorgan failure, yielding CR rates of 39-54% and day +100 OS rates of 43-65%. The purportedly higher pooled CR and OS rates observed with retrospective (vs. prospective) studies are likely due to assignment-bias inherent to observational studies. Moreover, although the pooled hemorrhage (any site) rates of 15-21% is considered proportionally significant, the pooled rates of PA and GI hemorrhage were ≤ 5%, in prospective studies.
Clinical Trial Registry: Not applicable
Disclosure: M.A.K-D: Consultancy for Pharmacyclics
M.M: received lectures honoraria and research support from Jazz Pharma
P136 Efficacy and safety of defibrotide in the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome following hematopoietic stem cell transplantation: Interim results from the defifrance study
Mohamad Mohty1, Myriam Labopin2, Delphine Lebon3, Ana Berceanu4, Charlotte Jubert5, Ibrahim Yakoub-Agha6, Stéphane Girault7, Marie Detrait8, Cécile Pochon9, Fanny Rialland10, Virginie Gandemer11, Régis Peffault de Latour12, David Michonneau12, Floriane Delaval13, Gerard Michel14, Anne Sirvent15, Laurence Clement16, Anne-Lise Menard17, Anne Huynh18, Virginie Bouvatier19, Raj Hanvesakul20, Zakaria Medeghri19, Jean-Hugues Dalle21
1 Hôpital Saint-Antoine, Paris, France, 2 Hôpital Saint-Antoine, Paris, France, 3 Chu Amiens Picardie Hôpital, Amiens, France, 4 Hôpital Jean Minjoz, Besançon, France, 5 Hôpital des Enfants, Bordeaux, France, 6 Hôpital Claude Huriez, Lille, France, 7 Hôpital Dupuytren - CHU Limoges, Limoges, France, 8 CHU Nancy, Nancy, France, 9 Hôpital D'Enfants, Nancy, France, 10 Hôtel-Dieu, Nantes, France, 11 CHU Hôpital Sud, Rennes, France, 12 Hôpital Saint-Louis, Paris, France, 13 Jazz Pharmaceuticals, Paris, France, 14 Hôpital de la Timone, Marseille, France, 15 Hôpital Arnaud de Villeneuve, Montpellier, France, 16 Hôpital Haut-Lévèque, Pessac, France, 17 Centre Henri Becquerel, Rouen, France, 18 IUCT Oncopole, Toulouse, France, 19 Jazz Pharmaceuticals, Lyon, France, 20 Jazz Pharmaceuticals, Oxford, United Kingdom, 21 Hôpital Robert Debré, Paris, France
Background: Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of conditioning for hematopoietic stem cell transplant (HSCT) but may occur after non-transplant chemotherapy alone. VOD/SOS with multi-organ dysfunction (MOD) may be associated with >80% mortality with supportive care alone. Diagnosis of VOD/SOS was traditionally based on Baltimore or modified Seattle criteria; however, the EBMT recently published separate diagnostic criteria for adults and children. Defibrotide is approved for treating severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the EU, and for hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the USA. The goal of the DEFIFRANCE study, requested by the French health authorities, is to collect real-world data on safety and efficacy in a broader patient population in France, including all indications. This is the first interim analysis of the largest current evaluation of defibrotide for the treatment of VOD/SOS in Europe.
Methods: DEFIFRANCE is an observational, multicenter, post-marketing study that includes any patient treated with defibrotide from HSCT centers in France. This interim analysis is based on all patients treated with defibrotide, including those with severe and very severe post-HSCT VOD/SOS. VOD/SOS was diagnosed using traditional criteria. Day+100 survival, complete remission (CR; total serum bilirubin < 2 mg/dL and resolution of MOD), and safety profile are reported.
Results: A total of 324 patients treated with defibrotide were included retrospectively and prospectively between July 2014 and October 2018 from 36 French sites. VOD/SOS was diagnosed in a subset of 140 patients (99 adults, 41 pediatric patients). Of these, 109 patients (74 adults; 35 pediatric patients) had severe or very severe VOD/SOS, divided in 50 severe VOD/SOS (31 adults; 19 pediatric patients) and 59 very severe VOD/SOS (43 adults; 16 pediatric patients).
Overall in the 140 VOD/SOS patients, Kaplan-Meier estimated Day+100 survival was 58.2% (95% CI, 49.2%-66.1%). Kaplan-Meier estimated Day+100 survival was 55.9% (95% CI, 45.8%-64.9%) in the combined severe/very severe VOD/SOS group (severe: 77.2% [95% CI, 62.6%-86.7%]; very severe: 37.2% [24.6%-49.8%]). CR rates were: overall, 52.8%; combined severe and very severe VOD/SOS: 52.0%; severe, 73.9%; very severe: 33.3%. The Table shows the safety profile.
Conclusions: This interim analysis of the DEFIFRANCE registry demonstrated estimated Day+100 survival of 58.2% overall in the patients with VOD/SOS and 55.9% in patients with confirmed severe or very severe VOD/SOS. The higher estimated survival for severe (77.2%) versus very severe (37.2%) VOD/SOS highlights the importance and impact of earlier intervention. Survival, CR rate, and safety findings, consistent with prior clinical trials, provide supportive evidence for the clinical utility of defibrotide for treatment VOD/SOS patients.
Support: Jazz Pharmaceuticals
|Events of Interest (>2%) n (%)||Overall Patients with VOD/SOS (n=140)||Patients with Severe or Very Severe VOD/SOS (n=109)|
|Total||75 (53.6)||57 (52.3)|
|Infection||34 (24.3)||26 (23.9)|
|Hemorrhage||28 (20.0)||20 (18.3)|
|Thromboembolic event||6 (4.3)||2 (1.8)|
|Low blood pressure||4 (2.9)||4 (3.7)|
[ [P136 Table] 1 . Table]
Mohamad Mohty: has received honoraria and research funding from Jazz Pharmaceuticals, Delphine Lebon: nothing to disclose, Ann Berceanu: none, Charlotte Jubert: has received funding from Jazz Pharmaceuticals, Ibrahim Yakoub-Agha: has received honoraria from Jazz Pharmaceuticals, Stéphane Girault: none, Marie Detrait: has received research funding from Jazz Pharmaceuticals, Cécile Pochon: none, Fanny Rialland: none, Virginie Gandemer: none, Jean-Hugues Dalle: has received honoraria from Jazz Pharmaceuticals, Régis Peffault de Latour: has received research grant / honoraria / board from Pfizer, Novartis, Alexion; research grant Amgen; and honoraria from Jazz Pharmaceuticals, David Michonneau: has received honoraria from Jazz Pharmaceuticals, Myriam Labopin: has received honoraria from Jazz Pharmaceuticals, Floriane Delaval: employee of Jazz Pharmaceuticals and holds stock and/or stock options in Jazz Pharmaceuticals plc, Gerard Michel: none, Anne Sirvent: none, Laurence Clement: none
Anne-Lise Menard: none, Anne Huynh: has received honoraria from Jazz Pharmaceuticals, Virginie Bouvatier: employee of Jazz Pharmaceuticals and holds stock and/or stock options in Jazz Pharmaceuticals plc, Raj Hanvesakul: employee of Jazz Pharmaceuticals and holds stock and/or stock options in Jazz Pharmaceuticals plc, Zakaria Medeghri: employee of Jazz Pharmaceuticals and holds stock and/or stock options in Jazz Pharmaceuticals plc
P137 Incidence and predictors of severe cardiotoxicity in patients with severe aplastic anemia after haploidentical hematopoietic stem cell transplantation
Zheng-Li Xu1, Lan-Ping Xu1, Yuan-Yuan Zhang1, Yi-Fei Cheng1, Xiao-Dong Mo1, Feng-Rong Wang1, Yu-Hong Chen1, Wei Han1, Chen-Hua Yan1, Yu-Qian Sun1, Ting-Ting Han1, Yu Wang1, Xiao-Hui Zhang1, Xiao-Jun Huang1
1 Peking University Institute of Hematology, Peking University People's Hospital, Beijing, China
Background: Severe cardiotoxicity after hematopoietic stem cell transplantation (HSCT) is a rare but fatal complication. The aim of this study was to evaluate the frequency of severe cardiac complications and to assess the ability of various factors to predict these complications in patients with aplastic anemia after haploidentical transplantation., this is the first study evaluating the values of both clinical and imaging factors in the prediction of severe cardiotoxicity among SAA patients after haploidentical transplantation.
Methods: A retrospective study was conducted in 216 consecutive aplastic anemia patients who received haploidentical transplantation from 2006 to 2017. All patients received a unified regimen including busulfan, cyclophosphamide (CTX) and antithymocyte globulin at our single center.
Results: A total of 12 (5.6%) patients developed grade III or IV cardiac toxicity. Patients with cardiotoxicity had significantly poorer overall survival (OS) than those without cardiotoxicity (12.5% vs. 89.6%, P< 0.001). Our multivariable model identified four independent adverse predictors of severe cardiotoxicity, including pre-transplant ECOG score (≥2), abnormal ST-T wave on 12-lead electrocardiogram (ECG), hyperlipemia and recalculated CTX dose (≥1.8 g/m2/d). A predictive risk model was refined as low risk (0-1 factor), intermediate risk (2 factors) and high risk (3-4 factors). The respective incidences of severe cardiotoxicity were 50.0%, 6.0%, and 1.3% in the high-, intermediate- and low-risk groups (P< 0.001). The corresponding OS rates were 49.0%, 80.4%, and 90.3% in the three groups (P< 0.001) at the last follow-up.
Conclusions: Patients with high risk scores had the poorest outcomes and should be monitored closely. A reduced intensity conditioning might be recommended for these patients.
Disclosure: There are no conflicts of interest to declare.
P138 Impact of acute renal failure in transplant-related mortality and development of chronic renal disease in allogeneic stem-cell transplantation
Marta Garrote1, Jesus Villarreal1, Roger Borràs2, Ana Moreno-Castaño1, Montse Rovira1, María Suárez-Lledó1, Luis Gerardo Rodríguez-Lobato1, Carmen Martínez1, Laura Rosiñol1, Noemi Llobet1, Carla Ramos1, Álvaro Urbano-Ispizua1, Francesc Fernández-Avilés1, Luis Fernando Quintana1, Gonzalo Gutiérrez-García1
1 Hospital Clínic de Barcelona, Haematology, Barcelona, Spain, 2 Institut de Recerca Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Background: Allogeneic stem-cell transplantation (allo-SCT) is associated with significant transplant-related mortality (TRM). Acute renal failure (ARF) is a frequent complication and usually presents early after the procedure, compromising its feasibility. The aim of this study is to analyse the incidence of ARF, its risk factors and its potential impact on TRM after allo-SCT.
Methods:422 patients were included (244 males [58%]; median age 43 years, range 16-67) treated with Allo-SCT consecutively between January 2001 and April 2012 in a single institution. Patient characteristics are detailed in table 1. Median follow-up was 1.8 years (range, 1.0-2.7). Renal function was evaluated using creatinine and data was collected pre-transplant (baseline) and at the point when ARF was developed after allo-SCT. ARF was evaluated using AKIN criteria, being AKIN-1 an increase 1.5- to 1.9-fold from baseline, AKIN-2 an increase 2.0- to 2.0-fold and AKIN-3 an increase ≥3-fold. Chronic renal disease was evaluated one year after the date of ARF using KDIGO criteria.
Results: Cumulative incidence of ARF at 1 year was 63% (AKIN-1, 25%; AKIN-2, 27%; AKIN-3, 15%). In the multivariate analysis, ARF (AKIN-1/2) was associated with: non-use of antithymocyte globulin in conditioning chemotherapy, p=0.02 (HR 2.3, 0.2 to 0.9) and development of severe aGvHD, p=0.04 (HR= 1.5, 1 to 2.3). In patients with ARF AKIN-3, the most important variables in the multivariate analysis were: use of methotrexate (MTX) plus cyclosporine vs mycophenolate mofetil plus cyclosporine as GvHD prophylaxis, p=0.009 (HR=1.9, 1.2 to 3.1); myeloablative conditioning vs reduced intensity, p=0.03 (HR=1.7, 1 to 2.8) and use of total irradiation therapy in conditioning, p=0.02 (HR=1.7, 1.1 to 2.8). TRM at 1 year increased significantly according to AKIN: AKIN-1, 25%; AKIN 2, 35%; AKIN 3, 51%; p=0,003; HR=11.2. Overall survival at 3 years according to AKIN was: AKIN 1, 52%, AKIN 2, 45% and AKIN 3, 29%; p=0,004 (figure 1). The incidence of chronic renal disease at 1 year after allo-SCT according to ARF was: no ARF (8%), AKIN-1 (11%), AKIN-2 (15%) and AKIN-3 (16%); p=0.006.
Conclusions: ARF is a frequent complication during the first year after allo-SCT and is associated with several factors. ARF AKIN-3 was associated with more intensive strategies received during conditioning, meanwhile AKIN-1/2 were related to development of GvHD. There is an association of ARF (AKIN-1, 2 or 3) with development of chronic renal disease.
|Diagnosis||Acute leukemia, 189 (44); MDS, 41 (10); lymphoma, 102 (25); other, 90 (21)|
|Donor type||Sibling, 232 (55); unrelated, 190 (45)|
|HLA 8/8 identity||357 (85)|
|Stem-cell source||Peripheral blood, 333 (80); bone marrow, 63 (15); umbilical cord, 22 (5)|
|Conditioning||Myeloablative, 208 (49); reduced intensity, 214 (51)|
|Total body irradiation||188 (45)|
|GvHD prophylaxis||Cyclosporine + MTX, 191 (46); cyclosporine + mycophenolate, 183 (44); other, 41 (10)|
|Risk for CMV reactivation||Low, 158 (41); intermediate, 127 (33); high, 102 (26)|
[ [P138 Table] 1 . Table 1. Patients characteristics, N (%)]
[ [P138 Image] 1 . Figure 1. Overall survival according to acute renal failure AKIN criteria]
Gonzalo Gutiérrez-García: honoraria from Gilead. Grant from Jazz Pharmaceutical.
The other authors do not have any disclosure to declare.
P139 Allogeneic stem cell transplantation at-home program in the post-transplant cyclophosphamide GVHD prophylaxis era
Gonzalo Gutiérrez-García1,2,3, Montserrat Rovira1,2,3, Pilar Ayora1, Ariadna Domenech1, Cristina Gallego1, María Teresa Solano1, Ana B Moreno-Castaño1,2,3, María Suárez-Lledó1,2,3, Nuria Borràs1, Luis Gerardo Rodríguez-Lobato1,2,3, Julio César Solano-Vega1, Laura Rosiñol1,2,3, Carmen Martínez1,2,3, Pedro Marín1,2,3, María Adelina Hernando1, Álvaro Urbano-Ispizua1,2,3, Francesc Fernández-Avilés1,2,3
1 Hospital Clínic de Barcelona, Hematology, Barcelona, Spain, 2 University Barcelona, Barcelona, Spain, 3 Institut de Recerca Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Background: The introduction of cellular therapies such as CAR-T and modalities of GvHD-prophylaxis with post-transplant/cyclophosphamide (PtCy) that increase the number of admission days have boosted the pressure of available beds in the BM-units. In this sense, our centre started an at-home allogeneic stem cell transplantation (allo-SCT) program to follow aplasia from the D+1 until independent ambulatory patient. To evaluate the feasibility and safety of alloSCT, we compared two groups: alloHSCT/at-home (AH-Group) vs. alloHSCT/in-patient (IP-Group).
Methods: We included 78 patients receiving alloSCT (January 2014-November 2018) in a single centre: 39 patients, AH-Group and 39, IP-Group. All patients received conditioning at the hospital. GvHD-prophylaxis consisted in tacrolimus (TK) plus mycophenolate (MPM) or methotrexate, or PtCy (D+3, D+4) plus TK (D+5). All patients received prophylaxis with levofloxacin, fluconazole and acyclovir. Besides that, AH-Group patients received prophylaxis with ceftriaxone 1g/24h IV or ertapenem 1g/24h IV, and Aspergillus-prophylaxis with inhaled liposomal amphotericin-B or posaconazole during neutropenia. Patients of AH-Group since D+1 or D+6 (in PtCy-prophylaxis) received a nurse visit at-home once daily. The visits by the physician were performed at the hospital and only during complication events. First-line therapy of neutropenic fever was meropenem 1 g/8h in both groups, using a portable infusion pump in AH-Group. In this group, the absence of focal infection or signs of severe sepsis allowed returning home after the initiation of antibiotics. The platelets support was performed at-home and the red blood support at hospital.
Results: The median (range) age (years) of the series was 54 (19-70). The median follow-up of the series has been not achieved. The source of the SCT was peripheral blood in all cases. We didn't find statistical differences between two groups (AH vs IP) in terms of age, diagnosis, type of donor, intensity of conditioning, GvHD-prophylaxis, toxicity (mucositis, acute renal injury, neutropenia and thrombocytopenia), aGvHD, Aspergilosis and TRM. Interestingly, a significant reduction of neutropenic fever was observed resulting the lower use of meropenem in the AH-group than IP-group. The admission median days were similar in the both groups and it represented 21-23 days the reduction in the total economic cost of the AH-group. The whole analysis of the results are detailed in table:
|N=78||In-Patient Group, (N=39), N(%)||At-Home Group, N=39, N(%)||P|
|Donor: Sibling, URD, Haploidentical||19 (49%), 19 (49%), 1 (2%)||14 (36%), 24 (62%), 1 (2%)||0.5|
|Conditioning: MAC||14 (36%)||17 (44%)||0.5|
|GvHD prophylaxis: TK/MMF; TK/MTX; PtCy/TK||23 (59%), 4 (10%), 21 (31%)||26 (68%), 2 (5%), 11 (28%)||0.6|
|Neutropenia <0.5x10e9/L (Median-range,days)||17 (11-37)||17 (8-23)||0.8|
|Neutropenic fever and Aspergillosis||35 (90%), 1 (3%)||11 (39%), 1 (3%)||<0.0001 and 0.6|
|Mucositis (grade 3-4) and Acute renal injury||10 (26%), 24 (62%)||5 (13%), 27 (69%)||0.3 and 0.5|
|Re-admission rate, only for At-Home group||-||3 (8%)||-|
|aGVHD||27 (69%)||30 (77%)||0.4|
|1-year-TRM and 2-year- OS||26% and 69%||21% and 66%||0.5 and 0.8|
[ [P139 Table] 1 . Results]
Conclusions: In our experience, at home alloSCT, including PtCy-GvHD prophylaxis, is a feasible and safe procedure reflected in similar TRM and Aspergillosis incidence. At-home allo-SCT is associated with a significant lower risk of neutropenic fever than in-patient group, as well as a very low readmission rate.
Gonzalo Gutiérrez-García: honoraria from Gilead. Grant from Jazz Pharmaceutical and Janssen.
Laura Rosiñol: honoraria from Takeda, Janssen, Amgen and Celgene.
The others author do not have any disclosures to declare.
P140 Stable renal function in children and adolescents with sickle cell disease after non-myeloablative conditioning hematopoietic stem cell transplant
Sasia Julie Volden Pedersen1, Dania Monagel2, Cherry Mammen3, Victor A. Lewis4, Greg M. T. Guilcher4, Aisha Bruce5
1 University of Alberta Hospital/Stollery Children's Hospital, Edmonton, Canada, 2 Alberta Children's Hospital, Calgary, Canada, 3 British Columbia Children's Hospital, Vancouver, Canada, 4 Alberta Children's Hospital, Calgary, Canada, 5 University of Alberta Hospital/Stollery Children's Hospital, Edmonton, Canada
Background: Renal complications in sickle cell disease (SCD) include episodes of acute kidney injury (AKI), progressive chronic kidney disease (CKD) and hyperfiltration, defined by abnormally high glomerular filtration rates (GFRs). Hematopoietic stem cell transplant (HSCT) from an HLA identical sibling donor is a well-established curative treatment for SCD, but traditional myeloablative conditioning (MAC) regimens pose risks of kidney injury due to intensive use of chemotherapeutic agents, infectious risks, and use of calcineurin inhibitors (CNIs). AKI and subsequent fluid overload (FO) are common in pediatric HSCT with reported AKI incidence of 21%-50% (Kyung-Nam Koh et. Al., 2017). We report renal outcomes in pediatric patients with SCD who received HSCT following a non-myeloablative conditioning (NMA) regimen without CNI exposure.
Methods: Retrospective chart review describing renal outcomes in pediatric patients (18 years of age or younger) with SCD (HbSS) who underwent NMA HSCT in Alberta, Canada from July 2013 to February 2018. The NMA regimen is illustrated in Figure 1. Reported renal outcomes: 1) measured GFR (DTPA) pre-HSCT, 2) AKI (KDIGO definition) post-HSCT by reviewing all serum creatinine levels from pre-HSCT to one month post-HSCT, 3) %FO calculated: (max post HSCT weight - baseline weight)/baseline weight x 100 for the two first weeks post-HSCT, and 4) estimated GFR (eGFR) using the pediatric Schwartz formula at last follow-up post-HSCT, CKD defined as eGFR < 60 mL/min/1.73 m2, mildly reduced GFR: 60-90mL/min/1.73 m2, and hyperfiltration: GFR ≥ 150 mL/min/1.73 m2.
[ [P140 Image] 1 . Figure 1: NMA regimen used]
Results: Eighteen patients (33% male, 3-18 years old at transplant) were included. Most common pre-morbid events: vaso-occlusive crisis (n=17), acute chest syndrome (n=8), splenic sequestration (n=6), and cholelithiasis (n=4). Median follow-up time: 27 months (range: 7 - 62 months). All patients engrafted successfully with no acute or chronic GVHD.
Baseline measured GFRs were all > 60 mL/min/1.73 m2 (range: 79-227) with mildly reduced GFR and hyperfiltration seen in one (5.6%) and 12 (66.7%) patients respectively.
At baseline (pre-HSCT), the only AKI event was one transplant related AKI secondary to delayed hemolytic reaction after exchange transfusion in preparation for transplant. Post-HSCT, there were no AKI events. Additionally, no substantial %FO post-HSCT was observed. Average %FO week one post-HSCT: +0.01% (Range: -4.2% - +1.0%) and week two post-HSCT: +0.04% (Range: -4.24% - +1.5%).
Post-HSCT eGFR remained > 90 mL/min/1.73 m2 at last follow-up in all patients. Hyperfiltration was present in 5 (27.8%) of the patients.
Conclusions: This is the first study describing stable kidney function in children with SCD after the present NMA HSCT regimen with alemtuzumab/300 cGy total body irradiation (TBI) with prolonged post-HSCT Sirolimus. No episodes of AKI or significant fluid overload were observed during the first month post-HSCT, and no patient developed CKD during follow-up. Further prospective studies are needed to confirm our findings and to determine if stable renal function persists during longer-term follow-up.
Disclosure: Nothing to declare.
P141 Lung microbiota in patients with idiopathic pneumonia syndrome (IPS) after HCT
Sachiko Seo1,2, Andrew Connell3, John Everett3, Joshua Hill1,4, Terry Stevens-Ayers1, Keith Jerome1,4, Frederic Bushman3, Collman Ronald3, Michael Boeckh1,4
1 Fred Hutchinson Cancer Research Center, Seattle, WA, United States, 2 Dokkyo Medical University, Tochigi, Japan, 3 University of Pennsylvania Perelman School of Medicine, Pennsylvania, PA, United States, 4 University of Washington, Seattle, WA, United States
Background: Idiopathic pneumonia syndrome (IPS) is a non-infectious pulmonary complication after hematopoietic cell transplantation (HCT) and the etiology remains unknown. Recent studies have reported that various diseases are associated with changes of microbiota. The aim of this study was to evaluate the lung microbiota in HCT recipients with IPS and identify microorganisms potentially associated with IPS.
Methods: Frozen bronchoalveolar lavage (BAL) samples from HCT recipients with IPS (N=18) and research BAL samples from asymptomatic HCT recipients as controls (N=12) were retrospectively analyzed. All samples were negative for common viruses by quantitative PCR. Sequencing libraries were made with 1ng of input DNA per sample (Nextera XT, Illumina). Samples were pooled and sequenced by HiSeq 2000 to obtain 100-bp paired end data. Sequence data analysis and read classification were performed with Sunbeam and the quality control and read classification were performed using Komplexity and Kraken, which classifies bacterial, archeal, and viral genomes. We used sequence data of bronchoscope prewashes from a separate cohort as controls for environmental sources (N=24). Bray-Curtiss dissimilarity among samples was calculated using the Vegan R packages. PERMANOVA and a two-sided Wilcoxon rank sum test were used to compare between the study groups.
Results: BAL samples started at a median of 22x106 raw read pairs per sample and reduced to 21x103 reads assignable to microbial taxa following quality control. The bacterial phyla Proteobacteria and Firmicutes were most abundant followed by Bacteroidetes and Actinobacteria in both BAL and bronchoscope prewash samples. Separation of BAL and prewash microbiota using Bray-Curtiss dissimilarity plots showed that BAL samples were distinguished by sequences assigned to Staphylococcus, Acidovorax, and Bradyrhizobium species, while prewash samples were distinguished mostly by Pseudomonas and Elizabethkingia species, consistent with environmental sources (Figure). Within BAL samples, Staphylococcus species were the main drivers of separation between IPS cases and the controls (p=0.002, PERMANOVA, Figure). Consistent with this, a linear discriminant analysis to identify taxa best distinguishing cases and controls identified Staphylococcus, especially S. epidermidis, in IPS cases with Lactobacillus and Streptococcus species in controls. We then compared relative abundances of S. epidermidis between all study groups. IPS case samples were significantly enriched in S. epidermidis compared to control (p< 0.001, two-sided Wilcoxon rank sum test) and prewash samples (p< 0.001). Viruses were classified by category as human pathogens, non-human pathogens, and bacteriophages. Torque teno viruses (TTV) was the most commonly detected virus among viruses that replicate on human cells, and there was a trend towards higher abundance in IPS case samples than controls.
Conclusions: Lung microbial sequences in HCT recipients predominantly consisted of Proteobacteria and Firmicutes, and had considerable overlap with environmental background. Patients with IPS had significantly more Staphylococcus sequences detected than asymptomatic HCT patients. These results suggest that patients with acute lung injury post-HCT show distinct patterns of lung microbiota, although heterogeneity of sample collection and processing cannot be excluded and no singular organism was uniquely associated with IPS. A prospective study is required to confirm these findings and define the clinical significance of differences in abundance patterns.
Disclosure: Nothing to declare
P143 Romiplostim for the treatment of thrombocytopenia after allogeneic stem cell transplantation
Maria Liga1, Nikos Spyridis1, Dimitris Aggelinas1, Chara Korovila1, Evangellia Triantafyllou1, Panagiotis Bountouris1, Markos Marangos1, Alexandros Spyridonidis1
1 University Hospital of Patras, Patras, Greece
Background: Thrombocytopenia is a common complication after allogeneic stem cell transplantation (allo-HCT). with variable possible causes, such as drug side effects, infections, poor graft function, Graft vs Host disease (GvHD) and immune mediated. The purpose of this study was to evaluate the efficacy of romiplostim, a thrombopoietin receptor agonist, in patients with prolonged thrombocytopenia with no obvious cause after allogeneic transplantation.
Methods: Retrospective analysis of allo-HCT patients who received romiplostim at a single BMT Unit between November 2015 and November 2018. Romiplostim was given because of prolonged (>3 weeks) thrombocytopenia (< 60,000 µL) that couldn't be explained by obvious causes such as administration of drugs (antibiotics/antivirals), infection or GvHD. All patients were in complete remission and had complete chimerism. Response to romiplostim treatment was considered transfusion independence or PLT>80.000/µL.
Results: In total, 19 patients (median 45 years, 19-67) received romiplostim. Patients (10 male, 9 females) had AML (10 pts), ALL (8), MDS (2) or Hodgkin (1), received a myeloblative (busiphex-based: 16, TBI-based:1) or RIC (2) conditioning and were transplanted from a sibling (5), VUD (11) or haploidentical (3) donor with PBSC (16) or BM (3). All patients revealed primary neutrophil (median 14 days, range 10-19) and >20.000/µL platelet (13 days, 7-31) engraftment. Romiplostim was started at median day+104 (range 58-419) with a median dose 5 µg/kg (1-5). The median platelet count before commencement of treatment with romiplostim was 24.000/µL (range 12.000-57.000) and 10 them (59%) were transfusion-dependent. In total 14/17 (82%) patients responded to romiplostim treatment. Eight out of the 10 (80%) transfusion dependent patients responded to the administration of romiplostim. Six out of the 7 patients (86%) who were transfusion independent at romiplostin initiation (PLT median 28.000/µL, range 19.000-56.000) responded. The median duration of treatment was 74 days (15-253) and the median follow up from the commencement of romiplostim was 177 days (15-1080). Three out of 17 (18%) patients experienced relapse of thrombocytopenia after discontinuation of romiplostim and re-initiation of romiplostim was commenced in all of them, of which 2 responded and 1 didn't. The administration of romiplostim was done on an external basis and was well tolerated by the patients. Two patients experienced GvHD during romiplostim treatment (both patients transplanted from 7/8 unrelated donor, 25 and 42 days after initiation treatment with romiplostim). 3/19 patients interrupted romiplostim due to disease relapse. 11/19 patients receiving romiplostim are alive in complete remission and 8 died (3 due to relapse, and 5 due to TRM).
Conclusions: We present high response rates to romiplostim in patients with prolonged thrombocytopenia after allogeneic transplantation. In this retrospective study there were no side effects from the administration of romiplostim. However, the administration of romiplostim after allo-HCT should be controlled in prospective trials.
Disclosure: Nothing to declare
P144 Thrombopoietin receptor agonists for management of poor graft function in adult patients after allogeneic HSCT
Tatiana Rudakova1, Alexander Kulagin1, Olesya Klimova1, Irina Golubovskaya1, Tatiana Bykova1, Elena Darskaya1, Sergey Bondarenko1, Ivan Moiseev1, Ildar Barkhatov1, Elena Babenko1, Alexander Alyanskiy1, Boris Afanasyev1
1 Pavlov First Saint Petersburg State Medical University/Raisa Gorbacheva Memorial Institute of Children's Oncology, Hematology and Transplantation, St. Petersburg, Russian Federation
Background: Poor graft function (PGF) is a life-threatening complication of allo-HSCT. Currently there is no standard therapy for treatment PGF. Thrombopoietin receptor (TPO) agonists showing desirable results in severe aplastic anemia may be a possible strategy to resolve severe PGF (sPGF) after allo-HSCT. The aim of our study was to assess an efficacy of TPO agonists for PGF after allo-HSCT in adult patients.
Methods: We report a single-center analysis of 29 adult patients (median age 22 years, range 18-57, M/F 13/16), receiving TPO agonists for isolated severe thrombocytopenia (n=7) and sPGF (n=22) after allo-HSCT. Primary diagnoses were AML (10), ALL (6), MDS (7), PMF (4), MDS/MPN (4), SAA (4), CML (1), NHL (1). Severe PGF was defined as cytopenia in ≥ 2 lineages (platelet < 20 × 109/L, ANC < 0.5 × 109/L, hemoglobin < 70 g/L any time after sustained engraftment), full or stable mixed donor chimerism > 90 % and no signs of relapse. Median dose of romiplostim was 5 (range, 3-5) mcg/kg weekly, eltrombopag - 50 (range, 50-150) mg/day. Overall response (OR) included CR (platelet ≥ 100 × 109/L, ANC ≥ 1.5 × 109/L, and hemoglobin ≥ 100 g/l) and PR (platelet > 20× 109/L, ANC ≥ 0,5 × 109/L, hemoglobin > 70 g/l).
Results: Median time from PGF diagnosis to treatment with TPO agonists was 14 days (0-119), median treatment duration was 3 weeks (1-43). TPO agonists were well tolerated with no cases of grade III-IV toxicity. TPO agonists were combined with rituximab (n=4), rituximab and DLI (n=3) and HSC boost (n=1) in 8 (28 %) patients. A total of 14 (48 %) patients met criteria of response (CR: n=4, 14 %; PR: n=10, 34 %). Combination therapy showed no difference in OR compared to TPO agonists alone. OR was not depended on the TPO agonist used nor the time to therapy initiation. Median increase in ANC in responders was 3.4 × 109/L (0.8-6.0), in platelet count - 48×109/L (21-205). A total of 15 patients died due to relapse (n=2), GVHD III-IV grade (n=3) and infection (n=10). Two-year OS from the start of TPO agonist therapy was 44 % (95 % CI, 25-62) with a significant difference between responders and non-responders: 71 % (95 % CI, 33-90) vs. 18 % (95 % CI, 3-40) (p=0,002).
Conclusions: This study showed promising results of TPO agonists for management of sPGF. Further studies are warranted to specify optimal timing and dosing regimen, predictors of response.
[ [P144 Image] 1 . Two-year OS in responders and non-responders to TPO agonist therapy]
Disclosure: There are conflicts of interest to disclose
P145 Cytomegalovirus reactivation kinetics and peak titers as novel predictors of survival and relapse after allogeneic cell transplantation for hematologic malignancies
Saskia Leserer1, Evren Bayraktar1, Nikolaos Tsachakis-Mück1, Michael Koldehoff1, Lara Kasperidus1, Esteban Arrieta-Bolanos1, Mirko Trilling1, Katharina Fleischhauer1, Dietrich W. Beelen1, Amin T. Turki1
1 University Hospital Essen, Essen, Germany,
Background: After allogeneic hematopoietic cell transplantation (HCT), human Cytomegalovirus (CMV) reactivation associates with non-relapse mortality (NRM) but also with reduced relapse in patients with leukemia, as shown by numerous studies that evaluated CMV reactivation as a qualitative yes/no parameter in the first months post-transplant. We hypothesized that longitudinal quantitative assessment of CMV reactivation kinetics and virus loads might improve patient-specific clinical outcome associations.
Methods: This retrospective study included 705 patients with HCT for hematologic malignancies treated between 01/2012 and 12/2017 at University Hospital Essen, Germany. CMV titers were monitored weekly by quantitative PCR (qPCR); CMV reactivation was defined by a cut-off of >500 genome copies per ml. Patients were included for analysis, if at least 5 measurements were available during the first 200 days after HCT. In total, 11,508 samples were analyzed. Subgroup analyses were performed according to the time of CMV reactivation (before/after +30d) or the CMV viremia titer (>100,000, 20,000 - 100,000 and 500 - 20,000 copies/ml).
Results: CMV reactivation was detected in 350 (median age 58 years; range 17-76 years) out of 705 patients. Baseline characteristics (age, gender, underlying disease, transplant) of patients without CMV reactivation were comparable. CMV reactivation kinetics followed a Gaussian normal distribution with a median first reactivation at +33d and peak titers at +47d. All except 1 patient reactivated before 100d, 40 % before +30d. Overall survival (OS) of the CMV reactivation group as a whole did not significantly differ from the non-reactivation group (34 vs. 38 months).
However, in subgroup analyses OS was significantly reduced in patients with very early (< +30d) compared to later reactivation (17 vs. 59 months, p=0.040). Moreover and importantly, OS was significantly reduced in patients with CMV reactivation at high titers of >100,000 copies/ml compared to those with lower titers ((10 vs. 45 months) p< 0.0001).Cox regression analyses confirmed significantly reduced OS for patients with CMV reactivation >100,000 copies/ml and < day +30 as compared to the other cohorts (HR 2.03, 95%CI 1.45-2.86, p< 0.0001 and HR 1.36, 95%CI 1.01-1.83, p=0.041) respectively). The NRM was consistently higher (HR 2.59; 95%CI, 1.69-3.97, p< 0.0001) for patients with CMV copies >100,000/ml. The risk of hematologic relapse was exclusively reduced in patients with a peak CMV viremia between 20,000 and 100,000 copies/ml (HR 0.55, 95% CI 0.32-0.95; p=0.033) as compared to patients without CMV reactivation. For other levels of CMV reactivation this effect was not observed.
Conclusions: Our data showed that CMV reactivations before +30d or with high titers of >100,000 copies/ml associated with significantly reduced OS, while CMV reactivations at intermediate titers between 20,000 and 100,000 copies/ml had a positive impact on relapse incidence. These findings underline the complexity of CMV reactivations after HCT outcome, and support longitudinal evaluation of CMV titers and individualized quantitative kinetics models for risk assessment after HCT to distinguish the advantageous from the detrimental aspects of CMV reactivation.
Disclosure: ATT has received lecture fees from Jazz Pharmaceuticals and travel subsidies from Neovii Biotech outside the submitted work. The other authors declare no competing financial interests within the submitted work.
P146 Association of serum ferritin levels before start of conditioning with mortality after alloSCT - a prospective, non-interventional study of the EBMT transplant complication working party
Olaf Penack1, Christophe Peczynski2, Steffie van der Werf3, Mohammad Mohty4, Ibrahim Yakoub-Agha5, Sylvia Montoto6, Jürgen Finke7, Arnold Ganser8, Helene Schoemans9, Jane Apperley10, Ritta Niittyvuopio11, Wilfried Schroyens12, A Unal13, Armin Gerbitz14, Michael Schaap15, J Sierra16, Agostino Cortelezzi17, Gerald Wulf18, Pascal Turlure19, Montserat Rovira20, Z Ozkurt21, M Pascual Cascon22, Johannes Clausen23, Hildegard Greinix24, Rafael Duarte25, Grzegorz Basak26
1 Charite Campus Virchow Klinikum, Hematology, Berlin, Germany, 2 EBMT Paris Study Office/CEREST-TC, Hôpital Saint Antoine, Paris, France, 3 EBMT Leiden Data Office, Leiden, Netherlands, 4 Hospital Saint Antoine, Paris, France, 5 CHRU Lille, Lille, France, 6 St. Bartholomew's and the Royal London NHS Trust, London, United Kingdom, 7 University Freiburg, Freiburg, Germany, 8 University Hannover, Hannover, Germany, 9 University Hospital Gasthuis, Leuven, Belgium, 10 Imperial College London, London, United Kingdom, 11 HUCH Comprehensive Cancer Center, Helsinki, Finland, 12 Antwerp University Hospital, Antwerp, Belgium, 13 Erciyes Medical School, Kayseri, Turkey, 14 Charité Univerisätsmedizin Berlin, Berlin, Germany, 15 Radboud University, Nijmegen, Netherlands, 16 Hospital Santa Creu i Sant Pau, Barcelona, Spain, 17 Fondazione IRCCS - Ca'Granda, Milan, Italy, 18 Universitätsklinikum Göttingen, Göttingen, Germany, 19 CHRU Limoge, Limoge, France, 20 Hospital Clinic, Barcelona, Spain, 21 Gazi University Faculty of Medicine, Ankara, Turkey, 22 Hospital Regional de Málaga, Malaga, Spain, 23 Ordensklinikum, Linz, Austria, 24 University Hospital Graz, Graz, Australia, 25 Hospital Universitario Puerta de Hierro, Madrid, Spain, 26 Central Clinical Hospital, Warsaw, Poland
Background: Elevated serum ferritin levels occur due to iron overload or during inflammation and macrophage activation. A correlation of high serum ferritin levels with increased mortality after alloSCT has been suggested by several retrospective analyses as well as by two smaller prospective studies.
Methods: This international multicentric study aimed to study the association of ferritin serum levels before start of conditioning with alloSCT outcome. Patients with acute leukemia, lymphoma or MDS receiving a matched sibling alloSCT for the first time were considered for inclusion, regardless of conditioning. Data were prospectively collected between 8/2014 and 2/2018. A comparison of outcomes between patients with high and low ferritin level was performed using univariate analysis and multivariate analysis using cause-specific Cox model. Variables included in the multivariate analyses were age, sex mismatch, diagnosis, disease status, Karnofsky score, number of CD34 cells given, intensity of conditioning, type of GVHD prophylaxis, ATG use, time from diagnosis to transplant, year of transplant and CMV status.
Results: Twenty centers from 10 European countries reported data on 385 alloSCT recipients. Patient characteristics are given in Table 1. The ferritin cut off point was determined at 1500µg/l (median of measured ferritin levels). Overall survival of alloSCT recipients with ferritin levels above cut off measured before start of conditioning was significantly shorter (Figure 1A, univariate HR=2.3 CI=1.4-3.6 p=0.00041; multivariate HR=2.5, CI=1.5-4.1, p=0.0005). Progression-free survival was also shorter (Figure 1B, univariate HR=2.1 CI=1.4-3.2 p=0.00014; multivariate HR=2.4, CI=1.6-3.8, p< 0.0001). Excess mortality in the high ferritin group was due to both higher relapse incidence (univariate HR=1.7 CI=1-2.8 p=0.03; multivariate HR=2.2, CI=1.2-3.8, p=0.007) and increased non-relapse mortality (univariate HR=3.1 CI=1.5-6.3 p=0.002; multivariate HR=3.1, CI=1.5-6.4, p=0.002). Non-relapse mortality was driven by significantly higher infection-related mortality in the high ferritin group (univariate HR=3.9 CI=1.6-9.7 p = 0.003; multivariate HR = 3.9, CI = 1.6-9.7 p = 0.003). Acute and chronic GVHD incidence or severity were not associated to serum ferritin levels.
Conclusions: Ferritin levels before start of conditioning can serve as routine laboratory biomarker to predict mortality after alloSCT.
|Ferritin <=1500µg/l (n=153)||Ferritin >1500µg/l (n=145)||p-value|
|Year of transplant median(range)[IQR]||2016(2014-2018)[2015-2017]||2015(2014-2018)[2015-2016]||0.6|
|Patient age (years) median(range)[IQR]||52(17.1-71.3)[38.1-60.2]||53.2(19-70.9)[42.9-62.3]||0.3|
|Time from diagnosis to transplant (months) median (range)[IQR]||5(1-71)[3-8]||4(1-61)[3-6]||0.05|
|Number of CD34+ cells infused (e+06) median (range)[IQR]||5.9(0.9-10.7)[4.5-7.2]||5.5(0.6-10.2)[4.2-6.7]||0.1|
|Sex mismatch Female to male Other combination||27(18%) 123(82%)||43(30%) 98(70%)||0.012|
|Diagnosis Acute leukaemia Lymphoma MDS||93(61%) 19(12%) 41(27%)||107(74%) 12(8%) 26(18%)||0.058|
|Disease status CR Not in CR||94(64%) 54(36%)||98(70%) 42(30%)||0.2|
|ATG No Yes||77(50%) 76(50%)||79(54%) 66(46%)||0.5|
|Conditioning intensity MAC/Chemo MAC/TBI RIC||30(20%) 26(17%) 95(63%)||32(22%) 25(17%) 87(61%)||0.9|
[ [P146 Table] 1 . Table 1]
Disclosure: The authors declare no confict of interest related to this study
P147 Prediction of reduced lung function and acute GVHD by surfactant protein D in allogeneic stem cell transplantation
Anne Mols Krarup1, Hilde Hylland Uhlving1, Rudi Steffensen2, Katrine Kielsen1, Carsten Heilmann1, Marianne Ifversen1, Kim Gjerum Nielsen1, Henrik Sengeløv1, Frederik Buchvald1, Grith Lykke Sorensen3, Klaus Gottlob Müller1
1 Rigshospitalet, University of Copenhagen, Copenhagen, Denmark, 2 Aalborg University Hospital, Aalborg, Denmark, 3 Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
Background: Obstructive impairment of lung function is a complication following allogeneic hematopoietic stem cell transplantation (HSCT) and may progress to bronchiolitis obliterans that has a high mortality rate.
Surfactant protein D (SP-D) is an innate defense molecule involved in immune regulation at the epithelial surfaces, particularly in the lungs, and elevated levels have been associated with exacerbation of chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate, whether SP-D plasma levels and variants in the gene encoding SP-D may predict the development of reduced lung function after allogenic HSCT.
Methods:We performed a population-based, single-center study of children (aged 6-18 years) treated with allogeneic HSCT. The study consisted of 1) a prospective study of serial plasma SP-D levels and rs721917 genotypes in 55 patients during the first 6 months after HSCT, and 2) a retrospective study of rs721917 genotypes within the SP-D gene in 247 patients transplanted between 1990-2017. Pulmonary function tests were performed regularly as part of the clinical monitoring.
Results: At the day of graft infusion (day 0) SP-D levels were reduced compared to levels before start of treatment with conditioning chemotherapy, defined as baseline (615 ng/ml (quartiles 441-1132) at day 0 vs 771 ng/ml (542-1348) at baseline, p< 0.01). From day +7 SP-D levels increased and remained increased during the whole study period (771 ng/ml (542-1348) at baseline vs 1287 ng/ml (713-2549) at 6 months, p< 0.01). Acute GvHD (aGvHD) occurred in 25 patients, of those 17 patients with grade 2-4. High SP-D levels at day +14 were associated with the development of aGvHD (1402 ng/ml (1244-2023) vs 839 ng/ml (523-1630), p< 0.01) (fig. 1).
The C/C genotype was associated with generally low SP-D levels and low FEV1/FVC at all time intervals compared to the other genotypes, significantly 24-36 months post-HSCT (p=0.02). There was no overall correlation between SP-D levels and lung function, but stratifying for genotype, high baseline SP-D levels were predictive for reduced FEV1/FVC at 8-24 months in CC and TT homozygous individuals.
Conclusions: Patients with a genotype causing low capacity for SP-D production are at increased risk of developing pulmonary impairment after HSCT. In addition, our data lend support to other studies indicating that SPD production may increase during inflammatory pulmonary disease, acting as a reactive, protective mechanism. Further research is warranted to define the role of SP-D levels and genotypes as a prognostic tool for lung function and aGvHD.
[ [P147 Image] 1 . Figure 1: SP-D levels in patients with and without aGvHD by time from the transplant.]
Disclosure: Nothing to declare.
P148 Positive effects of whole body vibration on patient´s physical capacity and quality of life during allogeneic hematopoietic cell transplantation - A randomized controlled study
Antonia Pahl1, Anja Wehrle1, Sarah Kneis1, Albert Gollhofer1, Jürgen Finke1, Hartmut Bertz1
1University of Freiburg, Germany, Freiburg, Germany
Background: Allogeneic hematopoietic cell transplantation (alloHCT) means a long period of restricted mobility and a range of therapy related side effects on muscle function. In this context patients demonstrated a huge decline of physical capacity and muscle mass in particular, accompanied with a decrease of quality of life (QoL). Resistance training could maintain muscle mass but is limited by patients´ blood values (platelet-count) and well-being. Whole body vibration (WBV) was shown to maintain muscle mass during bed rest and has less impact on blood pressure than conventional resistance exercises. Furthermore it was also shown to be feasible in patients during high dose chemotherapy. Therefore the aim of our study was to examine the effects of WBV during alloHCT on patients physical and functional performance as well as QoL.
Methods: 43 patients receiving alloHCT were randomly allocated to either a WBV exercise group (IG) or an active control group (CG) doing stretching and mobilization. Both groups exercised during the whole time of hospitalization for 5 times per week and underwent pre-, post- and follow-up-assessment. Physical capacity was determined by maximum oxygen consumption (VO2peak) and maximum power (Pmax) during cardiorespiratory exercise test and by maximum strength of the knee extensors and flexors (EXmax, FLEXmax) during isokinetic strength test. Functional performance was assessed by jumping height during counter movement jump (CMJ) and time of chair rising test (CRT) as well as power output during both tests. QoL was assessed by questionnaires of the EORTC.
Results: During alloHSCT VO2peak and Pmax decreased in both groups but till follow-up an increase is seen in the IG (P=0.035; P=0.011). At day +180/follow-up a VO2peak group difference is seen (P=0.034). EXmax (P=0.003) and FLEXmax (P=0.044) were only reduced in the CG during hospitalization. Jumping height and power output decreased in the CG during hospitalization (P=0.005, P=0.039) and a difference between groups were seen in changes of jumping height from pre- to follow-up-assessment (P=0.033): increase in the IG and decrease in the CG. The IG showed a decrease in time from baseline to follow-up (P=0.022) in the CRT and an increase of power output (P=0.009). QoL decreased only in the CG during hospitalization (P=0.015) while during follow-up QoL increased in both groups (IG: P=0.013; CG: P=0.037). In the CG physical functioning decreased during intervention (P=0.001) whereas an increase was seen in the IG from pre- to follow-up-assessment (P=0.035). Body image was significant worse in the CG compared to the IG at hospital discharge (P=0.007) as well as at follow-up measurement (P=0.030) where it got worse over time (P=0.036).
Conclusions: WBV was shown to maintain maximum strength, jumping performance and QoL during alloHCT. Although cardiorespiratory fitness could not be maintained by WBV during hospitalization, it seems in the follow up period till day + 180 that recovery of the cardiorespiratory system is enhanced by WBV carried out during alloHST. Nevertheless reasons for this changes in recovery have to be analyzed in further studies as well as treatment effects of WBV compared to conventional resistance training.
Disclosure: Supported by a grant of the faculty of medicine and Comprehensive Cancer Center Freiburg
P149 Respiratory virus infection within 1 year after of Allo-SCT is the significant risk factor of obstructive ventilatory disturbance
Kosei Kageyama1, Michiho Ebihara1, Mitsuhiro Yuasa1, Daisuke Kaji1, Aya Nishida1, Shinsuke Takagi1, Hisashi Yamamoto1, Go Yamamoto1, Yuki Asano-Mori1, Naoyuki Uchida1, Atsushi Wake1, Akiko Yoneyama1, Shigeyoshi Makino1, Shuichi Taniguchi1
1 Toranomon Hospital, Hematology, Tokyo, Japan,
Background: Obstructive ventilatory disturbance (OVD) is one of the major life-threading complication at the chronic phase of allogeneic stem cell transplantation (Allo-SCT). Bronchiolitis obliterans has been the most established etiology as a part of chronic graft-versus-host disease and major cause of late non-relapse mortality of Allo-SCT. But other etiologies impact on respiratory function after Allo-SCT and risk factor of OVD have not been well understood.
Methods: To address these issues, we retrospectively reviewed the medical record of 747 consecutive patients who first Allo-SCT at Toranomon Hospital between 2009 and 2017. To detect OVD, forced expiratory volume in 1 second (FEV1.0) showed less than 80% of predicted in spirometry test was defined as positive. In the recipients who showed FEV1.0 less than 80% in pre-transplant test, more than 20% reduction of FEV1.0 was regarded as positive. Nasopharyngeal swab of those who had upper respiratory tract symptoms were tested for the presence of respiratory viral antigens (ADV, PIV, and RSV). Patients with ECOG performance status of 4, had active infection at transplant were excluded from this analysis. The cases of early death or relapse before 30 days post-transplant, and the cases of graft failure were also excluded.
Results: The median age was 55 years (range, 16-74). Underlying diseases were AML in 403, MDS/MPD in 73, CML in 26, ALL in 82, ATL in 19, HL in 12, NHL in 104, and others in 28. Five hundred twenty-nine (71%) were not in remission at the time of transplant. Five hundred eighty-three patients (78%) were conditioned with myeloablative regimens, whereas 164 patients received reduced-intensity regimens. Donor sources consisted of related peripheral blood /bone marrow (BM) (n=85), unrelated BM (153) and cord blood (509). One hundred seventeen developed respiratory virus infection on median of 45(0-363) days post-transplant. ADV in 3, PIV in 61, RSV in 38, ADV/PIV in 4, ADV/RSV in 1, PIV/RSV in 10. With median observation period of survivors of 1438 (30-3390) days, 490 recipients (66%) underwent spirometry at least once. Forty-six developed OVD on median of 198 (60-804) days post-transplant. Cumulative incidence of OVD was 6.4% in total population. In 490 recipients those who could spirometry, overall survival at 5 years was 73.2% in patients who developed OVD and was comparable with those who did not develop it (64.3%, p=0.486). In univariate analysis, disease status (CR/AA or nonCR), recipient age (age< 55 or ≥55), prior autologous stem cell transplantation (yes or no), intensity of conditioning regimen (MAC or RIC), TBI dose (< 8 Gy or ≥8 Gy), busulfan dose (< 9.6mg/kg or ≥9.6mg/kg), donor source (cord blood or non-cord) had no impact on the incidence of OVD. Patients who developed respiratory virus infection showed significantly higher incidence of OVD compared to those who did not developed it (12.4% vs 5.3%, p< 0.01). In multivariate analysis, respiratory virus infection was the only significant risk factor for the development of OVD (HR=2.43, 95% CI 1.30-4.57, p< 0.01).
Conclusions: Respiratory virus infection within 1 year after Allo-SCT is the significant risk factor of OVD.
Disclosure: Nothing to declare.
Abstract already published.
P151 increased risk of metabolic syndrome in male survivors after allo-HSCT in childhood despite normal BMI at long-term follow-up
Ena Muhic1, Sidsel Mathiesen1, Marianne Ifversen1, Kaspar Sørensen1, Anders Juul1, Klaus Müller1
1 Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Background: Metabolic Syndrome (MetS) is related to increased risk of cardiovascular disease and type-2 diabetes (DM-2) and usually seen in overweight individuals in the general population. We investigated MetS and clinical risk factors two decades after HSCT.
Methods: All male survivors treated with myeloablative allo-HSCT during childhood (< 17 years) between 1980-2010 in Denmark were invited to a follow-up study. MetS was defined as the presence of at least three NCEP ATP III criteria: fasting plasma triglyceride (TG) ≥1.7 mmol/L, high density lipoprotein (HDL) < 1.03 mmol/L or medical treatment of hyperlipidemia; fasting plasma glucose (FPG) ≥5.6 mmol/L; abdominal circumference (AC) >102 cm; BP ≥130 mmHg (systolic) / ≥85 mmHg (diastolic) or medical treatment for hypertension.
Patients with overt DM-2 were included into the MetS group. Furthermore, patients were examined for chronic graft-versus-host disease (cGvHD) by the NIH-criteria at the time of follow-up and high sensitivity C-reactive protein (hsCRP) was measured. The prevalence of MetS was compared to a Nordic reference group (Hildrum et al. 2009).
Results: We included 49 out of 97 eligible males (participation rate 51%) aged 18-44 years, median 29 years. Median (range) follow-up was 21 (8-32) years. Of these 49 males, 74% had a malignant diagnosis and 65% were treated with TBI-based conditioning. Donors were matched siblings (n=21), matched relatives (n=3) or matched unrelated donors (n=25).
MetS was more prevalent (33%) in the young adult survivors compared to the prevalence reported for 20-39-year-olds in the Nordic reference (16 %). Instead the prevalence was comparable to that reported for the 50-69-year-olds (32%). Of the components of Mets, elevated TG (51%), hypertension (47%), and decreased HDL (40%) were frequent, while FPG was elevated in 16%. Importantly, only 4% of those with MetS had increased AC and mean BMI (23.8 kg/m2) of the HSCT survivors was within normal range in contrast to features of MetS observed in the background population.
Having MetS was significantly associated with TBI (RR = 7.9, 95%CI (1.1-55.3), p=0.004) as was the following single components of MetS (mean in TBI group vs. mean in non-TBI group): elevated TG (2.34 mmol/L vs. 0.93 mmol/L, p= 0.006), lower HDL (1.04 mmol/L vs. 1.38 mmol/L, p=0.001) and higher diastolic BP (80 mmHg vs. 72 mmHg, p=0.03).
MetS was only demonstrated in one patient who received non-TBI based conditioning.
Sixteen of 49 patients had cGvHD of which nine were moderate to severe cases, but cGvHD was not associated with MetS. However, low-grade inflammation measured by hsCRP was related to increased AC (rho=0.41, p=0.004) and TG (rho=0.34, p=0.028).
Conclusions: Our results indicate that male long-term survivors of allo-HSCT during childhood have a high risk of MetS at an earlier age than the general population. The presence of MetS despite normal BMI in several patients suggests unconventional etiologies like the effect of TBI and low-grade inflammation.
Disclosure: Nothing to declare.
P152 current practice in vitamin D management across adult and paediatric allogeneic haematopoietic stem cell transplant centres: A survey by transplant complications working party of EBMT
Jose Ros-Soto1, John A. Snowden2, Nina Salooja3, Maria Gilleece4, Anne Parker5, Diana Greenfield2, Chloe Anthias6, Arun Alfred7, Alenca Harrington8, Christophe Peczynski8, Karl Peggs9, Alejandro Madrigal1, Grzegorz W. Basak10, Hélène Schoemans11
1 Anthony Nolan, London, United Kingdom, 2 Sheffield Teaching Hospitals NHS Trust, Sheffield, United Kingdom, 3 Imperial College London, London, United Kingdom, 4 St James's Hospital, Leeds, United Kingdom, 5 Queen Elizabeth University Hospital, Glasgow, United Kingdom, 6 Royal Marsden NHS Trust, London, United Kingdom, 7 The Rotherham NHS Foundation Trust, Rotherham, United Kingdom, 8 EBMT Data Office, Paris, France, 9 University College London Hospital, London, United Kingdom, 10 Medical University of Warsaw, Warsaw, Poland, 11 University Hospital Leuven and KU Leuven, Leuven, Belgium
Background: Vitamin D (VD) has immune-regulatory properties and can affect the course of haematopoietic stem cell transplantation (HSCT).
Methods: To describe the current clinical practice of diagnosis and treatment of VD deficiency in allogeneic HSCT patients, directors of 326 EBMT affiliated allogeneic transplant centres from 42 countries were invited to participate in an online survey comprising 34 questions.
Results: This survey was completed by transplant directors (46%), transplant consultants (41%), non-consultant grade physicians (8%), HSCT clinical nurses specialists (CNS) (3%) and other (2%) from 114 centres in 24 countries. 58% of the centres are adult-only, 21% paediatric-only and 21% treat adult and paediatric patients (mixed centres). 46% are located higher than 50 degrees latitude (northern countries) and 54% lower than this latitude (southern countries). At the time of the survey 84% were members of the European Union (EU).
Measurement of serum VD is routinely performed in 47% of the centres prior and in 70% after allogeneic HSCT. The main clinical indications are known osteopaenia/osteoporosis (86%), previous fracture (71%), treatment with steroids (68%), premature menopause (46%) and established menopause (32%). Monitoring occurs every 3 months (39%), every 6 months (24%), once a year (18%) or at other time-points (19%). In this regard, seasonality is not taken into account in the majority of the centres (94%). Local and national/international guidelines (NICE) are only followed by 19% and 18% of the centres, respectively. The most common cut-off value of serum VD for commencing on replacement is 50 nmol/L (32%). Northern countries tend to use values of ≥75 nmol/L whereas southern countries ≤50 nmol/L. 15% do not use cut-off values.
Following HSCT, 83% of centres prescribe VD supplements to maintain calcium metabolism and bone health (92%), enhance immune reconstitution post-HSCT (24%), GvHD prevention (17%), enhance immune-suppression to treat GvHD (10%), treat depression/fatigue (3%) and reduce relapse risk 2%. A “loading” dose is administrated in 30% (54% adult, 25% mixed and 22% paediatric), with a mean duration of 4 weeks (1-52). The median daily loading dose is 2,000 IU (286-20,000). The median “maintenance” daily dose is 800 IU (67-10,000). There are not remarkable differences between adult and paediatric centres or northern and southern countries.
VD replacement is prescribed by transplant physicians (75%), family physicians (10%), endocrinologists (3%), CNS (3%), others (4%) and in 5% of the centres, patients are advised to buy it over-the-counter. VD is prescribed combined with calcium carbonate in 52% and alone in 48% of the centres. It is eventually discontinued by 69% of the centres when therapeutical levels of VD are reached (69%), DEXA scan returns to normal (12%) and symptomatic improvement (9%).
Conclusions: This survey has demonstrated discrepancies in monitoring and replacement of VD across EBMT allogeneic HSCT Programmes. Although awareness has arisen over the last decade, there is still lack of evidence about the optimal levels of VD required for immune-modulation post-HSCT. This survey emphasises the need for specific guidelines to harmonise the current management of VD deficiency in adult and paediatric HSCT setting.
Disclosure: Nothing to declare
P153 Poor graft function after unmanipulated haploidentical SCT with post-transplant high dose cyclophosphamide
Ignacio Gómez-Centurión1, Pascual Balsalobre1,2, Ana Perez Corral1,2, Nieves Dorado1,2, Laura Solán1,2, Rebeca Bailén1,2, Silvia Monsalvo1,2, Carolina Martinez Laperche1,2, Ismael Buño1,2,3, Javier Anguita1,2, José Luis Diez-Martin1,2, Mi Kwon1,2
1 Hospital General Universitario Gregorio Marañón, Madrid, Spain, 2 Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain, 3 Unidad de Genómica, Hospital General Universitario Gregorio Marañón, Madrid, Spain
Background: The use of unmanipulated Haploidentical SCT (Haplo-SCT) with post-transplant Cyclophosphamide (PT-Cy) as GVHD prophylaxis has widely extended. Primary and secondary graft failure are relatively uncommon complications. However, poor graft function (PGF) after Haplo-SCT with PT-Cy has not been described thoroughly. The objective of this study is to describe characteristics, treatments and outcomes of patients with PGF after Haplo-SCT with PT-Cy.
Methods: We retrospectively analyzed 132 Haplo-SCT with PT-Cy consecutively performed between 2011 and 2017 in our centre. PGF was defined as either occurring after initial engraftment: persistent neutropenia (ANC < 500/uL) with the need of at least 3 doses of G-CSF and/or thrombocytopenia (platelets < 20.000/uL) with platelet transfusion dependence, with complete donor chimerism and without concurrent severe GVHD or disease relapse.
Results: Nineteen patients were excluded from the analysis due to early mortality (death before day +30), primary graft failure (absence of neutrophil engraftment by day +28, with mixed chimerism) or secondary graft failure (development of severe cytopenias and mixed chimerism after initial achievement of neutrophil engraftment). Thirty one patients (27,5%) were diagnosed with PGF. Main characteristics of these patients are summarized in Table 1. Twenty six patients (84%) presented with neutropenia and were treated with G-CSF, while 5 patients (16%) only developed severe thrombocytopenia without neutropenia, and were treated only with platelet transfusion. Twenty four patients (77,5%) had at least 1 CMV reactivation, 15 patients (48%) had 2 or more CMV reactivations and 21 patients (67%) received valganciclovir for CMV reactivation treatment. Although most patients achieved adequate peripheral blood counts (PBC) with initial salvage therapy, 6 patients (19%) had persistent cytopenias in spite of G-CSF, platelet transfusion, CMV reactivation resolution and myelotoxic drugs withdrawal. Four of them were treated with a boost of CD34+ selected peripheral blood donor cells at a median of 170 days after HSCT (range 150-190). Median CD34+ cells infused was 3,42 x106/kg. These 4 patients achieved adequate PBC after salvage therapy and two developed GVHD. The other 2 patients were treated with increasing doses of thrombopoietin (TPO) receptor agonist (TRA) eltrombopag. One patient started treatment 160 days after HSCT with 25mg daily and increased dose to 125mg daily, with complete recovery of PBC 6 months after initiating TRA. The second patient started treatment 110 days after HSCT with 25mg daily and increased dose to 100mg daily, with complete recovery of PBC 2 months after initiating TRA. Twenty one patients (67%) with PGF diagnosis had long term survival.
|Number of patients||31|
|Median age, y (range)||46 (18-64)|
|Median CD34+ cells/kg infused||5.46x10e6 (2.24-11.4)|
|2 or more episodes||15|
|Only platelet transfusion||5|
|TPO receptor agonist||2|
[ [P153 Table] 1 . Characteristics, treatments and outcomes of PGF patients]
Conclusions: Poor graft function is a frequent complication after Haplo-SCT with Cy-post. CMV reactivation and myelotoxic drugs could be the most relevant factors associated with development of this entity. Although most patients recover PBC without specific therapies beyond G-CSF and platelets transfusion, there is a small group of patients with persistent cytopenias. Boost of CD34+ selected cells is effective in reverting this condition, with GVHD as main complication of this procedure. Use of TRA seems to be an interesting option for these patients, although more experience is needed to draw definitive conclusions.
Disclosure: Nothing to declare.
P154 Late complications and quality of life assessment (FACT-BMT, HADS, NCCN distress thermometer) for survivors after allogeneic hematopoietic stem cell transplantation; tablet-PC based surveys
Yunsuk Choi1, Jaekyoung Cheon1, SuJin Koh1, Jin-Ho Baek1, Young Ju Min1, Ji Hyun Lee2, Jae-Cheol Jo1
1 Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea, Republic of, 2 Dong-A University College of Medicine, Busan, Korea, Republic of
Background: Allogeneic hematopoietic stem-cell transplantation (allo-HCT) is an only curative modality for hematologic malignancies. Allo-HCT, however, is physically and psychosocially demanding and can induce long term complications. Therefore, we aimed to investigate the unmet needs for physical and phycological late complications and clinical factors affecting the quality of life for allo-HCT survivors.
Methods: The survivorship surveys for allo-HCT recipients have been conducted to build survivorship care plan on regular follow up visit at the survivorship outpatient clinic of Ulsan University Hospital, Ulsan, Korea, using Tablet-PC based patients report forms. We retrospectively analyzed the survivorship survey data in adult allo-HCT survivors over two year post-transplant between 2015 and 2018 at Ulsan University Hospital, Ulsan, Korea. A total of 69 patients completed the Tablet-PC surveys for quality of life (FACT-BMT, Korean language version), anxiety (HADS-A), depression (HADS-D), distress (NCCN distress thermometer [DT]), fatigue (Brief Fatigue Inventory), physical and psychological symptoms, function (physical, social, sexual, cognitive, work); life styles (exercise, tobacco use, alcohol, nutrition); and health screening.
Results: The median age was 46 years (range, 20-70). The most common symptom was fatigue (80.6%). Oral pain (34.3%), ocular and oral dryness (37.3% and 22.4%), insomnia (34.3%), memory disturbance (29.9%), joint stiffness or pain (20.9%), cough or sputum (26.9%), skin pruritis (19.4%), dyspepsia (19.4%), headache (13.4%) were also frequently observed. The high risk patients for anxiety (HADS-A score ≥ 8) and depression (HADS-D score ≥ 8) was found in 14.9% and 13.6%, respectively. 10.4% of patients was in high distress status (NCCN DT score ≥ 4). We found that younger age (< 60 years) was significantly associated with poor quality of life score (FACT-BMT) (P=0.001) and high risk of fatigue (P=0.008), anxiety (HADS-A) (P=0.001), and depression (HADS-D) (P=0.025). Female sex was significantly related to lower physical well-being score and higher distress score (P= 0.046 and P=0.05, respectively). Acute lymphoblast leukemia (ALL) survivors after allo-HCT showed significantly worse quality of life score (FACT-BMT) (P=0.006) and higher depression score (HADS-D) (P=0.028) compared to those with other disease. Chronic graft versus host disease (GVHD) and continuous immunosuppressant usage also have significant adverse impact on lower FACT-BMT score (P=0.024 and P=0.033, respectively) and higher HADS-D score (P=0.015 and P=0.019, respectively). But there was no significant difference in FACT BMT, HADS-A, HADS-D, NCCN DT according to donor type, conditioning intensity, anti-thymocyte globulin use, acute GVHD. Smoking and alcohol drinking was continued in 7.5% and 17.9% of allo-HCT survivors. 20.9% of survivors did not exercise regularly. Regular health screening tests have been done only in 40 patients (59.7%).
Conclusions: Allo-HCT survivors over 2 years following allo-HCT still have many physical and psychological symptoms. Younger patients (< 60 years), female, ALL, chronic GVHD, and sustained use of immunosuppressant were significant risk factors for poor quality of life and anxiety. We need to build more active survivorship care plan after allo-HCT especially for those patients.
Disclosure: All authors have nothing to declare.
P155 Evaluation of the new EBMT criteria for the diagnosis of VOD/SOS in 693 consecutive transplant patients using an electronic patient record analysis system
Asha Aggarwal1, Nicola Gray1, Oliver Lomas1, Katalin Balassa1, Nadjoua Maouche1, Robert Danby1,2, Andy Peniket1, Grant Vallance1
1 Oxford University Hospitals, Oxford, United Kingdom, 2 Anthony Nolan Research Institute, London, United Kingdom
Background: Veno-Occlusive disease (VOD), or sinusoidal obstruction syndrome (SOS), is a recognised complication of haematopoietic stem cell transplantation. Hepatic vasculature endothelial cells are damaged by conditioning chemotherapy, leading to venous occlusion and centrilobar necrosis. The EBMT criteria for diagnosis of VOD are bilirubin >=34 with two of painful hepatomegaly, >5% weight gain and ascites. VOD is often under-diagnosed, and as a result, treatment may be delayed.
Integrated electronic patient record (EPR) systems are now widely used, and provide an opportunity to retrospectively audit practice to identify patients in whom VOD may have been un-diagnosed or in whom treatment was delayed. In addition these systems have potential for alerting clinicians to the potential diagnosis of VOD.
Methods: We have developed software to analyse the data downloaded from EPR to identify patients in whom VOD was a possible diagnosis according to the new EBMT criteria.
In order to identify patients who may have had VOD we first screened for patients with a bilirubin of >= 34 mmol/l (which is an absolute requirement for the clinical diagnosis of VOD) within the first 50 days of transplantation. EPR data was then used to assess whether patients had >5% weight gain. Radiology reports were reviewed for patients who had bilirubin >= 34 mmol/L to ascertain if they revealed ascites or painful hepatomegaly.
Results: 652 patients underwent 693 transplant procedures (January 1st 2013 to July 31st 2018). 162 of all transplant patients (23.4%) were found to have a bilirubin of >= 34 mmol/l. 39 of 403 (9.6%) autograft patients and 123 of 249 (49.4%) allograft patients had an elevated bilirubin at this level. These 162 patients were assessed for evidence of 5% weight gain. This was the case in 30 patients overall- 1% of autograft patients, 10.5% of allograft patients. Seven patients (2 autograft and 5 allograft) had radiological evidence of ascites. Two patients had a recording of painful hepatomegaly (both post allograft).
Overall our analysis identified 5 patients (0.7% overall) fulfilling the EBMT diagnostic criteria for classic early VOD all of whom received defibrotide. All patients had received allogeneic transplants. We failed to identify any cases of late onset VOD or any undiagnosed patients over this period.
Conclusions: This analysis enabled us to efficiently perform a complete audit of our practice to identify patients with VOD. We would recommend using electronic patient records to retrospectively audit practice in this way. The tool that we have created for this analysis will be made freely available for public use and the details will be presented at the EBMT meeting.
We now plan to extend the function of our EPR system to provide alerts to clinicians when VOD is a possible diagnosis and may lead to more rapid treatment of these patients. Our data suggests that elevation of bilirubin and weight gain of > 5% will be the most frequently occurring criteria on which to base these alerts.
Disclosure: G.Vallance has performed consultancy work for Jazz pharmaceuticals.
P156 Endothelial activation and stress index in predicting outcome of allogeneic stem cell transplantation- A retrospective cohort analysis
Zinaida Peric1, Tomislav Taborsak1, Nadira Durakovic1, Lana Desnica1, Alen Ostojic1, Ranka Serventi-Seiwerth1, Radovan Vrhovac1
1 University Hospital Centre Zagreb, Zagreb, Croatia
Background: Endothelial dysfunction is a common pathophysiology of major complications after allo-SCT, such as graft-versus-host disease, veno-occlusive disease, thrombotic microangiopathy and sepsis. Endothelial Activation and Stress Index (EASIX) is a simple score comprised of standard laboratory parameters (creatinine, LDH and thrombocytes) developed as a potential tool to predict allo-SCT mortality by Luft and colleagues. A recent validation of EASIX included three retrospective cohorts and showed that EASIX taken before start of conditioning can be used as an independent predictor of survival after allo-SCT.
Methods: The aim of our study was to retrospectively evaluate pre-transplant EASIX in our cohort of consecutive patients who underwent allo-SCT in the University Hospital Centre Zagreb between 2012 and 2017. With the use of a cut-off used in the validation cohorts, we compared two groups of patients for overall survival (OS) and transplant-related mortality (TRM). Group comparisons were done using the log-rank test or Gray test for competing risks outcomes. A multivariate analysis evaluated the association of OS with relevant variables by using a Cox's proportional-hazard regression model.
Results: Our study group included 313 patients and comprised 180 males (57%) and 133 females (43%, with a median age of 48 years (range, 18 to 67 years) at the time of transplantation. The most frequent malignancies in our population were acute leukemia (196 patients, 63%) and myelodysplastic/myeloproliferative neoplasm (451 patients; 16%). The donor was an identical sibling for 106 patients (34%), matched unrelated donor for 176 patients (56%) and haploidentical for 31 patients (10%). 104 patients (33%) received a myeloablative conditioning regimen while 209 patients (67%) received a reduced-intensity conditioning regimen. With a median follow-up of 16 months (range, 12-60) for the whole study group, the OS at 24 months was 60%, (95%CI 54-68) in the group of patients with low EASIX score and 43% (95% CI 33-56) in the group of patients with high EASIX score (p=0.004). This difference was mainly attributed to higher TRM in the group with high EASIX score (32%, 95%CI 22-45 at 12 months) compared to the group with low EASIX score (18%, 95%CI 13-23 at 12 months) (p=0.009). In the multivariate analysis which included EASIX, patients' age, intensity of conditioning, diagnosis (lymphoid vs myeloid), status of the disease at transplant and type of the donor, worse OS was independently associated only with older age of patients (HR 1.66; 95% CI, 1.07-2.59, p=0.02) and high EASIX score (HR 1.51; 95% CI, 1.01-2.24, p=0.04).
Conclusions: Our retrospective data support previous data and suggest that EASIX could potentially serve as a valid tool for prediction of allo-SCT outcomes. As a simple biomarker panel, EASIX could easily be implemented in clinical decision making in the field of allo-SCT. These retrospective data need validation in a prospective study which is currently being conducted.
Clinical Trial Registry: NA
P157 Management of veno-occlusive disease: Virtual simulation improves clinical performance of hematologists/oncologists and advanced practice providers
Lauren Willis1, Gwen Littman1
1 Medscape Oncology, LLC, New York, NY, United States
Background: Veno-occlusive disease (VOD) is a potentially devastating complication that can occur after hematopoietic stem cell transplant (HSCT) and in severe cases can lead to multi-organ failure. (Mohty 2016) Defibrotide has been proven to be effective to prevent and treat VOD, and it is critical that clinicians are aware of how to diagnose and treat this serious complication of HSCT. This study was conducted to determine if an online, simulation-based continuing medical education (CME) intervention could improve performance of hematologists/oncologists (hem/onc) and advanced practice providers (nurse practitioners and physician assistants, APPs) in the diagnosis and treatment of patients with VOD.
(Reference: Mohty M, et al. Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant. 2016 Jul;51(7):906-912).
Methods: A CME certified virtual patient simulation (VPS) was made available via a website dedicated to continuous professional development. The VPS consisted of 2 cases presented in a platform that allows clinicians to assess the patients and make diagnostic and therapeutic decisions supported by an extensive database of diagnostic and treatment possibilities, matching the scope and depth of actual practice. Clinical decisions were analyzed using a sophisticated decision engine, and tailored clinical guidance (CG) employing up-to-date evidence-based and faculty recommendations was provided after each decision. One case was about VOD and the other case was about acute myeloid leukemia (AML). Decisions were collected post-CG and compared with each user's baseline (pre-CG) decisions using a 2-tailed paired t-test to determine p-values (P < .05 indicates significance). Data were collected between 9/21/2017 and 11/7/2018.
Results: At the time of assessment, 115 hem/oncs and 409 APPs had fulfilled the participation criteria for completing the VOD case simulation.
|Diagnose VOD||24% RI (p < 0.001); post-CG 88%||53% RI (p < 0.001); post-CG 49%|
|Baltimore Criteria||1% RI (p < 0.103); post-CG 77%||11% RI (p < 0.103); post-CG 50%|
|Seattle Criteria||5% RI (p < 0.140); post-CG 69%||11% RI (p < 0.140); post-CG 41%|
|Order defibrotide||103% RI (p < 0.001); post-CG 63%||209% RI (p < 0.001); post-CG 34%|
|Order intravenous fluids||116% RI (p < 0.001); post-CG 54%||83% RI (p < 0.001); post-CG 44%|
|Continue ursodiol||11% RI (p = 0.015); post-CG 91%||8% RI (p < 0.001); post-CG 90%|
|RI = relative improvement pre-CG to post-CG|
[ [P157 Table] 1 . Table 1. Post-CG Diagnosis and Treatment Decisions]
[ [P157 Image] 1 . Figure 1. Rationales for Ordering Defibrotide (can select up to 2 choices)]
Conclusions: This study demonstrates that VPS that immersed and engaged clinicians in an authentic and practical learning experience improved evidence-based clinical decisions related to the management of VOD. This VPS increased the percentage of clinicians who utilized standardized criteria to diagnose VOD and who ordered defibrotide and IV fluids for VOD management. However, further education is needed to increase the competence and performance of clinicians, particularly APPs, in these areas in order to positively impact patients.
Disclosure: Nothing to declare.
P158 A nationwide retrospective study of hematopoietic stem cell transplantation in solid organ transplant recipients: On behalf of JSHCT, transplant complications working group
Akihito Shinohara1, Kumi Oshima2, Shigeo Fuji3, Katsutsugu Umeda4, Atsuta Yoshiko5, Takahiro Fukuda6, Junji Tanaka1, Masao Ogata7
1 Tokyo Women's Medical University, Tokyo, Japan, 2 Tokiwa Hospital, Fukushima, Japan, 3 Osaka International Cancer Institute, Osaka, Japan, 4 Kyoto University Hospital, Kyoto, Japan, 5 Japanese Data Center for Hematopoietic Cell Transplantation, Aichi, Japan, 6 National Cancer Center Hospital, Tokyo, Japan, 7 Oita University Hospital, Oita, Japan
Background: The outcome of hematopoietic stem cell transplantation (HSCT) in solid organ transplant remain unclear. To address this issue, we conducted a retrospective survey of the 404 Japan Society for Hematopoietic Stem Cell Transplantation centers.
Methods: To address this issue, we conducted a nationwide retrospective survey of the Japan Society for Hematopoietic Stem Cell Transplantation (JSHCT) centers. A first questionnaire was emailed to JSHCT centers requesting information on cases of HSCT in SOT recipient. Patients' data about SOT were collected by sending a second questionnaire to the centers with the patient. Based on these reports, patients' data about HSCT was identified in the Japan transplant outcomes registry database by the Transplant Registry Unified Management Program (TRUMP), confirmed in 2017.
Results: Of the 404 JSHCT centers, 238 responded to the survey (58.9%). 14 of the responding centers reported a total of 19 patients who had undergone SOT from living donor, and subsequent HSCT. They consist of three autologous HSCT (auto-HSCT) and 13 allogeneic HSCT (allo-HSCT). In auto-HSCT, all patients had received liver transplant for hapatoblastoma. They achieved neutrophil engraftment at 30 days after HSCT, and two of three patients were alive at one year after HSCT. In allo-HSCT (n=16), seven patients had received liver transplants, and nine patients had received kidney transplants. Five patients received HSCT from unrelated donor, and 11 patients received HSCT from related donor; two donors were identical in SOT. Their stem cell sources were seven peripheral blood stem cell, six bone marrow, and three cord blood. All but one patients achieved neutrophil engraftment at 30 days after HSCT. Five-year overall survival (5yOS) was 37.5%. While 5yOS in patients with bone marrow failure (n=4) was 100%, that in patients with malignant disease (n=12) was 16.7%; all but one patients with malignant disease received allo-HSCT in non-remission. Seven of nine kidney-transplant recipients experienced dialysis, and three patients experienced renal rejection after HSCT. On the contrary, no liver-transplant recipient experienced hepatic rejection.
Conclusions: In SOT recipients, the outcome of allo-HSCT for malignant disease was poor, partly due to disease status before allo-HSCT. Severe renal complications were common in kidney-transplant recipients, suggesting renal care with caution during and after allo-HSCT.
Disclosure: This work was supported in part by the Practical Research Project for Allergic Diseases and Immunology (Research Technology of Medical Transplantation) from Japan Agency for Medical Research and Development, AMED.
P159 High incidence but low mortality of EBV related PTLD after T-cell replete allo-peripheral blood HCT with aggressive monitoring and without pre-emptive rituximab
Maria Queralt Salas1, Shruti Prem1, Wilson Lam1, Zeyad Al-Shaibani1, David Loach1, Santhosh Thyagu1, Fotios V Michelis1, Dennis (Dong Hwan) Kim1, Jeffrey Howard Lipton1, Rajat Kumar1, Auro Viswabandya1, Arjun Datt Law1
1 Princess Margaret Cancer Centre, Hans Messner Allogeneic BMT Program, Toronto, Canada
Background: The aim of the study is to report the incidence and outcome of post-transplant lymphoproliferative disorder (PTLD) in the setting of allogeneic peripheral blood hematopoietic stem cell transplantation (allo-HSCT) combining post-transplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG) as graft versus host disease (GVHD) prophylaxis.
Methods: Between October 2015 and May 2018, 195 adult patients diagnosed with hematological malignancies underwent a first T-cell replete allo-HSCT in our center. All patients received a reduced intensity conditioning regimen with fludarabine, busulfan, and 200cGy of total body irradiation, combined with rabbit-ATG, PTCy and cyclosporine (CsA).
EBV titres were monitored weekly by quantitative PCR in plasma samples. The cut-off value for test positivity was >600 copies of EBV DNA/ml of plasma. Last follow up was November 2018. Median follow up for patients known to be alive was 19 months (range 5-35).
Results: Patient information is summarized in Table 1. EBV reactivation was documented in 117 (60%) patients. Median time to EBV reactivation and the diagnosis of presumed/proven (P/P)-PTLD were 75 (16-326) days and 97 (54-306) days [3 (0-10) months], respectively. Median time between first EBV reactivation to P/P-PTLD was 21 (0-175) days.
Seventeen (14%) of the 117 patients developed P/P-PTLD. Median age was 55 years (22-73). Two (12%) received MRD, 9 (53%) 10/10 MUD, 1 (6%) 9/10 MUD, and 5 (29%) haploidentical donor grafts. Twelve (71%) were on therapeutic cyclosporine at diagnosis.
Pre-Emptive therapy was not given to any case and only Probable or Proven PTLD were given rituximab. Treatment was based on reduction of the immunosuppression in 3 patients and with the addition of weekly Rituximab 375 mg/m2 in 15 cases. Fifteen (88%) achieved complete clinical responses with PCR negativity. Two (12%) patients died secondary to PTLD.
Conclusions: ATG based conditioning is associated with increased viral reactivations. Frequent EBV monitoring and pre-emptive treatment may lead to rapid disease control. Further research is required to optimize monitoring and management strategies in allo-HSCT recipients.
Disclosure: Nothing to declare
P160 Acoustically enriched extracellular vesicles as potential markers for allogeneic hematopoietic stem cell transplantation complications
Hooi-Ching Lim1, Robert Palmason2, Stig Lenhoff2, Thomas Laurell1, Stefan Scheding1,2
1 University of Lund, Lund, Sweden, 2 Skåne University Hospital Lund, Lund, Sweden
Background: Extracellular vesicles (EVs) contain a number of condition-specific proteins, DNA and RNA types and might therefore be used for the early detection of post-transplant complications. However, traditional EV isolation (ultracentrifugation) is time consuming and requires large sample volumes thus making it difficult to perform longitudinal studies on larger patient cohorts. We therefore investigated whether recently-developed acoustic trapping could be applied to isolate EVs from patient plasma for biomarker development.
Methods: Plasma samples were collected from 10 consecutive patients before and up to 3 months after allogeneic hematopoietic stem cell transplantation. Patients (age: 22-58 years) with high-risk or refractory/relapsed diseases were transplanted with mobilized PBSC from related (n=2) and unrelated donors (n=8) after standard conditioning. GvHD prophylaxis was cyclosporine and methotrexate. Plasma samples were frozen and thawed for EV enrichment using a novel acoustofluidic-based technology (acoustic trapping). Acoustic trapping uses ultrasound as a local λ/2 acoustic standing wave produced by a piezoelectric transducer over a capillary. First, 12 µm polystyrene beads are captured which serve as seeding particles. After washing, target particles (EVs) are then captured (“trapped”) in the acoustic field. A semi-automatic trapping device (AcouTrap) was used to isolate EVs from diluted plasma (1:2 in PBS). The number of EVs and size distribution were analyzed by nanoparticle tracking analysis. miRNA analysis was performed by qPCR.EVs were enriched in duplicate from 50µl and 300µl of diluted plasma for nanoparticle tracking analysis and qPCR analysis, respectively.
Results: EVs were successfully isolated from all plasma samples. A total of 89 plasma samples were processed. Numbers of trapped EVs ranged from 3.7x108 - 5.5x109 before conditioning to 4.4x108- 1.5x1010 per 50µl diluted plasma after transplantation. The maximum change in EV numbers in individual patients compared to pre-transplantation values ranged from 2-fold to 7-fold. Most patients showed slight increases in EV size after transplantation. Eight of the patients showed signs of infection and received i.v. antibiotics. Increased levels of EVs (> 2-fold) were recorded in three patients during these episodes. Furthermore, increased EV numbers were observed in a patient who required i.v. antiviral therapy for CMV reactivation. Acute grade I GvHD was observed in five patients of which two had increased EV numbers (> 2-fold). One patient developed grade IV GvHD which was accompanied by a 4-fold increase in EV numbers. Interestingly, progressively increasing EV numbers preceded the detection of early relapse in a pre-B ALL patient by three weeks. RNA isolation from trapped EVs yielded sufficient material for miRNA profiling. Here, first miRNA profiling data demonstrated that miRNAs were detected in EV samples (miR-103a, -23a, -30c, -142 and -451a), and that acoustically enriched EVs were not affected by hemolysis in contrast to the corresponding whole plasma samples (dCq of miR-23a and miR-451a).
Conclusions: Acoustic trapping allows for efficient and rapid enrichment of EVs from small
volume plasma samples. Trapped EV samples contain sufficient amounts of miRNA for downstream analysis and are thus promising candidates for biomarker development in transplantation.
Disclosure: Laurell and Scheding are founders and board members of Acousort AB, a Lund-based biotech SME that develops particle and cell sorting methods based on ultrasound.
P161 The incidence, risk factors and outcomes of primary poor graft function after allogeneic hematopoietic stem cell transplantation
Fei Gao1,2, Jimin Shi1,2, Yi Luo1,2, Yamin Tan1,2, Xiaoyu Lai1,2, Jian Yu1,2, He Huang1,2, Yanmin Zhao1,2
1 Bone Marrow Tranplantation Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China, 2 Institute of Hematology, Zhejiang University, Hangzhou, China
Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for both hematologic malignancy and many other blood disease. While, primary poor graft function (PGF) is still a severe complication following HSCT which lead to poor prognosis. Up to now, the incidence and risk factors of PGF have not been totally revealed.
Methods: From January 2013 to December 2017, a total of 647 patients who received allo-HSCT in our center were analyzed retrospectively. There were 9 males (47.4%) and 10 females (52.6%) with a median age of 36.21 years (21-49 years). PGF was defined as persistent neutropenia (≤0.5×109/L), thrombocytopenia (platelets≤20×109/L), and/or hemoglobin≤70 g/L after engraftment with hypocellular bone marrow and full donor chimerism, without concurrent graft-versus-host disease or disease relapse. Incidence was calculated from all patients. Of the 647 total patients, nineteen (2.94%) developed primary PGF. A 1:4 ratio of nested case control study using the good graft function (GGF) subjects transplanted in the same year with the same sex and age of ±5 years was carried out.
Results: Data was analyzed by univariate and multivariate logistic regression, and univariate analysis identified disease species, the time from diagnosis to transplantation, disease states, myelofibrosis, splenomegaly, serum ferritin(SF) level, CMV infection, mononuclear and CD34+ cells in graft as potential risk factors (P <0.1) for PGF. multivariate analysis identified 3 elements as the independent risk factors (P <0.05), including CD34+ cells <5×105/kg (P=0.013, OR=4.316, 95% confidence interval(CI):1.362-13.682), serum ferritin (SF) levelå 2000 ng/ml (P=0.017, OR=4.173, 95% CI: 1.285-13.551) and splenomegaly (P=0.044, OR=3.679, 95% CI: 1.036-13.062). Furthermore, cox regression model suggests PGF (P <0.001, OR=9.311, 95% CI: 3.784-22.913), together with SF level (P=0.032, OR=2.595, 95%CI: 1.084-6.210) strongly influence the one-year overall survival for all patients. Five patients who suffered from primary PGF received second donor stem cell infusion (DSI), but only one of them responded, indicating DSI did not improve the hematologic recovery. After a median follow-up of 6.08 months (1-48 months), three out of 19 PGF patients (15.8%) both have achieved hematologic recovery after supportive therapy and survived till now. Compared to cases with GGF, patients with primary PGF experienced poor overall survival (one-year OS: 26.3 vs. 88.2%, P< 0.001). The reason for death is as follow: 10 patients died of multiple organ failure owing to severe infection, other 4 patients perished because of disease relapse, intracranial or gastrointestinal hemorrhage.
Conclusions: In conclusion, primary PGF is a rare but life-threatening complication after allo-HSCT. Low CD34+ cells in graft, high SF level and splenomegaly are major risk factors for PGF, and effective therapies need to be explored.
[ [P161 Image] 1 . One-year OS PGF VS GGF]
Disclosure: Nothing to declare
P162 Utilization of opioid analgesics in a large cohort of patients affected by severe chronic graft-versus-host disease
Ana Zelic Kerep1,2, Filip Pirsl1, Seth Steinberg3, Sandra Mitchell4, Lauren Curtis1, Ann Berger5, Laura Parsons-Wandell1, Megan Kenyon1, Judy Baruffaldi1, Jeannette Nashed1, Drazen Pulanic1,6,7, Kristin Baird8, Ronald Gress1, Steven Pavletic1
1 Experimental Transplantation and Immunology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, United States, 2 University Hospital Center Zagreb, Zagreb, Croatia, 3 Biostatistics and Data Management Section, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, United States, 4 Outcomes Research Branch, NCI, NIH, Rockville, MD, United States, 5 Clinical Center, NIH, Bethesda, MD, United States, 6 University of Zagreb School of Medicine, Zagreb, Croatia, 7 Faculty of Medicine Osijek, J.J. Strossmayer University of Osijek, Osijek, Croatia, 8 Pediatric Oncology Branch, CCR, NCI, NIH, Bethesda, MD, United States
Background: Transplant survivors affected by cGVHD usually take one or more immunosuppressants, as well as prophylactic antimicrobials; use of multiple medication classes concurrently poses a risk for drug-drug interactions or amplified side-effects. The use of medications other than cGVHD-direct immunosuppressive therapies has not been well-characterized. This study aims to evaluate patterns of opioid analgesic use in a cohort of patients severely affected by cGVHD.
Methods: Patients (n=335) with cGVHD were consecutively enrolled in a cross-sectional natural history study (NCT00092235) from 10/2004-12/2016 at the NIH. Participants underwent a comprehensive evaluation including a detailed history and physical examination (including current medications), multidisciplinary evaluations, and laboratory and diagnostic testing. For this analysis, respondents were classified as receiving or not receiving an opioid analgesic. Following the initial screening by univariate methods (n=335), multivariable logistic regression analysis (MLR) was used to identify a set of factors which could jointly impact opioid use. For MLR data were divided into a training (n=167 patients) and a validation set (n=168).
Results: Study participants´ median age was 48.5 years (19-75), 44% were female, 74% had severe cGVHD per NIH scoring criteria, and 77% were currently receiving high or moderate levels of systemic immunosuppression. Approximately one third (33%) were taking opioid analgesics (OA). Based on the univariate screening results (p< =0.05), a set of 24 parameters was evaluated by univariate logistic regression in the 167-patient training set, and the following parameters retained their significance and were included in the MLR model: NIH average score per organ, total LSS, patient impression of severity, NIH cGVHD severity, presence of skin erythema, Karnofsky performance score (KPS,) clinician's therapeutic intent, NIH joint score, and with the presence of several cGVHD symptoms including rashes, mouth sores, avoidance of food, vomiting, weight loss, joint and muscle aches, joint limitation, energy loss, need for naps, fevers, anxiety. Multivariable logistic regression identified KPS < 77% as predictive of OA use, OR 0.92, 95% CI 0.89-0.95. In the training set 56.4% of pts using opioids were correctly identified, 78.2% of those not taking opioids were identified, an overall fraction of correctly identified pts was 70.9% (95% CI 63.3 - 77.7%), while in the testing set, 45.5% of those using opioids were correctly identified, and 67.9% of those not taking opioids were correctly identified, with overall 60.5% (95% CI: 52.6-68.0%) classification accuracy.
Conclusions: This study showed the burden of OA in this cGVHD cohort. Lower KPS was significantly associated with OA use, as well as self-reported symptoms and a more severe cGVHD disease, which could be of interest in the development of non-pharmaceutical interventions in this patient population. Additional, prospective studies are needed to explore the indications for and effectiveness of OA in this population of survivors.
Disclosure: No conflict of interest to declare.
P163 Patients and caregivers inform the design of a mobile app platform for hematopoietic cell transplantation survivorship care
Jaime M. Preussler1,2, Ellen M. Denzen1,2, Navneet S. Majhail3, K. Scott Baker4, Meggan McCann1, Linda J. Burns1,2, Jean C. Yi4, Karen L. Syrjala4
1 National Marrow Donor Program/Be The Match, Minneapolis, MN, United States, 2 Center for International Blood and Marrow Transplantation, Minneapolis, MN, United States, 3 Cleveland Clinic, Cleveland, OH, United States, 4 Fred Hutchinson Cancer Research Center, Seattle, WA, United States
Background: Technology is improving the ability of patients to participate in their own health care and to access survivorship tools as they need them. INSPIRE (INteractive Survivorship Program with Information and REsources) is an online health program that includes a mobile app, website, and individualized survivorship care plans for adult autologous and allogeneic hematopoietic cell transplant (HCT) survivors. The INSPIRE program will be tested for efficacy in a randomized control trial (RCT) at 13 transplant centers. The project integrates two previously effective RCTs that tested an internet-based program and patient-centered survivorship care plans for HCT survivors. Patient and caregiver input is essential to inform the design and features for the mobile app platform so that it is usable and engaging for those it targets.
Methods: Using a qualitative research design, we conducted telephone focus groups of adult patients and caregivers in the United States. Adult (age >18 years at the time of study entry) HCT recipients had to be at least one-year post-HCT to participate. Participants had to be able to communicate in English, and could have received a HCT for any diagnosis, and from any donor source or stem cell type. Those who had multiple transplants were included. Participants were asked to review printed and online visual presentations of the mobile app before the focus groups so they were prepared to discuss their responses to the materials during the call. Focus groups were conducted to saturation, when no new qualitative content was offered.
Results: Three focus groups were conducted with 22 total participants (20 patients, two caregivers/patient advocates). All patients received an allogeneic HCT; average time since HCT was 8 years (range: 2-22 years).The majority of participants were female (77.3%). Participants had differing perspectives on the usefulness of the app to track follow-up appointments, lab values, and other health care plans. There was high interest in having the app tailored to meet specific needs of patients, including tracking information over time (e.g. test results, medications), and having health information available specific to their needs. To minimize duplication of information and data entry, participants recommended syncing the app with their calendars and online patient portals they already use. Reasons provided for not using the app included perception that the materials repeated information already received, side effects such as graft-versus-host disease that restricted vision or motor skills, and lack of comfort with apps for some older participants.
Conclusions: Many health technology and mobile apps are being created to improve patients' health and survivorship care. In this study, HCT survivors and caregivers identified a variety of features that they would want in an app or website, in particular, features tailored to individual needs. Health technologies provide an opportunity to improve survivorship care, but patients and caregivers should be engaged in the process of developing these tools to assure the technology fits their needs and will be used. Given the effort required to maintain these technologies, they require testing for health benefits in rigorous clinical trials.
Clinical Trial Registry: ClinicalTrials.gov: NCT03125070
Disclosure: Nothing to disclose
P164 Determinants of the physical performance less than 1 year following allogenic hematopoietic stem cell transplantation: A retrospective study about 59 patients
Virgile Pinelli1, Anne Huynh2, Philippe Marque3, Marc Labrunée3
1 IUCT Oncopole, Supportive Care, Toulouse, France, 2 IUCT Oncopole, Hematology, Toulouse, France, 3 CHU Toulouse, Physical Medicine and Rehabilitation, Toulouse, France
Background: Thanks to allogeneic stem cell transplantation (allo-HSCT) patients suffering from hematologic malignancies have seen an increase in there life duration expectancy, but they are many side effets including decreasing in physical performance and in quality of life. The intensity of physical performance decrease is variable between patients, and today we did not know why. The aim of our study was first to characterize the physical performance of subjects less than 1 year following allo-HSCT by the use of a cardiopulmonary exercise testing (CPET), and then to determine the predictive factors of exercise performance.
Methods: We did a retrospective analysis from 59 patients who had an allo-HSCT at hematology department of Toulouse-Oncopole and CPET from 01/2015 to 09/2017. The CPET was performed using a cycle ergometer with O2 and CO2 analyzer breath by breath, (Masterscreen CPX CareFusion, San Diego, USA), a continuous 12-lead electrocardiogram, and a blood pressure monitoring. The protocol included a 2-min rest period, a 2-min warm-up of 20W pedaling followed by a 10W/min incremental phase, up to exhaustion, then a 2-min active recovery of 20W pedaling, then a 2-min passive recovery. Three exercise markers were analysed: the peak of oxygen uptake (peak VO2), the VE/VCO2 slope and the first ventilatory threshold (VT1). Data relative to conditioning regimen, short-term complications, impairment at CPET day, and physical activity since allo-HSCT were gathered.
Results: After allo-HSCT, nearly 3 over 4 patients reported fatigue, a half reported dyspnea, and 1 over 4 or more reported pain, muscular, neurological or psychological impairment. More than 60% of patients suffer from moderate or severe physical intolerance, particularly when myeloablative conditioning regimen was used. Only 37% of patients followed rehabilitation sessions supervised by a physiotherapist, and non- supervised physical activity has been performed by 87% of patients. Despite normal lung function tests and echocardiography findings in most patients, 80% had exercise intolerance (EI), 85% exercise deconditioning, and 55% had abnormal ventilatory efficiency. Patients with moderate and severe impaired exercise capacity were significantly younger at diagnosis and at allo-HSCT, such as patients with severe deconditioning
Conclusions: Based on a retrospective study, we reported for the first time complete results from CPET and detailed clinical evaluation concerning deficiency and disability following first year after allo-HSCT. These results confirm that exercise impairment is very frequent with more than a half of patients suffering from alterations of one or more of the three performance markers, despite being active.
Disclosure: Nothing to declare
P165 Demyelinating disorders: A paradigm of immunity disorders after hematopoietic stem cell transplantation
Anna Amelia Colombo1, Oscar Borsani2, Daniela Caldera1, Paolo Bernasconi2
1 University of Pavia, San Matteo Hospital, Hematology Oncology, Pavia, Italy, 2 University of Pavia, San Matteo Hospital, Molecular Medicine, Pavia, Italy
Background: Neurologic complications are a major problem in patients who undergone Hematopoietic Stem Cell Transplantation (HSCT). Given the higher survival of transplanted patients, the burden of neurological complications is increasing in the last years. A significant reduction in overall survival was demonstrated in patients who developed neurological complication after HSCT, irrespectively of the hematopoietic stem cell (HSC) source. Neurologic disorders in transplanting setting comprise a wide variety of ethiologies including demyelinating disease, which are caused by immune and non-immune mechanisms. Here, we analyzed the clinical presentation and the underlie ethiologies of patients developing HSCT-related demyelinating disorders in order to give diagnostic and prognostic clues useful to manage these severe but treatable complications in the transplant setting.
Methods: A total of 45 patients of our department which developed neurological complications after HSCT were consecutively collected and 33 (73%) of them, namely those having a diagnosis of a demyelinating disorder, were grouped and described according to the ethiologies of their neurological disorder.
Results: In 14/33 (42%) patients, an immune-mediated process was found, while 10/33 (30%) were diagnosed as having an infective etiology and 2/33 (6%) were supposed to have a demyelinating disorder caused by toxic exposition. A definitive etiologic diagnosis was not formulated in the remaining 7/33 (21%) patients. When patients who developed an immune-mediated demyelinating disorder (10/33) were compared to those in which a clear immune pathogenic mechanism was not detected (23/33), a higher incidence of acute graft-versus-host disease (aGVHD) was detected in the former than in the latter (20% vs 8%). Moreover, comparison of these two groups revealed that those with no evidence of immune-mediated process have a slight higher prevalence of T-cell depleted HSCT thanthose with an immune-mediated demyelinating disorder (60% vs 50%). Finally, a lymphoproliferative disorder pre-existing the HSCT was detected in 5/14 (36%) patients with immune-mediated demyelinating disorder but only in 4/19 (21%) of those without evidence of immune-mediated processes.
Conclusions: Demyelinating disorders may be responsible of near 40% of neurologic complications in the post-transplant setting and, among them, an immune-mediated process is likely to be involved in more than 40% of cases. Our results suggest that the immune mechanism that underliesthe aGVHD may also be involved in developing demyelinating disease in transplanted patients. It also may be possible that the lymphoproliferative disorder pre-existing the HSCT is a risk factor able to increase the risk to develop an immune-mediated demyelinating disorder in the post-transplanting setting. Using a T-cell depleted HSCT can increase the risk of immune-mediated disorders in at least a small fraction of transplanted patients.
Despite our results should be validated on a larger cohort of patients, we can speculate on the possible connections between the wide range of complex and still poorly defined immunity disorders which can influence the prognosis and course of transplanted patients.
Disclosure: Nothing to declare
Abstract already published.
P167 Risk factors and implications of oral mucositis in recipient of allogeneic hematopoietic stem cell transplantation: A prospective single center study
Roni Shouval1, Liza Kouniavsky1, Joshua A. Fein1, Ivetta Danylesko1, Noga Shem Tov1, Ronit Yerushalmi1, Avichai Shimoni1, Arnon Nagler1
1 Chaim Sheba Medical Center, Tel Aviv University, Ramat Gan, Israel
Background: Injury to the mucosal barrier and subsequent development of oral mucositis (OM) is among the most common toxicities of allogeneic stem cell transplantation (SCT). Despite the high prevalence of OM and its debilitating nature, prospective studies evaluating determinants of OM are scarce. We therefore prospectively evaluated the occurrence of OM following SCT. Risk factors for OM and its implications short and long-term outcomes were assessed.
Methods: OM was prospectively evaluated on a weekly basis in patients undergoing allogeneic HSCT. The grade of OM was determined based on the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) scale (v. 4.0). Severe OM was defined as grade II to IV. Conditioning regimens were evaluated individually and according to intensity; myeloablative (MAC), reduced intensity (RIC) or reduced toxicity (RTC). The latter category included only patients receiving Fludarabine and Treosulfan at dose of 30-42 g/m2 (Flu/Treo). Risk factors for the development of severe OM were initially identified by a univariate analysis and then analyzed in a multivariate logistic regression model. Association of OM with peri-transplant infectious complications, IV morphine consumption, hospitalization length, neutrophil engraftment, acute and chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM) and overall survival were assessed in a univariate analysis. Competing events were considered in analyzing engraftment, GVHD, and NRM.
Results: 115 patients who underwent an allogeneic SCT between 2016 and 2017 were included. Median follow-up was 316 days. Leading indications for transplantation were acute myeloid leukemia (49%), lymphoma (16%), and myelodysplastic syndrome (15%). The majority of patients received an allograft from a matched sibling or unrelated donor (88%) and methotrexate GVHD prophylaxis (74%). The median time to OM onset was 7 (interquartile range [IQR] 5-9) days. Prevalence of grade II-IV OM was 60%. The median duration OM was 10 [6-13] days, and IV morphine was administrated for a median of 5 [6-12] days for patients with grades III-IV OM (45%). In a univariate analysis a younger age (p=0.023), lower BMI (p=0.01), recent smoking history (p=0.08), recent antibiotics exposure (p=0.018), MAC (p< 0.001), and use of methotrexate (p=0.009) were associated with an increased risk for grade II-IV OM. In a multivariable model the risk for grade II-IV OM was lower with RTC (i.e., Flu/Treo) vs. MAC (odds ratio [OR] 27.31; p< 0.001) and RTC vs RIC (OR 7.25; p=0.001), mycophenolate mofetil vs. methotrexate (OR 3.43; p=0.027) and recent smoking (OR 4.7; p=0.075). Compared to lower grades, grade II-IV OM was associated with a longer hospitalization duration (median 29 days vs. 27 days; p=0.006), delayed neutrophil engraftment (median 14 vs. 12 days; p=-0.004), and more gastrointestinal related infections (10% vs. 0%; p=0.045). Grade II-IV OM was not associated with increased risk of bloodstream infections, acute or chronic GVHD, non-relapse mortality, and increased mortality.
Conclusions: Oral mucositis is prevalent among allogeneic-SCT recipients. Importantly, fludarabine-treosulfan, which is considered a myeloablative is associated with a markedly reduced risk for OM. Consequences of OM include prolongation of hospitalization, delay in neutrophil engraftment, and a tendency for gastrointestinal infections, but does not increase the risk for GVHD and mortality.
Disclosure: Nothing to declare
P168 Hepatic focal nodular hyperplasia after hematopoietic stem cell transplantation: A single centre retrospective analysis
Alessandro Cattoni1, Anna Fornari1, Adriana Balduzzi1
1 San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy
Background: The advent of recent diagnostic techniques for the assessment of iron overload (T2*- MRI) and their systematic use as screening tools in the setting of secondary hemochromatosis have led to an increased awareness that focal nodular hyperplasia (FNH) represents a possible incidental finding after hematopoietic stem cell transplantation (HSCT).
Methods: Clinical and radiological features of patients undergoing HSCT in a single pediatric institution have been retrospectively reviewed for FNH. In order to provide an estimate of the prevalence of FNH after HSCT, we analysed all the T2*-MRI scans performed during the last 5 years in our Centre and recorded the number of patients with FNH (group A). In addition, data about patients incidentally diagnosed with FNH at abdominal imaging performed for different clinical indications have been collected (group B).
Results: Eight out of 118 (7%) transplanted patients who underwent at least one T2*-MRI scan from September 2013 to September 2018 were incidentally diagnosed with FNH. Group B included 3 subjects with FNH incidentally found at ultrasound or non-T2* MRI scans performed before 2013. Overall, 11 transplanted patients (5 males, 45%), transplanted for AL (9 cases) or bone marrow failure (2 cases) at a median age of 13.1±3.6 years, were diagnosed with FNH between 0.6 and 12.8 years after HSCT, namely 3.2±2.6 years in Group A and 7.0±4.1 years in Group B.
A variable degree of iron overload was demonstrated in all patient (LIC: 230-340±50 microg/g; baseline serum ferritin: 685-3189 ng/mL). The potential risk factors for FNH are reported in table 1.
In 8/11 patients, the radiological finding was pathognomonic; in 1/11 the diagnosis of FNH was confirmed histologically, while 2/11 subjects were labelled as “FNH-like”, although a potential diagnosis of hepatic adenoma could not be ruled out. In 3/11 patients, FNH presented with an isolated lesion, while 8/11 had 2 to more than 10 hepatic nodules at diagnosis. The size of nodules at diagnosis ranged from 3 to 41 mm. In unenhanced MRI scans, lesions were predominantly hyperintense on both T1- and T2-weighted sequences. In dynamic studies with contrast medium, all lesions strongly enhanced during the arterial phase, with a variable degree of wash-out in the late venous scans. Hepatic function tests were normal in all the enrolled patients at diagnosis of FNH. Among the 9/11 patients for whom at least a follow-up scan was available, 1 presented a complete regression, 3 a reduction and 3 an increase in the size and/or number of lesions, while in 2 patients the nodules remained substantially unchanged after a mean radiological follow-up of 4.5±3.3 years. No malignant transformations were observed.
Conclusions: FNH represents a relatively frequent incidental finding after HSCT. Although a malignant transformation is rare, given the demonstrated variable evolution of the hepatic nodules, a radiological follow-up is highly recommended.
Disclosure: Nothing to disclose.
P169 Incidence and risk factors for hepatic sinusoidal obstruction syndrome after allogeneic transplantation: Retrospective multicenter study of Turkish hematology research and education group (THREG), updated data
Nur Soyer1, Mehmet Gunduz2, Emre Tekgunduz3, Burak Deveci4, Hakan Ozdogu5, Handan Haydaroglu Sahin6, Esra Ermis Turak7, Mufide Okay8, Irfan Kuku9, İpek Yonal Hindilerden10, Pervin Topcuoglu2, Feviz Altuntas3, Ihsan Karadogan4, Mustafa Pehlivan6, Ali Unal7, Hakan Goker8, Mehmet Ali Erkurt9, Sevgi Kalayoglu Besısık10, Filiz Vural1
1 Ege University Medical Faculty, Izmir, Turkey, 2 Ankara University, Ankara, Turkey, 3 Ankara Oncology Hospital, Ankara, Turkey, 4 Medstar Antalya Hospital, Antalya, Turkey, 5 Baskent University Medical Faculty, Adana, Turkey, 6 Gaziantep University, Gaziantep, Turkey, 7 Erciyes University, Medical Faculty, Kayseri, Turkey, 8 Hacettepe University, Ankara, Turkey, 9 Inonu University, Malatya, Turkey, 10 Istanbul University, Istanbul, Turkey
Background: Hepatic sinusoidal obstruction syndrome (HSOS) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The mean incidence of HSOS was found to be 13.7% (0%-40%) in the literature. We examined the incidence and risk factors for HSOS after allo-SCT.
Methods: Ten centers from Turkey were enrolled in the study. We retrospectively evaluated the medical records of patients who were treated with allo-SCT between January 2012 and December 2015. A Baltimore criterion was used for assessment of HSOS. Four hundred twenty six (97.2%) of 438 patients who were treated with prophylaxis with defibrotide alone or one or more of the N-Acetylcysteine, diuretics and heparin used defibrotide (10-25 mg/kg/day).
Results: The study included 1153 patients (687 males/466 females) with median age of 38 (15-71) years. The demographic and clinical characteristics of patients were summarized in Table 1. The incidence of HSOS was 7.5% (86). Prophylaxis for HSOS was used in 42 (48.1%) of patients, who developed HSOS. Defibrotide as prophylaxis was received by 34 of 42 (81%) of patients. HSOS developed in a median of 13 (0-34) days after stem cell infusion. Seventy-eight (90.7%) of patients who developed HSOS had infection at the time of diagnosis. Forty-eight of them had ascites, 65 had hepatomegaly and, 76 had weight gain.
|Characteristics||Patients without HSOS (n=1067)||Patients with HSOS (n=86)||Statistics|
|Age, median (range)||38.68±13.77||39.06±12.33||P=NS|
|Male (n; %)||631 (59.1)||56 (65.1)||P=NS|
|MAC regimen as conditioning (n; %)||585 (54.8)||51(59.3)||P=NS|
|HSOS prophylaxis yes/no (n; %)||396/671 (37.1)||42/44 (48.8)||P=0.031|
|MTX/CsA as GVHD prophylaxis (n; %)||905 (84.8)||81 (94.1)||P=NS|
|Use of PB as stem cell source (n; %)||1022 (95.8)||78 (90.7)||P=NS|
|Use of matched-related donor (n; %)||854 (80)||64 (74.4)||P=0.042|
|Successful engraftment (n; %)||949 (88.9)||58 (67.4)||P= 0.000|
[ [P169 Table] 1 . Patients' characteristics (*Peripheral blood: PB, Bone marrow: BM, MAC: Myeloablative conditioning, NS: not significant, RIC: Reduced-intensity condi)]
Seventy-three (84.9%) of patients with HSOS were treated with defibrotide after diagnosis. The median time of starting defibrotide in these patients was 13.5 (2-29) days. Thirty-seven (43%) of patients with HSOS recovered completely and forty-nine (57%) of them died as a result of multi organ failure. The incidence of HSOS-related mortality in allo-HSCT cohort was found to be 4.2%. In univariate analysis, statistically significant associations were not found between HSOS incidence and age/sex of recipient, type of conditioning regimen, stem cell source and type of GVHD prophylaxis. On the other hand donor type, engraftment status and prophylaxis for HSOS were significantly associated with HSOS development. HSOS prophylaxis was significantly decreased HSOS-associated mortality (p=0.001).
Conclusions: HSOS still remains a serious life-threatening complication of allo-SCT. Although the incidence is low, HSOS is associated with increased 100-day non-relapse mortality. HSOS prophylaxis especially with defibrotide, seems to reduce HSOS associated mortality in high risk patients.
Disclosure: Nothing to declare
P170 Prophylaxis with defibrotide in adults at very high risk of veno-occlusive disease: Results in 11 patients
Fabio Giglio1, Elisabetta Xue1, Lorenzo Lazzari1, Raffaella Greco1, Teresa Daniela Clerici1, Sarah Marktel1, Maria Teresa Lupo-Stanghellini1, Andrea Angelo Assanelli1, Magda Marcatti1, Consuelo Corti1, Massimo Bernardi1, Simona Piemontese1, Jacopo Peccatori1, Fabio Ciceri1,2
1 IRCCS San Raffaele Scientific Institute, Milano, Italy, 2 University Vita-Salute San Raffaele, Milano, Italy
Background: Hepatic Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease (SOS/VOD) is a life threatening complication that can occur after Hematopoietic Stem Cell Transplantation (HSCT). Severe SOS/VOD rapidly evolves in Multiple Organ Dysfunction Syndrome (MODS), associated with a mortality rate exceding 80%. Precocity of defibrotide (DF) treatment is the leading factor for efficacy. Prophylactic use of DF is recommended in children, but its value has not been validated in the adult population, although factors for individual risk assessment for VOD are debated. We here present a real-world experience of DF prophylaxis in adult patients at very high risk of SOS/VOD receiving allogeneic HSCT.
Methods: From 2016 to 2018 we treated with prophylactic Defibrotide and Ursodeoxycholic Acid (UDCA) 11 patients, median age 30 years (range 21-59). Nine patients received allogeneic HSCT for acute lymphoblastic leukemia (8 B-ALL and 1 T-ALL), one patient for Severe Aplastic Anemia, one patient for Primary Myelofibrosis. They were all at high risk for SOS/VOD because of previous hepatotoxicity (3 patients), previous HSCT (6 patients), double alkylating agent (5 patients) or previous treatment with Inotuzomab Ozogamicin (IO; 7 patients). Of the 7 patients treated with IO, 6 received 2 cycles of IO, and 1 received 1 cycle, with the last IO dose administered a median 41.5 days before HSCT (range 34-61 d). Defibrotide was administered in 4 daily doses for a total dose of 25 mg/kg per day and UDCA at the dose of 300 mg twice per day, starting from day -6 prior transplant. All patients received Treosulfan-Fludarabine based conditioning. In 5 patients Thiotepa was added to the conditioning and in 2 patients a low dose 4Gy TBI. GvHD prophylaxis included post-transplant cyclophosphamide, rapamycin and mycophenolate in all patients, except one patient with Aplastic Anemia receiving ATG, rapamycin and mycophenolate. Donor source was PBSC in all cases. Seven patients received family haploidentical (MMRD) transplant, 1 patient a MRD transplant and 3 patients a MUD transplant.
Results: The median duration of defibrotide therapy was 34 days (range 32-64 days). Documented non-severe gastrointestinal bleeding occurred in 2 patients requiring defibrotide temporarily discontinuation, no other significant bleedings were experienced. Four patients developed grade II-IV acute GVHD and no transplant-associated thrombotic microangiopathy were diagnosed. Overall, SOS/VOD occurred in 3/11 cases within 21 days after HSCT (days 9, 10 and 13) and no late-onset SOS/VOD were diagnosed. SOS/VOD was very severe, causing MODS and death in all 3 cases. All 3 patients were characterized by a common pattern of very high risk factors for SOS/VOD by prior HSCT and salvage treatment for B-ALL with 2 cycles of IO close to HSCT. Furthermore, they all received a fully myeloablative conditioning regimen with Treosulfan and Thiotepa and a MMRD transplant.
Conclusions: Defibrotide prophylaxis was safe and well tolerated with no severe related complications.
SOS/VOD occurred despite continuous DF prophylaxis in 3/7 patients treated with Inotuzomab Ozogamicin close before undergoing 2nd transplant. To reduce the incidence of severe VOD, pre allo-HSCT treatment with Inotuzomab Ozogamicin should prompt avoidance of other cumulative risk factors for VOD, such as use of double alkylating agents.
Disclosure: Nothing to declare
P171 Pulmonary injury in children receiving high-dose busulfan
Ron Rabinowicz1, Patrick Stafler1,2, Anat Yahel1, Daniel Kurnik3, Jerry Stein1,2
1 Schneider Children's Medical Center, Petah Tikva, Israel, 2 Tel Aviv University, Sackler Faculty of Medicine, Tel Aviv, Israel, 3 Rambam Medical Center, Haifa, Israel
Background: Busulfan is the backbone of many preparative regimens administered to children undergoing allogeneic and autologous hematopoietic stem cell transplantation (HSCT). Among its many long-term adverse effects, Busulfan can cause various degrees of pulmonary injury. Although well described in adults, there are few large series exploring pulmonary toxicity of Busulfan in children.
We describe long-term pulmonary follow-up in a large group of children treated at a single center who had received high-dose Busulfan and examine the relationship of systemic drug exposure and lung function over time.
Methods: All surviving children who had received high-dose Busulfan between 1993-2013 in the context of HSCT at the Schneider Children´s Medical Center, were referred for serial pulmonary function monitoring (including spirometry, plethysmography and diffusing capacity for carbon monoxide [DLCO]. Pre-transplant testing was available for children who were old enough to perform the procedure. Spirometry results were adjusted according to the revised Global Lung Initiative formulas for age, gender, and height. Pulmonary injury was defined as a Z score below -1.96 for spirometry, or < 80% of predicted for the other parameters. Busulfan levels were monitored following the second drug dose. All patients received Busulfan in four daily doses. Area Under the Curve (AUC) calculations were performed by Bayesian calculations.
Results: Between 1993-2013, 263 patients aged 0-18 years were diagnosed with malignant or non-malignant diseases and treated with high-dose Busulfan. Of 130 short-term survivors, 75 had at least one post-transplant pulmonary function evaluation. The mean age at treatment with Busulfan was 7.9 years (range, 0.4-27 years). Of these 75 children, 22 children had undergone autologous transplantation and 53 children had an allogeneic transplant. 7 of these patients eventually relapsed and 3 died. 26 children had one or more pulmonary risk factors before HSCT - chest or upper abdomen radiation (13), chest wall tumors or lung metastasis (8), chest surgery (5), prior administration of pulmonary-toxic drug (3) or asthma (2). During follow-up (up to 14 years, median 5.5 years), FEV1 and FVC spirometry tests both decreased significantly (p=0.002 and 0.001, respectively), while the decrease in DLCO was not statistically significant. 35% of patients had abnormal pulmonary function tests and seven children had symptomatic disease which in two may have been manifestations of GVHD. Interestingly, no correlation was found between Busulfan AUC, Busulfan peak levels, the number of Busulfan doses administered, the type of transplantation (autologous vs. allogeneic) or primary disease to pulmonary injury. Even after censoring of children with pre-transplant pulmonary risk factors we noted a decrease of FEV1 and FVC.
Conclusions: As in adults, pulmonary injury is observed in children treated with high-dose Busulfan prior to HSCT. No correlation was observed between Busulfan AUC and pulmonary injury. Follow-up of children who receive this drug should include regular pulmonary monitoring, referral to a pulmonologist when subclinical pulmonary compromise is found, and counseling regarding measures that might prevent or ameliorate pulmonary damage. Continued follow-up of this cohort of patients should inform our pre-transplant patient information sessions, and the future use of Busulfan in children.
Disclosure: Nothing to declare
P172 Predictors of survival in patients with transplant-associated thrombotic microangiopathy
Mikhail M. Kanunnikov, Zhemal Z. Rakhmanova, Olesya V. Paina, Elena I. Darskaya, Tatiana A. Bykova, Asmik G. Gevorgian, Elena V. Morozova, Ludmila S. Zubarovskaya, Sergey N. Bondarenko, Ivan S. Moiseev, Boris V. Afanasyev
1 First Pavlov Saint Petersburg State Medical University, Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Saint Petersburg, Russian Federation
Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is a specific complication of allogeneic hematopoietic stem cell transplantation (HSCT).
Post-HSCT TMA has been attributed to the vascular endothelial damage caused by high-dose chemotherapy, calcineurin inhibitors (CNIs), graft-versus-host disease (GVHD), infections. There is a little evidence published regarding the efficacy and factors influencing the outcome of withdrawal of CNIs.
Methods: The analysis comprised a total of 54 patients, with diagnosed hematologic malignancy (AML (16), ALL (12), MDS (4), Hodgkin lymphoma (5), CML (3) and Neuroblastoma (1) received allo-SCT, from a matched related, unrelated or haploidentical donor between 2007 and 2018. Patients were diagnosed with TA-TMA based on Cho criteria. The median age of patients was 23 (37 adults, 17 children). GVHD prophylaxis was performed with tacrolimus (Tac) in 42, cyclosporine A(CsA) in 11, combination tacrolimus+sirolimus (Sir) in 12. 24 patients received ATG and 26 PTCy. Withdrawal of CNIs was accompanied by administration of systemic steroids (21 patients) or substitution with Sir after reaching levels of CsA< 100 ng/ml or Tac < 3 ng/ml in 13. The target concentration of Sir was 3-9 ng/ml. In pediatric patients who received combination Tac+Sir, the Tac was discontinued in one step while Sir continued. Median time to development TMA was 31,5 days after allo-SCT (range 1-408). Median follow-up of surviving patients was 395 days. The primary outcome was overall survival (OS) up to 2 years after development of TA-TMA.
Results: The following significant predictors of 2-year OS were identified: Tac replacement with Sir (p< 0,001), PTCy in prophylaxis (p< 0,001), acute GVHD (aGVHD) grade 2-4 (p=0,029), previous sepsis (p=0,003), level of LDH in debut (p=0,001), combination Sir+Tac in prophylaxis (p=0,05), major AB0-mismatch (p=0,022), severity of CNS symptoms (p< 0,001). There was no significant difference in OS according to patients' age, sex, “salvage” disease status at transplantation, previous VOD, viral (HHV 1,2,6, CMV, EBV) reactivations, count of CD34+ cells transfused, LDH level, shizocytes and creatinine in the debut of TA-TMA. In the multivariate analysis replacement of CNIs with Sir (HR 0.27, 95%CI 0.08-0.96, p=0.018) and baseline LDH level (HR 1.01, 95%HR 1.00-1.01, p=0.029) were associated with survival differences. The cut off for LDH was 4xUNL. aGVHD grade 2-4 (HR 1.96, 95%CI 0.92-4.17, p=0,081) and use of PTCy (HR 0.535, 95%CI 0.16-1.82, p=0.317) were not significant in the multivariate analysis (figure 1). TA-TMA cases after PTCy were significantly less frequently associated with clinically significant aGVHD (19% vs 68%, p< 0,001). The survival was higher after PTCy (74% vs 15%), but not significant due to sample size and other TA-TMA factors. Leading causes of death were: GVHD progression (11%), bacterial infection (11%), TMA (17%) and other (19%).
Conclusions: Replacing Tac by Sir is an effective therapeutic strategy in a group of patients with debut of TA-TMA at least after PTCy, where it is less likely to be associated with aGVHD. There is a significant overlap of populations with PTCy prophylaxis and substitution with Sir, thus the study is not powered to provide guidance for patients on conventional prophylaxis with TA-TMA.
[ [P172 Image] 1 . Figure 1. Factors influencing overall survival in TA-TMA (multivariate analysis)]
Disclosure: None of the authors has anything to disclose.
P173 Donor-recipient AB0 mismatch effect on the allogeneic hematopoietic stem cell transplantation outcome: A single-center retrospective study
Giorgia Saporiti1, Andrea Busani1, Giorgia Levati1, Elena Tagliaferri1, Federica Grifoni1, Cristina Manera1, Luca Baldini1, Francesco Onida1
1 Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano - University of Milan, Milano, Italy
Background: Because transmission of major histocompatibility complex and blood group system genes is independent from each other, approximately 40-50% of all allogeneic hematopoietic stem cell transplantations (allo-HSCT) are realized crosswise the AB0-blood group boundary. However, due to the widespread expression of AB0 antigens on a variety of human tissues other than erythrocytes, AB0 incompatibility may have an impact on the outcome of allogeneic HSCT that goes beyond the well-known immune-hematological complications such as immediate hemolysis due to the presence of isoagglutinins and delayed hemolysis due to passenger B lymphocytes. Here we aimed to assess the donor-recipient AB0 mismatch effect on the allo-HSCT outcome, comprising non-relapse mortality (NRM), overall and relapse-free survival, post-transplant PRC transfusion requirement, as well as relapse rate, incidence of graft- failure and acute GvHD.
Methods: Clinical and laboratory data from 180 consecutive patients undergoing allogeneic HSCT between 01/2008 and 06/2018 at the Fondazione IRCCS Ca' Granda Maggiore Policlinico Hospital in Milan, Italy, were retrospectively collected. Kaplan Meier estimates were used for the analysis of survival outcomes while NRM, relapse and acute GvHD cumulative incidences were investigated by competing risk analysis.
Results: The patient series included 105 AB0-match, 31 major AB0-mismatch, 34 minor AB0-mismatched and 10 bidirectionally AB0-mismatch transplants. Indication for allo-HSCT were mainly AML/MDS (77 pts), ALL (34 pts) and T-NHL/CTCL (32 pts). Mean overall survival for groups of patients undergoing AB0-identical, major AB0 mismatch and minor AB0 mismatch HSCT were 66 months (95% CI [55 ;77]), 47 months (95% CI [28; 65) and 46 months (95% CI [31; 61]), respectively. NRM in the three groups were significantly different, with point estimates of 12%, 29% and 26% at 5 years, respectively, whereas no significant differences were observed for relapse rate and graft failure incidence. Although not statistically different, incidence of acute grade III-IV GvHD was twice as high in patients transplanted from minor AB0-mismatched donors than in the AB0 identical group (16% vs 8%). Following transplantation, PRC transfusion requirement was significantly higher in the major AB0 mismatch then in the AB0-match transplanted patients (median 14 vs 7, p=0.01), with a marginal positive correlation between the anti-donor A/B IgG titers measured prior HSCT and the total number of PRC transfused during the first year following transplantation.
We observed only one case of PRCA occurring in a 50-year-old 0+ woman who was transplanted from a 32-year-old male A+ HLA-identical sibling using peripheral blood as the stem cell source following a myeloablative conditioning for AML in first complete remission. Anti-A IgG isoagglutinin titers prior to transplantation were 1:256. During the first year post transplantation, the patient required a total of 46 PRC transfusions, with gradual resolution occurring only after introduction of danazole treatment.
Conclusions: In our patient cohort, both major and minor AB0 mismatch associated to a significantly higher NRM. Major AB0 mismatch associated to a higher PRC transfusion requirement. A more frequently occurring severe acute GvHD was also suggested in minor AB0-mismatch transplants. Altogether, our results suggest that allo-HSCT outcome may be significantly affected by AB0 blood group mismatch.
Disclosure: Nothing to declare
P174 Intestinal transplant-associated thrombotic microangiopathy (TA-TMA): histopathological review. An infradiagnosed complication
Javier Carrillo Checa1, Oscar Javier Blanco Nuñez1, Luis Miguel Chinchilla Tabora1, Alejandro Avendaño Pita1, Estefanía Pérez López1, Mónica Cabrero Calvo1, Ana África Martín López1, Fermín Sánchez-Guijo Martín1, Lourdes Vázquez López1, Almudena Navarro Bailon1, Antonio Velasco Guardado1, Félix López Cadenas1, María Diez Campelo1, Oriana López Godino2, Miguel Alcoceba Sánchez1, Dolores Caballero Barrigon1, Lucía López Corral1
1 Complejo Asistencial Universitario de Salamanca-IBSAL-Gerencia Regional de Salud de Castilla y Leon, Salamanca, Spain, 2 Hospital Morales Meseguer, Murcia, Spain
Background: AT-TMA is a severe endothelial injury complication and it may involve the intestinal vasculature. Intestinal TMA could be fatal and missdiagnosed. Clinical and pathological criteria to differentiate from intestinal GVHD are needed. The aim of this study was to analyze the incidence and histological characteristics of intestinal TMA in patients diagnosed of systemic TMA.
Methods: We analyzed the incidence of TMA in 555 patients who underwent allo-HSCT in our institution between january 2010-august 2018. TMA diagnosis was based on Ho criteria. We do a pathological review in 103 biopsies from 25 out of 52 patients in whom an endoscopy have been performed 30 days before and 60 days after the diagnosis of TMA for suspicious of GVHD. Review was performed by a pathologist expert in GVHD, who examined the biopsies in search of hystopathological features of GVHD, TMA or viral infection. Diagnosis of gastrointestinal GVHD was stablished according to Mcdonald and Sales criteria, while intestinal TMA diagnosis was stablished by Warren et al criteria.
Results: 52 out of 555 patients (9,4%) were diagnosed of TMA. Transplant characteristics and TMA data of patients with systemic TMA are shown in image. 47 out of 52 patients with TMA (90%) had been diagnosed with prior/simultaneous acute GVHD, 20 of them grade III-IV, and 80% with gastrointestinal GVHD.
Intestinal TMA have been reported only in 7 out of 25 patients (28%) at diagnosis, whereas when review based on Warren criteria was performed, in 19 patients (76%) the pathologist found at least 1 of the criteria of endothelial damage and 48 % of the patients 3 or more Warren criteria were founded. The most frequent features were endothelial cell swelling (n=16, 64%) and perivascular mucosal hemorrhage (n=15, 60%). Review hystological features of biopsies are shown in table 3 of the image.
Regarding GVHD, it was found in 21 patients (84%) at diagnosis and in 23 (92%) at pathological review.
With a median follow-up of 10 months (1-73) 32 patients of the 52 with systemic TMA (62%) are dead. 9 of the deaths (41%) were related to TMA (3 TMA, 3 TMA+GVHD, and 3 TMA+infection). Patients with 3 or more Warren criteria in pathological review had poor outcome compared with patients less than 3 criteria (30% alive VS 51% at 12 months, p=0.9).
Conclusions: Intestinal TMA is a life-threatening underdiagnosed entity. Only 7 patients of 25 patients were diagnosed of intestinal TMA.
We found that most of our patients had endothelial damage in the gastrointestinal biopsy pathological reviews. GVHD histological criteria were present in most of the patients, mainly histological grade I-II. Prognosis of these patients is poor and pathologist effords in diagnosed the entity is guarranted.
Disclosure: Nothing to disclosure
P175 Strategies to reduce neutropenic fever and hospital readmission in multiple myeloma patients managed at home after autologous stem cell transplantation
Luis Gerardo Rodríguez-Lobato1, Alexandra Martínez-Roca1, Sandra Castaño-Díez1, Alicia Palomino-Mosquera1, Gonzalo Gutiérrez-García1, María Suárez-Lledó1, Montserrat Rovira1, Carmen Martínez1, Laura Rosiñol1, Alexandra Pedraza-Navarrete1, Ana Moreno-Castaño1, Cristina Gallego1, Adelina Hernando1, Susana Segura1, Álvaro Urbano-Ispizua1, Francesc Fernández-Avilés1
1 Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Josep Carreras Leukemia Research Institute (IJC), Barcelona, Spain
Background: Neutropenic fever (NF) is the most frequent cause of readmission in the outpatient autologous stem cell transplantation (ASCT) programs. In our at home model for multiple myeloma patients, we added primary prophylaxis with ceftriaxone, decreasing the incidence of fever during aplasia phase from 85% to 57.6%. The aim of this study was to analyze the addition of two strategies to reduce the non-infectious NF: withdrawal of G-CSF and the addition of primary prophylaxis for engraftment syndrome with corticosteroids after ASCT.
Methods: Between January 2002 and August 2018 111 myeloma patients were managed at-home since day +1 of ASCT. All were conditioned with Mel200. All patients received prophylaxis with quinolone, fluconazole, aerolized pentamidine, low-dose acyclovir (HVS+), and ceftriaxone (since day +4). The patients were classified into 3 groups: group A (n=33; G-CSF since day +7 without corticosteroid), group B (n=32; no G-CSF and no corticosteroid), group C (n=46; no G-CSF with prednisone 0.5 mg/kg/day since day +7 until granulocyte recovery). First-line therapy at home of NF was piperacillin-tazobactam 4.5 g/6h i.v. using a portable intermittent infusion pump. Fever was an indication of immediate medical consultation and those patients presenting signs of focal infection or severe sepsis were admitted. Other indications for readmission were: willingness of the patient or caregiver, uncontrolled nausea, vomiting or diarrhoea, and mucositis requiring total parenteral nutrition or i.v. morphics.
Results: The main characteristics of the patients and outcomes are shown in table 1. There were no differences between groups regarding age, gender, immunological subtype, response before ASCT, HCT-CI, and CD34 cell dose infused. There were more patients with advanced disease (ISS III) in group C compared to group A (19.5% vs. 6.1%; P=0.003). The duration of neutropenia was longer in those groups that did not receive G-CSF (A: 8 days, B: 11 days, C: 10 days; P< 0.01). Comparing group A with group C, we observed that the incidence of NF and the readmissions rates were lower in group C (NF: 57.6% vs. 23.9%; P=0.002; relative risk reduction: 0.41, and number needed to treat 2.97; readmissions: 12.1% vs. 2.2%; P=0.07, respectively). The 10-day cumulative incidence of NF were 54.5% in group A, 40.6% in group B, and 23.9% in group C; P=0.009. The non-administration of G-CSF with the addition of prophylactic corticosteroid did not modify the incidence and grade of mucositis, the first day and duration of fever, nor the number of bacterial infections documented. In the multivariate analysis, this combination (no G-CSF with corticosteroid) maintained its protective effect for the development of NF and hospital readmission (OR 0.07; P=0.001 and OR 0.07; P=0.05, respectively).
Conclusions: The non-use of G-CSF and the addition of prophylactic corticosteroid in MM patients managed at home after ASCT minimize the incidence of non-infectious fever and optimize hospital resources by reducing hospital readmissions.
Disclosure: Nothing to declare.
Abstract already published.
P177 Safety of vaccines in a cohort of allogeneic stem cell transplantation recipients
Clara Targhetta1, Maria Pina Simula1, Cristina Depau1, Adriana Vacca1, Eugenia Piras1, Tania Durzu1, Rodrigo Rojas2, Valentina Serreli1, Sara Cardani1, Giorgio La Nasa1
1 Ospedale A. Businco, Azienda Ospedaliera G. Brotzu, U.O. Ematologia e CTMO, Cagliari, Italy, 2 Università degli Studi di Sassari, UOC Ematologia, Sassari, Italy
Background: Antibody titers to vaccine-preventable diseases decline during the 1-10 years after allogeneic Hematopoietic Stem Cell Transplantation (HSCT) if the recipient is not revaccinated. It is therefore considered best practice to try to offer HSCT recipients the same level of protection against all vaccine preventable diseases as the general population. Few data in the literature are available concerning vaccine-related problems in HSCT recipients. We performed a farmacovigilance evaluation in a cohort of allotransplanted patients followed in our clinic during a 1 year period.
Methods: From October 2017 to November 2018 we administered a list of recommended vaccines to 49 HSCT recipients attending our routine out patient clinic who fulfilled the following criteria: CD4 T cells>200/µl, CD19 B cells>20/µl, anti-CD20 antibody infusion>6 months, IVIG therapy>2 months, no active and severe Graft-versus-Host-Disease (GvHD), no chemotherapy or biological therapeutic agents on going. Vaccines suggested were Influenza, Pneumococcal conjugate (PCV13), Polio (inactivated polio vaccine), Diphteria, Tetanus, Acellular pertussis, Hepatitis B, Hepatitis A, Haemophilus influenzae type B, Meningococcal quadrivalent (MCV4), Human papillomavirus, Meningococcal B, Measles-Mumps-Rubella (MMR), Varicella. Live vaccines (MMR and Varicella) were not recommended before 2 years after HSCT and in patients with chronic GvHD. All the patients were asked to take the list to the local health facilities in order to have the vaccines injected and a vaccination table arranged with the doses already received and those to receive. We checked the vaccination tables at each visit and monitored potential side effects and GvHD status at 3, 6, and 12 months after the first vaccine injection.
Results: Twenty-nine out of 49 patients were evaluable (table 1), 16 without GvHD and 13 with chronic GvHD (5 mild, 4 moderate, 4 severe). Median time after HSCT was 34 months (16-240). Median number of vaccines received was 8 (1-14). As regards patients without chronic GvHD, 2 out of 16 experienced fever after vaccine injections; 1 out of 16 developed transient mild reduction of platelet count; 1 patient reported headache and otalgia after vaccine injection, while another one transient joint pain; 1 out of 16 patients presented signs of mouth chronic GvHD (score 1 NIH) and transaminase increase (grade 1 according to World Health Organization Toxicity Scale) 3 months after the first vaccine dose, so that cyclosporine dose had to be augmented. As regards patients with chronic GvHD, 4 out of 13 experienced fever after vaccine injections; 2 patients with mild chronic GvHD of the mouth presented hepatic flare two and three months after the first vaccine dose, respectively. In both cases a new increase of cyclosporin and methylprednisolone doses determined progressive normalization of liver enzymes.
Conclusions: These data show that vaccines were globally well tolerated in HSCT recipients, even when they suffered from chronic GvHD. However, close monitoring is warranted in order to better evaluate possible vaccine side effects in this setting of patients.
|Disease: AML 11 ALL 5 NHL 3 HL 3 MDS 2 SAA 2 PMF 1 CML 1 SCD 1|
|Conditioning Regimen: MAC 19 Non MAC 10|
|Donor: Sibling 18 MUD 7 Haplo 4|
[ [P177 Table] 1 . Table 1]
Disclosure: Nothing to disclose
P178 Allogeneic HSCT in the treatment for patients 60+ with AML: Is good QOL attainable, and how can we select for this?
Rachel Wright1, Maximilian Oremek2, David Davies3, Emma Kempshall3, Keith Wilson3,4, Wendy Ingram3
1 Taunton & Somerset NHS Trust, Taunton, United Kingdom, 2 Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany, 3 University Hospital of Wales, Cardiff, United Kingdom, 4 Cardiff University School of Medicine, Cardiff, United Kingdom
Background: Allogeneic HSCT improves survival for AML patients over the age of 60 years of age when compared to chemotherapy alone. The haematopoietic stem cell transplantation comorbidity index (HCT-CI) and EBMT score predict for non-relapse mortality and overall survival, yet little is known about whether QoL is preserved in this patient group and whether HCT-CI and other performance scores pre-BMT correlate with QoL post allo-HSCT.
Methods: We conducted a retrospective analysis of patients 60 years and older who underwent RIC allo-HSCT at the University Hospital of Wales, Cardiff between September 2011 and December 2017 (n=41). HCT-CI, Karnofsky Performance Score (KPS) and EBMT scores were calculated prior to transplant and QoL measured using the FACT BMT (version 4) questionnaire, which was completed at 3, 6 and 12 months post transplant. Patients were grouped at the 3-, 6- and 12-month time points for each of the different performance indices, allowing group comparison against compound sub scores using the Mann-Whitney U test.
Results: 41 patients were included in this study, with median age 65 years (range 60-74). Patient characteristics, including conditioning, donor type, pre-transplant HCT-CI and KPS scores are summarised in table 1. The 2 year and 5 year overall survival (OS) for the patient cohort was 65.4% and 48.7% respectively. HCT-CI of ≥3 vs 0 was significantly associated with poorer BMT-related QoL domains at 3 months (p=0.035) and general QoL domains at 6 months (p=0.025) post-transplant. While EBMT score showed no correlation with QoL parameters, patients with KPS of 100 vs ≤90 showed significant differences in both general (p=0.01) and BMT-related QoL (p=0.04) at 3 months and in all QoL domains at 6 months (symptom-related QoL p=0.05, general QoL p=0.01, BMT-related QoL p=0.01). Importantly neither the HCT-CI nor the KPS pre-transplant predicted for QoL at 12 months post transplant.
Conclusions: Patient selection is key to ensuring maximum benefit from allo-HSCT both in terms of overall survival but also with regards to QoL and survivorship. We note that while patients with HCT-CI ³3 or KPS ≤90 had significantly poorer QoL at 6 months post allo-HSCT, QoL was recovered by 12 months post transplant, with this significant difference no longer seen. Our data shows that in selected AML patients over the age of 60 years with good performance status and low comorbidity index, a favourable outcome can be achieved with good QoL maintained throughout the post transplant period.
|Characteristics||Total (%)||Characteristics||Total (%)||Characteristics||Total (%)|
|Median age, yr (range)||65 (60-74)||Donor||HCT-CI|
|Gender, male||24 (58.5)||Sibling||9 (22.0)||0||17 (41.5)|
|Conditioning||Matched unrelated donor (10/10)||21 (51.2)||1-2||9 (21.9)|
|FMC||32 (78.0)||Mismatched unrelated donor (≤9/10)||11 (26.8)||≥3||15 (36.6)|
|Other||4 (9.8)||High Risk||25 (61.0)||100||22 (53.7)|
|Diagnosis||Standard Risk||15 (36.6)||90||14 (34.1)|
|AML||28 (68.3)||Good Risk||1 (2.4)||≤80||5 (12.2)|
[ [P178 Table] 1 . Table 1: Patient Characteristics]
Disclosure: Nothing to declare.
P179 High prevalence of vertebral fractures and bone disease within the first 24 months post-alloSCT
María Suárez-Lledó1, Ana Monegal1, Teresa Solano1, Gonzalo Gutiérrez-Garcia1, Alexandra Pedraza-Navarrete1, Alejandra Patricia Martínez-Roca1, Ana Moreno-Castaño1, Gerardo Rodriguez-Lobato1, Laura Rosiñol1, Francesc Fernández-Avilés1, Alvaro Urbano-Ispizua1, Montserrat Rovira1, Carmen Martinez1
1 Hospital Clínic de Barcelona, Hematology, Barcelona, Spain
Background: Advances in alloSCT technology, supportive care, and use of reduced intensity conditioning regimens for older patients have led to significant improvements in long-term survival after transplant. The survivors have an elevated probability of late morbidity and mortality, including abnormalities in phosphocalcic metabolism and bone disease. Rapid and progressive bone loss occurs within the first 6-12 months after transplant, and this is followed by a slow process of recovery, with bone loss persisting for 48 to 120 months. Bone fractures can worsen the quality of life of alloSCT survivors, but the real burden of the disease is unknown. The objective of the study is to ascertain the prevalence of bone pathology and vertebral fractures early after transplant in our center.
Methods: This is a retrospective and observational study. Forty-nine patients (25 male/24 female, median age 54y, range 19-69) that underwent alloSCT were included in the study in the period of 6 to 24 months after transplant (May 2016-December 2017). Pre- and post-transplant risk factors associated with bone disease were recorded: age >65 years, female sex, menopause, hormone replacement therapy, previous treatment with steroids, previous fractures, weight < 40 kg, BMI < 20-25, low physical activity, low calcium intake, smoking, alcohol intake, and history of femoral fractures in parents. In all patients laboratory data (including serum calcium, 25-hydroxyvitamin D, and PTH), lumbar and femoral BMD (DXA), and spinal x-ray were also evaluated. A vertebral fracture was defined as a reduction of >20% in the anterior, middle or posterior high of the vertebral body.
Results: We identified vertebral fractures in 12 (24%) patients. Five patients had fractures prior to transplantation, and 7 patients presented “de novo” vertebral fractures following transplantation; therefore, the prevalence of “de novo” postransplant fractures was 7/49 (14%). Most (85%) of these fractures were asymptomatic at the time of diagnosis. Most patients (64%) with vertebral fractures had >3 pre-SCT risk factors (median risk factors pre-SCT 3, range 2-6), the most frequent being low calcium intake, steroid exposure, presence of previous fractures, and menopause. Those patients with fractures and less than 3 risk factors pre-TPH, added new risk factors after transplant, mainly steroid treatment. Forty-four patients (90%) had vitamin D insufficiency (< 30ng/ml), 15 (32%) had osteopenia and 9 (18%) had osteoporosis. Vitamin D insufficiency and bone disease were more frequent in women than in men (98% vs. 84% for vitamin D, 37% vs. 28% for osteopenia, 29% vs. 8% for osteoporosis, and 25% vs. 20% for vertebral fractures, respectively).
Conclusions: The prevalence of post-transplant bone disease and vertebral fractures in our series is high. Most fractures appearing "de novo" after alloSCT were asymptomatic and were diagnosed by x-ray. Patients who presented vertebral fractures frequently had more than 3 risk factors identified pre-SCT. Patients undergoing alloSCT should have their bone health assessed early in their treatment and, if indicated, should start preventative therapy to avoid bone loss and fractures. Other measures such as physical exercise, vitamin D and calcium supplementation, and DXA and spinal x-ray at baseline and following transplantation are also highly recommended.
María Suárez-Lledó received a grant from DKMS-Spain Foundation.
Other Authors have Nothing to declare
P180 The use of G-CSF in selected patients after autologous stem cell transplantation is associated with low incidence of engraftment syndrome
Lucrecia Yañez1,2, Miriam Sanchez Escamilla2, Cristina Amunárriz3, Guillermo Martín Sánchez1,2, Mercedes Colorado1,2, Sara Garcia Avila1, Mónica López Duarte1,2, José Luis Arroyo3, Enrique Ocio1,2, Arancha Bermudez1,2
1 Hospital Universitario Marqués de Valdecilla, Santander, Spain, 2 Instituto de investigación Marqués de Valdecilla - IDIVAL -, Santander, Spain, 3 Banco de Sangre y Tejidos de Cantabria, Santander, Spain
Background: The use of G-CSF after autologous stem cell transplantation (ASCT) accelerates neutrophil recovery, however it has been related to an increased risk of engraftment syndrome (ES) development in some studies. For this reason, we do not routinely prescribe G-CSF after ASCT and we only use it in patients with significant complications (enterocolitis, severe sepsis, atrial fibrillation) after stem cell infusion.
The main objective of this study is to evaluate the incidence of ES in patients who receive ASCT for monoclonal gammopathies (MG), non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) and receive G-CSF only if needed. As secondary objectives we evaluate differences in the engraftment day as well as the length of inpatient stay.
Methods: We retrospectively analyzed patients with MG or lymphoma, who underwent ASCT conditioned with high dose melphalan (140-200 mg/m2) or BEAM, respectively, between 2015 and 2017 in our center. Specific clinical features for ES according to Spitzer and Maiolino criteria were evaluated between 3 days before and 7 days after the engraftment. Statistical analysis was performed with SPSS v. 15.0.
Results: Thirty-one patients with MG and 34 patients with lymphoma were analyzed. Median age at transplant was 56.8 years (48.7-65.4) and 41 patients (63.1%) were male. Median prior lines of treatment in patients with GM or lymphoma were 1 (1-3) and 2 (1-5), respectively. Table 1 shows patients´characteristics.
Mobilization with G-CSF ± Plerixafor was performed in 27 patients (36%) and chemotherapy + G-CSF ± Plerixafor in 38 patients (64%). Median CD34 x 106/Kg cells infused was 3.6 (2.7-5.3).
Eleven patients (16.9%) received G-CSF, 5 due to infection (2 enterocolitis, 1 listeriosis, 1 acute hepatitis, 1 septic shock) and 6 because of atrial fibrillation or fibrillo-flutter. Median time from SCT to first day of G-CSF was 5 days (5-7) and median time on G-CSF treatment was 5 days (4-7). Patients who received G-CSF showed a short time to neutrophil engraftment (≥0.5x106/L), 10 days vs. 13 days, p< 0.001 but longer duration of hospitalization, 18 days vs. 15 days, p =0.050. Non-relapse mortality at day +30, +100 and +180 was 0%.
ES was diagnosed in 4 (6.2%) patients, 1 amyloidosis, 2 multiple myeloma and 1 plasmablastic lymphoma. There was not statistical difference in the incidence of ES between patients who received G-CSF (9.1%) and patients who did not (5.6%), p=0.533. Analyzed by disease, ES appeared in 1 of 6 patients who received G-CSF in the lymphoma group (16.6%) but none of the 7 patients with MG that received G-CSF developed it. We did not find statistical differences between patients who developed ES and those who did not in age (49 years vs. 56 years, p=0. 314), length of hospitalization (19 days vs. 15 days, p=0.185) and the number of CD34 x 106/Kg cells infused (3.65 vs. 4.62, p=0.408).
Conclusions: The use of G-CSF in selected patients is associated with low incidence of ES. Our study confirms that the use of G-CSF accelerates neutrophil recovery but it is unclear if it can increase the incidence of ES, especially in patients with lymphoma.
[ [P180 Image] 1 . Table 1. Patient´s characteristics]
Disclosure: Nothing to declare
P181 Recipient T-memory cell subsets count before ATG as the main prognostic factor of primary graft failure after allo-HSCT
Mikhail Drokov1, Natalia Popova1, Yulia Davydova1, Nikolay Kapranov1, Ekaterina Mikhaltsova1, Olga Koroleva1, Vera Vasilyeva1, Darya Dubnyak1, Zoya Konova1, Ekterina Usikova1, Anna Dmitrova1, Maria Nareyko1, Valentina Dvirnyk1, Irina Galtseva1, Larisa Kuzmina1, Elena Parovichnikova1, Valery Savchenko1
1 National Research Centre for Hematology, Moscow, Russian Federation,
Background: Graft failure is one of the TOP-3 problems of allo-HSCT (after GVHD and relapse). The problem of graft failure becomes more significant due to increasing number of allo-HSCT with RIC conditioning regimen from haploidentical and HLA-mismatched unrelated donors. Role of T cells in graft failure is well known. Here we report an impact of T-memory cell subsets count before Antithymocyte globulin (ATG) administration on primary graft failure after allo-HSCT.
Methods: Sixteen patients with acute leukemia transplanted in National Research Center for Hematology were included on this prospective study. All patients received horse ATG at dose 10 mg/kg/day from day -4 to -1 before allo-HSCT as GVHD prophylaxis and were balanced by other factors that could affect engraftment. Detailed patients characteristics are listed in Table 1. Peripheral blood samples were collected on day -4 before allo-HSCT (before ATG injection) in EDTA-tubes. Flow cytometry analysis was performed on BD FACS Canto II (Becton Dickinson, USA) to define T-memory subsets: T-naive and T-stem cell memory (Tnv+scm) - CD45R0-CCR7+CD28+; T-central memory (Tcm) - CD45R0+CCR7+CD28+; T-transitional memory (Ttm) - CD45R0+CCR7-CD28+; T-effector memory (Tem) - CD45R0+CCR7-CD28-; T-terminal effector (Tte) - CD45R0-CCR7-CD28-, among CD4+ and CD8+ T-cells . Sysmex XE-2100 was used to calculate absolute count of different T-cell subsets. Mann-Whitney U test was used for nonparametric data analysis between two groups. Fisher's exact test was used for 2x2 tables. P-value less than 0.05 was considered statistically significant.
Results: An influence of T-memory cell subsets count before ATG administration on primary graft failure is shown in Figure 1. According to our data high absolute number of CD4+Ttm and CD4+Tte is associated with primary graft failure.
Conclusions: Based on these findings high absolute number of CD4+Ttm and CD4+Tte could be one of the prognostic factors of primary graft failure after allo-HSCT. Optimizing ATG dose due to recipient absolute T-memory cell subsets count before ATG administering may prevent graft failure and improve posttransplant results.
|Engrafted (n=13)||Primary graft failure (n=3)||p-value|
|Age (median with range)||34(23-61)||49(25-58)||0,331|
|Male / Female||8 / 5||2 / 1||0,99|
|ALL / AML||8 / 5||2 / 1||0,99|
|CR1 / CR2+||7 / 6||3 / -||0,25|
|MAC / RIC||1 / 12||- / 3||0,99|
|MMUD / MUD / Haplo / MRD||3 / 2 / 3 / 5||2 / - / - / 1||0,44|
|BM / PBSC||3 / 10||1 / 2||0,99|
|ATG / ATG+PT-CY||7 / 6||1 / 2||0,99|
[ [P181 Table] 1 . Table 1. Characteristics of patients]
Disclosure: No relevant conflicts
P182 Budesonide - a not so topical glucocorticosteroid? - The relevance of drug interactions
Catherine Prodger1, Katalin Balassa1,2, Nicola Gray1, Oliver Lomas1, Asha Aggarwal1, Nadjoua Maouche1, Vanderson Rocha1,2, Robert Danby1,3, Andy Peniket1
1 Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom, 2 NHS Blood and Transplant, Oxford, United Kingdom, 3 Anthony Nolan Research Institute, London, United Kingdom
Background: Upper gastrointestinal graft-versus-host disease (GI GVHD) has been an increasingly recognised entity following allogeneic stem cell transplantation (SCT). Budesonide, widely used in inflammatory bowel conditions, has also been found beneficial in GI GVHD. The major benefit of Budesonide is attributable to its poor absorption and extensive first-pass metabolism via cytochrome P450 (CYP) 3A4, which translates to less systemic steroid-related effects. However, transplant patients are often exposed to multiple drugs, among which some agents act as CYP3A4 inhibitors and therefore can increase Budesonide bioavailability and might lead to systemic toxicity. Azole antifungal drugs are probably the most common concomitantly used CYP3A4 inhibitors in transplant recipients.
Methods: We reviewed allogeneic SCT records for patients treated with oral Budesonide for GI GVHD at our transplant centre between 2015 and 2018 retrospectively. The aim of the work was to assess the development of adrenal suppression with or without clinical features of iatrogenic Cushing`s syndrome. The standard dose of Budesonide was 3 mg three times a day. Patients receiving Prednisolone or other glucocorticosteroids and those with no available serum cortisol level measurements were excluded.
Results: Our analyses identified four allogeneic SCT patients in whom adrenal suppression was diagnosed with undetectable serum cortisol levels during oral Budesonide treatment. Of these patients two developed iatrogenic Cushing`s syndrome and both patients were treated with CYP3A4 inhibitors concomitantly:
1. Clarithromycin and Fluconazole;
2. Clarithomycin and Voriconazole.
The development was rapid (within 3 and 4 weeks). Symptoms included morphological features such as moon face, high blood pressure, weight gain, peripheral oedema and proximal myopathy. Symptoms resolved gradually following cessation of azole antifungal agents and on gradual weaning of Budesonide.
Conclusions: Although single agent Budesonide treatment given for GI GVHD is rarely associated with systemic side effects, patients on azole antifungal drugs and macrolide antibiotics are at higher risk of systemic toxicity due to drug interactions. Patients who are allergic to Penicillin and receive macrolide-based prophylaxis can be especially vulnerable. To our knowledge the number of cases reported in literature about systemic effects of oral Budesonide in transplant recipients is less than 10. Our observation supports previous reports on the potential of oral Budesonide to induce systemic effects. We therefore advise careful monitoring of patients treated with Budesonide in combination with CYP3A4 inhibitors, including antimicrobial agents routinely used in SCT.
P183 Implemented strategies to overcome barriers in the establishment of a consolidated hematopoietic stem cell transplantation program in a developing country
Monica Rivera Franco1, Eucario Leon Rodriguez1
1 Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Hematology and Oncology, Mexico City, Mexico
Background: The National Institute of Medical Sciences and Nutrition “Salvador Zubiran” is a National Health Institute located in Mexico City. Although Mexico is considered an upper-middle income country, more than 50% of the population lives in poverty without health care coverage and patients within this social stratum are referred to our Institution. The first hematopoietic stem cell transplantation (HSCT) in Mexico was performed at our Institution in 1980. From this year until 1997, HSCT were sporadically performed (n=33), showing a poor overall survival (OS) and high non-relapse mortality (NRM). These outcomes resulted from an unstructured HSCT Program, limited-resources, patient low socioeconomic status, and paucity of population-adapted procedures. In 1998, according to these results, a decision to establish a HSCT Program was made. Therefore, in order to set up a successful HSCT Program, implementation of financial and medical strategies were necessary. The objectives of this study were to describe the barriers and implemented strategies for the establishment of a HSCT Program in Mexico along with the outcomes of patients undergoing this procedure throughout the reorganization of the Program.
Methods: This study is a health services research. Barriers were detected based on the results of the HSCT Program from 1980-1997 (not shown). Table 1 shows the financial, medical, and research strategies that were implemented for each barrier.
Results: From November 1998 to November 2018, 363 HSCT have been performed in 322 patients at our Institution. Most HSCT were autologous (n=213, 59%). Forty one patients underwent 2 HSCT. From the 322 patients, most were males (n=196, 61%) and the median age was 33.5 years (range, 15-65). The most frequent underlying diseases for auto-HSCT were lymphomas (n=68, 36%), non-seminomatous germ cell tumors (n=42, 22%), and multiple myeloma (n=42, 22%). Acute leukemias (n=41, 34%), aplastic anemia (n=25, 21%), and myelodysplastic syndromes (n=20, 17%) were the most frequent diagnosis for patients undergoing allo-HSCT; and acute leukemia was the most frequent diagnosis for patients undergoing haploidentical HSCT (n=10, 83%). Acute and chronic GVHD were present in 25% (Grades I-II 89%) and 35% (limited 76%), respectively. For allo-HSCT, 30, 100-day, and 1-year NRM was 2.5%, 8%, and 12%, respectively; 30 and 100-day NRM in auto-HSCT was 1.5%; 10-year OS was 63% and 56% for auto and allo-HSCT, respectively.
Conclusions: Future perspectives of the HSCT Program include the acquisition of funds for unrelated donors; to improve outcomes of patients undergoing haploidentical HSCT, and to increase the number of in-patient rooms. We conclude that despite paucity of resources and other limitations, the implementation of financial, medical, and research strategies have shown that barriers can be effectively overcome in a developing country in order to establish a consolidated and nationally renowned HSCT Program, providing good outcomes for patients.
Disclosure: None of the authors have any conflict of interest to disclose.
P184 The effect of protective buffering on daily stress and relationship quality in dyads following hematopoietic stem cell transplantation: Results from daily process methodology
Malgorzata Sobczyk-Kruszelnicka1, Aleksandra Kroemeke2, Zuzanna Kwissa-Gajewska2, Sebastian Giebel1
1 Maria Sklodowska-Curie Institute - Cancer Center, Gliwice Branch, Gliwice, Poland, 2 SWPS University of Social Sciences and Humanities, Warszawa, Poland
Background: Cancer-related support communication (e.g., protective buffering) may impact the risk for psychological and relationship distress in patients following hematopoietic stem cell transplantation (HSCT) and their caregivers. Previous studies have revealed that protective buffering (i.e., hiding one's concerns and denying one's worries) has mixed effects: is beneficial (for “protected” person), costly (especially for the person using it), or unrelated to dyadic well-being. There has been, however, little evidence linking dyadic protective buffering with distress using daily process methodology. We assessed (1) the relationship between daily protective buffering, and same- and next-day stress and relationship quality in patient-caregiver dyads following HSCT and (2) whether similarity or complementarity in protective buffering between dyads is adaptive.
Methods: Two hundred patients (after first autologous or allogeneic HSCT) and their caregivers (spouse or another relative) independently completed measures of daily protective buffering, daily relationship quality, and daily stress for 28 consecutive evenings after patients´ hospital discharge. Actor-Partner-Interdependence Model (i.e., both partners' and caregivers' reports regarding support communication and distress were studied) was used to test study hypotheses.
Results: For both patients and caregivers, multilevel structural equation modeling showed a significant positive relationship between daily protective buffering and same-day relationship quality. Association of protective buffering with same-day stress level was negative. In next-day analyses, patient-reported protective buffering was related to patient's higher relationship quality, whereas caregiver-reported protective buffering increased patient's daily stress. Complementarity in protective buffering was related to higher immediate same-day relationship quality for both patients and caregivers, while benefits from similarity have delayed effects, although only in patients.
Conclusions: Contrary to previous studies, protective buffering rather has a beneficial effect in dyads following HSCT. Protection of the partner and relationship against revealing negative emotions and powerlessness was not related to costs in both parties. The findings suggest that the effect of daily protective buffering in dyads following HSCT depends on support timing (same- or next-day effect) and differs for both parties. Patients seem to benefit the most from the similarity in protective buffering, while caregivers from complementarity. The “fit” between patient and caregiver in support communication ought to be taken into consideration in the practical approach.
Disclosure: Nothing to declare.
P185 Virus reactivation and low dose of CD34+ cell were associatied with secondary poor graft function within the first 100 days after allogeneic stem cell transplantation
Yuqian Sun1, Xiao-Jun Huang1
1 Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Beijing, China
Background: Secondary poof graft function (sPGF) was defined as the secondary cytopenia after initial engraftment of HSCT. It was shown to be associated with poor prognosis, however there are very few reports on the incidence, risk factors and outcomes of sPGF.
Methods: Patients who received transplantation from Peking University People's Hospitial during January, 2015 to December, 2015 were retrospectively reviewed if they fulfilled the following conditions:
(1) diagnosed with acute leukemia or myelodysplastic syndrome;
(2) received allo-SCT from either matched sibling donor (MSD) or haploidentical related donor (HID). PGF was defined as persistent neutropenia (≤0.5×109/L), thrombocytopenia (platelets ≤20×109/L), and/or hemoglobin ≤70 g/L for at least 3 consecutive days, transfusion-dependence, associated with hypoplastic-aplastic bone marrow (BM), and complete donor chimerism without concurrent graft-versus-host disease (GVHD) or disease relapse. Primary PGF was defined as the failure to achieve initial engraftment by days 28 after transplantation, while secondary PGF was defined as the fulfillment of the criteria after initial engraftment HSCT.
Results: During January, 2015 to December, 2015, 564 patients who received transplantation from Peking University People's Hospitial were retrospectively reviewed. Among the 490 patients who achieved initial engraftment, 28 patients developed sPGF. The cumulative incidence of sPGF on day 100 was 5.7%. The median time of secondary PGF was 54.5 (34-91) days after transplantation. Low (< median) CD34+ cell dose (p=0.019, HR 3.07(95%CI, 1.207-7.813)), EBV reactivation (p=0.009, HR 3.648(95%CI, 1.382-9.629)) and CMV reactivation (p=0.003, HR 7.827 (95%CI, 2.002-30.602)) were identified as independent risk factors with sPGF. There is no significant difference of PGF incidence in MSD group and HID patients (p=0.44). The overall survival of patients with sPGF at 1 year after transplantation was significantly poor than patients with GGF (50.5% versus 87.2%, p< 0.001).
Conclusions: In conclusion, sPGF develop in 5.7% patients after allo-SCT, especially in patients with CMV, EBV reactivation or infused with low dose of CD34+ cell. The prognosis of sPGF is still poor due to lack of standard treatment.
Disclosure: There is no conflict of interet
P186 Thiotepa with treosulfan and busulfan based conditioning are significantly more gonadotoxic than treosulfan
Nuthana Prathivadi Bhayankaram1, Denise Bonney1, Helen Campbell1, Cheryl Fitzgerald2, Robert Wynn1
1 Royal Manchester Children's Hospital, Manchester, United Kingdom, 2 St Mary's Hospital, Manchester, United Kingdom
Background: Haematopoietic stem cell transplant (HCT) can be used to treat malignant and non-malignant conditions. Prior to HCT, patients have conditioning with chemotherapy to ablate their bone marrow to make space for transplanted cells.
Previous studies suggest that busulfan results in long-term gonadal toxicity. No previous studies have compared gonadal toxicity outcomes after treatment with busulfan with treosulfan, a newer agent with similar marrow toxicity to busulfan but with reduced non-marrow toxcitiy.
Our aim was to determine whether there are differences in pubertal and fertility outcomes in paediatric patients treated with treosulfan compared with busulfan.
Methods: Inclusion criteria were patients who had received either busulfan or treosulfan or treosulfan with thiotepa, only one HCT and were aged 14 years and above in August 2018. Eligible patients were reviewed in clinic as part of their routine follow-up, thus research ethical approval was not required.
Follice Stimulating Hormone, Luteinising Hormone, oestradiol, and pubertal history were noted. Ovarian reserve was estimated in female patients by measuring serum Anti-Mullerian Hormone (AMH). Male patients had serum testosterone measured and were also offered semen analysis.
Results: Thirty-five patients met the inclusion criteria, of which twenty-five wanted to be reviewed (71%); seventeen females and eight males. Mean age at HCT was 13 years, mean age at review was 19 years and mean years since HCT was 5 years.
Female patients treated with busulfan or treosulfan with thiotepa (n=14) had minimal AMH and none of these patients were having regular periods. Females treated with treosulfan (n=3) had normal AMH and regular periods without needing hormone replacement.
Only four male patients opted for a semen analysis and all had significantly reduced sperm counts.
Conclusions: Our results suggest that females treated with treosulfan have minimal (if any) reduction in ovarian reserve compared to other conditioning regimens which casue significant compromise. Although this was a small study, and thus not suitable for statistical analysis, the clinical findings are marked. Future studies should further investigate optimal doses of treosulfan that could be used to achieve bone marrow engraftment and limit long-term effects on fertility.
Disclosure: Nothing to declare
P187 Hematopoietic stem cell transplantation patients admitted in the intensive care unit: Organ support and mortality
Walter Javier Zambrano Márquez1, Paula Lopez1, Jose Carlos Iglesias1, Paola Carolina Tamayo Arroyo1, Laura Escalada1, Christel Castañon1, Laura Francisca Avila Idrovo1, Antonio Sole Magdalena1, Lucia Morais Bras1, Tamara Arias Fernandez2, Ariana Fonseca1, Soledad Gonzalez Muñiz1, Joud Zanabili Al Sibai1, Ana Julia Gonzalez Huerta1, Pilar Palomo Moraleda1, Ana Pilar Gonzalez1
1 Hospital Universitario Central de Asturias, Hematology, Oviedo, Spain, 2 Centro Comunitario de Sangre y Tejidos de Asturias, Oviedo, Spain, 3 Hospital Universitario Central de Asturias,
Background: Autologous and allogenic hematopoietic stem cell transplantation (HSCT) are potentially curative treatments for hematological malignancies. Patients with related complications may need admission to the intensive care unit (ICU) for specific therapy and organ support. Mortality risk factors, supportive care and principal causes of admission in ICU are described in our cohort of patients (pts).
Methods: We retrospectively studied 326 pts, 185 male, with a median age of 56,63 years (range: 18-73) who underwent allo-HSCT in our center between July 2014 and October 2018. Two hundred and twenty-seven(69,6%) pts received autologous HSCT (auto-HCT) and 99 (30,4%) allogenic HSCT (allo-HSCT); 50 from unrelated donor, 38 from identical sibling, and the remainder, mismatched related donor 11.
Twenty-three (7,1%) out of 326 pts were admitted in the ICU in the transplant procedure admission.
Results: Fifteen (65,2%) out of 23 pts were male with a median age of 55 years (range: 28-69). Patients' baseline diseases were: multiple myeloma (34,8%), non-Hodgkin´s Lymphoma (26,1%), Hodgkin´s Lymphoma (8,7%), acute lymphoblastic leukemia (8,7%), myelodisplasic syndrome (8,7%), solid tumor (8,7) and acute myeloblastic leukemia (4,3%). Fifteen (65,2%) pts received auto-HSCT, 5 (21,7%) allo-HSCT from unrelated donor, 2 (8,7%) allo-HSCT from identical sibling, and the remainder haploidentical HSCT (1) (4,3%). So, 6,6% of auto-HSCT pts and 8% of allo-HSCT were admitted in the ICU. The median stay in the ICU was 5 days (range: 1-30) and reasons for admission were: respiratory insufficiency (60,8%), septic shock (30,4%), renal insufficiency (4,3%) and multi-organic failure (4,3%). Twenty-one (91.3%) pts required respiratory support with: nasal cannula or oxygen mask (C/M) (19%), non-invasive mechanical ventilation (NIMV) (66,7%) and invasive mechanical ventilation (IMV) (14,3%). Fourteen (60%) pts needed inotropic agents for shock treatment. Finally, 4 (4,5%) pts required substitutive renal therapy with hemodialysis or haemofiltration (HD/HF). Eleven (47,8%) out of 23 pts died, 7 (63,6%) were male with a median age of 55 years (range: 24-64). Ten of them (90,9%) needed IMV and were treated with inotropic agents. All patients who required HD/HF (n=4) died. IMV and treatment with inotropic agents were associated with ICU mortality (OR 6,5; p=0,03, OR 7; p=0,008; respectively).
Conclusions: In our series of pts, 7,1% needed admission in the ICU, presenting a mortality rate of 48% approximately. There were no differences in the prevalence of ICU admission regarding HSCT donor. Main reason for admission was respiratory failure with IMV requirement in 14,3% of pts. IMV and treatment with inotropic agents were associated with ICU mortality. An early identification of pts at risk of ICU admission could have a beneficial impact on survival improvement
Disclosure: Nothing to declare
P188 Is there any association between thrombotic risk factors and veno-oclusive disease in childhood allogeneic hematopoietic stem cell transplantation?
Meric Kaymak Cihan1, Fatma Belgin Atac2, Ozlem Arman Bilir1, Tekin Aksu1, Serife Mehtap Kanbur1, Namık Ozbek1
1 University of Health Sciences, Ankara Pediatrics and Pediatric Hematology and Oncology Hospital, Ankara, Turkey, 2 Baskent University Hospital, Medical Biology, Ankara, Turkey
Background: Veno-oclusive disease (VOD) is a major complication of hematopoietic stem cell transplantation (HSCT). In some studies levels of fibrinolytic factors especially plasminogen activator inhibitor-1 (PAI-1) level were found associated with VOD. However, little is known about the relationship between thrombophilia risk factors and VOD. In this study we aimed to investigate association of major thrombophilic gene mutations on VOD in pediatric HSCT patients.
Methods: We reviewed retrospectively 35 patients with VOD who underwent HSCT between 2010-2018 in Ankara Pediatrics and Pediatric Hematology-Oncology Training and Education Hospital, Bone Marrow Transplantation Unit, Turkey. Fifty-one patients who did not develop VOD and transplanted during the study period were accepted as control group. We evaluated plasma homocysteine and lipoprotein a level, protein S and C activity and antigen levels and factor V G1691A mutation, prothrombin G20210A mutation, methylenetetrahydrofolatereductase (MTHFR) C677T and A1298C mutations, plasminogen activator inhibitor-1 -675 4G/5G polymorphism before HSCT. We also evaluated the patients' hospital files and noted the demographic values and complications of HSCT. Statistical investigations were done with SPSS statistics 17.0 for windows and p< 0.05 has been accepted as significant.
Results: There was no difference between control and VOD groups as regard to age, sex, diagnosis, donor type, conditioning regimen, HSC source, and HLA typing . There was no difference between the groups according to homocysteine, lipoprotein a, protein S and C activity and antigen levels. We did not find any relation between the genetic variations of thrombophilia and VOD (Table 1). In VOD group there were 6 patients (17.1%) with acute graft versus host disease (aGVHD) and in control group there were 7 (15.9%) patients with aGVHD (p=0.046). Febrile episodes were more frequent in VOD group compared to the controls (respectively; n=30, 85.7% vs. n=23, 54.8%, p=0.006). 8-year overall survival was %77.1 in VOD group and 100% in control group (p=0.001). Disease free survival was also different between VOD and control groups (respectively; 74.3% vs. 97.3%, p=0.001).
Conclusions: In literature there are recent studies showing higher PAI-1 levels in patients with VOD. However, in our study we did not find any relationship between congenital thrombophilia factors and VOD. New studies with larger sample groups is necessary to better evaluate the association of congenital thrombophilia factors and VOD.
Disclosure: Nothing to declare
P189 Different strategies of chemotherapy-induced nausea and vomiting (CINV) prevention in hematological patients receiving an autologous hematopoietic stem cell transplantation: A single center experience
Ilaria Cutini1, Riccardo Boncompagni1, Chiara Nozzoli1, Antonella Gozzini1, Stefano Guidi1, Chiara Innocenti1, Massimo Di Gioia1, Lorenzo Tofani1, Riccardo Saccardi1
1 AOU Careggi, Florence, Italy
Background: Despite the improvements of pharmacological control, CINV still represents a major problem in patient undergoing hematopoietic stem cell transplantation (HSCT). We present here a comparison of two pharmacological strategies for preventing CINV in Multiple Myeloma (MM), Hodgkin (HL), and Non-Hodgkin Lymphoma (NHL) patients who received an autologous HSCT in our Institution.
Methods: From January 2015 to July 2018, we retrospectively analyzed 250 consecutive patients, median age 58 years (22-71yo), diagnosed with MM, HL, and NHL, who underwent an autologous HSCT following a Melphalan 200 mg/sqm and BEAM/FEAM condition regimens, respectively. The first 122 patients received CINV prophylaxis with palonosetron i.v and dexamethasone 8 mg die (Regimen A), whilst the following 128 were administered with fosaprepitant iv, ondansetron iv and dexamethasone 8 mg die (Regimen B) Both CINV prophylaxis was administered the day of melphalan infusion (day -1 form transplant). Emesis breakthroughs were treated with alizapride and metoclopramide. Nausea and vomiting were assessed through the CTCAE 4.0 score system. Categorical variables were compared with Pearson Chi-square test.
Results: The overall incidence of nausea was 78%, (55% grade 1, 41 % grade 2, and 4% grade 3, respectively). In Regimen A was shown to be 80%, (56% grade1, 41% grade 2, and 3% grade 3, respectively) while in Regimen B was 77% (54% grade 1, 41% grade 2, and 5% grade 3, respectively). Pearson Chi-square test did not show any differences between the 2 groups (p=0.679). The overall observed vomit was 32% (83% grade 1, 16% grade 2, and 1% grade 3). In Regimen A it was (47% (84% grade 14% grade 2, and 2% grade 3), and 17% in Regimen B (77% grade 1 and 23% grade 2). Conditioning regimens didn't' have any significant impact on either nausea or vomit.
Patientsyounger then median (58 yrs), were reported to have higher incidence of both nausea, (p=0.028) not related to CINV treatment, and vomit (40% vs 24%, p=0.012). In multivariate analysis the overall incidence of nausea is related to age (younger patients have higher probability to develop nausea (OR 2,282; p= 0,024) whilst the higher incidence of vomit is related to: Regimen A (OR 3.958; p< 0,001), previously reported nausea (OR 4,506; p< 0,001), and no smoking habits (OR 2,761; p=0,02).
Conclusions: Both regimens are equally effective for nausea control however Regimen B evidenced a better vomiting control. This finding is particularly relevant when the Center policies include an early discharge program, therefore improving both patient's Quality of Life and procedure cost-effectiveness.
Clinical Trial Registry: None
Disclosure: Nothing to declare
P190 Prospective single center analysis of a professionally-facilitated support group for patients after allogeneic hematopoietic cell transplantation
Karsten Geeck1, Daniela Heidenreich1, Sebastian Kreil1, Wolf-Karsten Hofmann1, Stefan A. Klein1
1 Universitätsmedizin Mannheim, III. Med. Klinik, Mannheim, Germany
Background: Patients who underwent an allogeneic hematopoietic cell transplantation (HCT) are challenged by medical, psychological and social complications. Support groups might help HCT-survivors to cope with these challenges. However, the existing literature about post-HCT support groups is scarce. Moreover, data on professionally-facilitated support groups do not exist. The aim of this project was (1) to establish a professionally-facilitated support group and (2) to assess the discussed topics.
Methods: From 11/2013 until 6/2017 all patients who received an allogeneic HCT at the adult stem cell transplantation program of the University clinic Mannheim were invited to participate in a professionally-facilitated support group. Additionally, spouses and life partners were invited. A theologian who is also a physician served as facilitator. He had no further function within the transplant team. The format of the group was unstructured without any rules regarding regular attendance. The facilitator did not provide topics or a curriculum. During the first year the group met every 14 days followed by a monthly schedule. From the fifth until the 39th meeting the attendance and the discussed topics were minuted by the facilitator. The content of the minutes was analysed by a combination of an inductive and a deductive approach. All participants provided their informed consent for the study.
Results: Altogether 23 patients (female: n=10; male: n=13) and 10 spouses/life partners (female: n=9; male: n=1) participated. 13 patients (57%) and 6 spouses (60%) attended more than one meeting. Among those who participated in ≥2 meetings the median time of participation was 16 months. The median count of participations was eight. 30% of the participants attended the meetings longer than one year, 9% longer than three years. There was no sex difference with respect to the frequency and the duration of participation. However, the frequency of participation decreased significantly the longer a participant was attending the meetings. During 35 group meetings the facilitator recorded 5138 thematically different contributions to the discussions divided in 37 distinct topics. These topics were grouped into 5 main categories [(a) medical topics, (b) private life and environment, (c) human relationships, (d) physical and mental condition and (e) the support group itself] and eight further categories [(1) compliance, (2) economic issues, (3) religion, (4) sexuality, (5) death and dying, (6) support and coping, (7) objectives and needs and (8) not otherwise specified issues] which could not be grouped in one of the main categories. The most frequent issues were medical topics (34%), human relationships (16%), physical and mental condition (15%), private life and environment (14%), financial issues (5%), the support group itself (4%), support and coping (4%) and objectives and needs (4%). Noteworthy, death and dying (0.5%) were rare topics and sexuality was never mentioned.
Conclusions: To our knowledge, this is the first prospective and systematic analysis of a professionally-facilitated support group for HCT-survivors. These data might help to establish support groups and to identify psychosocial needs of patients and targets for specific support.
Disclosure: Nothing to declare
P191 Endothelial dysfunction in multiple myeloma patients who underwent autologous hematopoietic stem cell transplant and developed engraftment syndrome
Ana Moreno-Castaño1, Marta Palomo2, Maribel Díaz-Ricart2,1, Ginés Escolar1, Sergi Torramadé-Moix1, Julia Martínez-Sanchez2, Enric Carreras2, Montserrat Rovira1, María Suárez-Lledó1, Francesc Fernández-Avilés1, Gonzalo Gutiérrez-García1
1 Hospital Clinic, IDIBAPS, Barcelona, Spain, 2 Hospital Clínic de Barcelona, Josep Carreras Leukemia Research Institute (IJC), Barcelona, Spain
Background: Endothelial damage is associated with inflammatory complications that appear early after HSCT, such as sinusoidal obstruction syndrome or acute GVHD. Engraftment syndrome (ES) is an inflammatory condition diagnosed by Maiolino clinical score. Potentially, ES can exhibit high morbidity and mortality, especially after autologous-HSCT in multiple myeloma (MM) patients since the introduction of new drugs such proteasome inhibitors and immunomodulatory drugs (IMiDs).
The objective of the present study was to evaluate if ES is associated with endothelial dysfunction in patients with MM who underwent auto-HSCT.
Methods: We included six patients with MM who received induction treatment including new drugs and consolidated their response with an autologous-HSCT. We analysed comparatively the effect of incubating endothelial cells in vitro with serum samples from patients with ES vs. no ES. Serum samples were collected before (PRE), and after 5, 7, and 10 days from the transplant. An additional sample was collected at the ES onset and at the discharge day (no ES group). Endothelial cells (HMEC) in culture were exposed to media containing 20% of serum from each patient for 24h. Cell growth was controlled morphologically. Expression of the adhesion receptor ICAM-1 on the cell surface was analysed by immunofluorescence, and activation of the inflammation related p-38 MAPK signalling pathway was evaluated by SDS-PAGE and western blot.
Results: Exposure of HMEC monolayers to sera from patients who developed ES (onset day, n=4) resulted in an increased ICAM-1 expression on the cell surface, higher that the observed with sera from patients who did not develop ES (discharge day, n=4) (26.4% of labelled area vs. 6.4%, respectively). In addition, in experiments with sera from patients not developing ES, ICAM-1 expression on cells exposed to sera from day +10 was reduced with respect to the observed with sera from day +5, probably due to the corticosteroid used as a prophylaxis in our centre. This reduction was not observed in ES patients. Regarding phosphorylation of p-38, it was significantly higher in cells exposed to sera from ES patients than in response to sera from patients who did not develop ES.
Conclusions: The increase in the expression of the adhesion receptor ICAM-1 on the surface and the intracellular activation of p38MAPK in endothelial cells exposed to sera from patients developing ES indicates the existence of endothelial activation in association with ES. Interestingly, the prophylaxis of ES with corticosteroid seems to be less effective in patients who developed ES than in patients who did not develop this complication. These results need to be validated in a higher number of patients and modifications in additional markers of endothelial dysfunction should be investigated.
Disclosure: Gonzalo Gutiérrez-García: Honoraria from Gilead. Grant from Jazz Pharmaceutical
The other authors do not have any disclosure to comment.
P192 association between uric acid levels before and after allogeneic haematopoetic stem cell transplant and transplant outcomes: A single centre experience
Anna Torrent1, Maria Jose Jimenez-Lorenzo1, Christelle Ferrá1, Mireia Morgades1, Susana Vives1, Miriam Moreno1, Montserrat Batlle1, Blanca Xicoy1, Juan Manuel Sancho1, Laura Abril1, Gladys Ibarra1, Albert Oriol1, Marta Peña1, Marta Sitges1, Josep Maria Ribera1
1 Institut Català d’Oncologia-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Badalona, Spain
Background: Uric acid (UA) is a known endogenous danger signal which activates the NOD-like receptor protein (NLRP)3 inflasome.UA is released from injured cells during conditioning in allogeneic stem cell transplantation (HSCT). A pre-clinical study has demonstrated that NLRP3 inflasome-mediated IL-1 production regulates graft-versus-host disease (GVHD). The UA role in inflammation and GVHD is unclear. There are discordant reports in the literature about a potential protective role of UA on GVHD after a HSCT.
Methods: We performed a retrospective study to assess the association between serum UA levels pre- and post-HSCT and transplant outcomes (overall survival [OS], cumulative incidence [CI] of grade II-IV acute GVHD [aGVHD], relapse and non-relapse mortality [NRM]) in 142 patients undergoing a 8/8 matched related or unrelated donor allogeneic peripheral blood HSCT from January 2008 to December 2017. UA levels were collected before conditioning and on days 0, +7 and +14 after HSCT.
|Characteristics||N = 142 (%)|
|Hematologic disease||AML/ALL MDS/CML/MF NHL/HL/Chronic lymphoproliferative disease Myeloma Other||68(48)/18(12) 17(12)/4(3)/4(2) 12(8)/5(4)/7(5) 4(3) 3(2)|
|Donor/Recipient sex combination||High risk (female Donor/male Receptor)||27(19)|
|GVHD prophylaxis||CsA + MTX / CsA + MMF/CsA + alemtuzumab / CsA + prednisone / Other||120(85)/8(6)/6(4)/6(4)/2(1)|
|Stage of disease||Advanced||44(31)|
[ [P192 Table] 1 . Table 1]
Results: The characteristics of the 142 patients are shown in Table 1. Median age was 52 years (range 15-69), and 80 patients (56%) were male. Twenty-seven patients (19%) received low doses ATG as part of GVHD prophylaxis. Allopurinol was from the day before start of conditioning therapy until day 0. The median levels of UA were 4,8 mg/dL before conditioning, 2,85 mg/dL at day 0, 3,1 mg/dL at day +7 and 3,2 mg/dL at day +14. There was no impact between the UA levels and OS at any time of the HSCT. UA levels at day +7 were associated with a higher CI relapse at 5 years (34% [95% CI, 20-49%] for UA level > 3,1 mg/dL, and 17% [95% CI, 8%-30%] for UA level ≤ 3,1 mg/dL [p= 0,046]). There was a trend for a higher CI of grade II-IV aGVHD for the subgroup of patients not treated with ATG with UA < 4,8 mg/dL (48% vs 30%; p= 0,083) on day -8 and a higher NRM with UA < 2,85 on day 0 (50% vs 30%; p=0,080).
Conclusions: In our study the UA levels showed no impact on OS, and only a tendency for CI of grades II-IV aGVHD grades II-IV and NRM for the subgroup of patients not treated with ATG. Surprisingly, high levels of UA at day +7 of HSCT were associated with a significant higher incidence of relapse.
Disclosure: DKMS Foundation, PI14/01971 (Instituto Carlos III) and SGR288 (GRC), Generalitat de Catalunya.
P193 early and late onset VOD prevalence and outcomes in a single centre retrospective study over 5 years: The King’s BMT experience
Shreyans Gandhi1, Simon Tetlow1, Varun Mehra1, Hugues deLavallade1, Austin Kulasekararaj1, Pramila Krishnamurthy1, Judith Marsh1, Sarah Ware1, Michelle Kenyon1, Ghulam Mufti1, Victoria Potter1, A Pagliuca1
1 King's College Hospital NHS Foundation Trust, London, United Kingdom,
Background: Veno-occlusive disease (VOD) is an early, uncommon but serious complication of stem cell transplantation (SCT) that is associated with high morbidity and mortality. Defibrotide is the only licensed treatment for VOD, and time to start of treatment (TsT) affects outcomes. Minor differences exist between the Seattle, Baltimore and classical EBMT (2016) criteria, which may trigger different start points for treatment. Late onset VOD (>21 days) is less recognised and we hypothesize, may have worse outcomes with longer time to diagnosis, and more limited treatment options across different healthcare systems.
Methods: Electronic patient records from Sept.2013 - Oct.2018 at King´s BMT centre and pharmacy databases were reviewed, timepoint to clinical and bio-chemical manifestation of VOD, diagnosis, TsT, survival and long-term outcomes were analysed.
Results: 30 of the 532 patients(5.6%) who underwent an allogeneic SCT, developed VOD, including 2 paediatric cases. None of the Autologous SCT patients developed VOD. The paediatric and Autologous SCT patients were not analysed any further.
28 adult patients (Male=22;78.5%) developed VOD at a median age of 56 years(range 26-72), of whom 21 developed < 21 days and 7 patients had late-onset VOD as per EBMT criteria(range 22-93 days). 24 cases classed as severe and 4 as moderate VOD.
10 patients received Defibrotide at diagnosis, 7 patients within 3 days, 5 patients between 4-7 days, and 6 patients received treatment after 7 days.
Overall mortality for this cohort was 50%(14/28). 12/21(57.1%) of patients with early onset VOD and 2/7(28.5%) patients with late-onset VOD died. Of the 14 deaths, 10 died of liver failure and a further 2 patients had VOD as a likely contributing factor in their deaths. 1 patient died with sub-arachnoid haemorrhage and 1 with relapsed disease.
Patients that received Defibrotide after 7 days, 5/6 patients(83.3%) died, as compared to 3/5(60%) for treatments between 4-7 days, 6/17(35.2%) for treatments within 3 days. The lone surviving patient who received treatment after 7 days has severe chronic liver disease and it's complications.
Of the 21 patients who fit Seattle criteria for early-onset VOD, only 6 fit the Baltimore or EBMT criteria for classical VOD. 4 of these 6 patients met the Baltimore criteria later than the Seattle criteria were met(range = 2-9 days).
Conclusions: VOD carries high morbidity and mortality, and beyond the known risk factors and with the caveat of limited numbers in this study, we strongly suspect this is further increased when time to definitive treatment with Defibrotide is delayed, particularly beyond 7 days.
Nearly a quarter of cases with VOD are late-onset as per classical EBMT criteria. However contrary to our hypothesis, their overall outcomes and mortality do not appear worse, with time to treatment again emerging as a strong predictive factor. Conditioning treatment related factors, which play a stronger role in endothelial dysfunction in the hepato-portal circulation, may not be as much at play, perhaps for late-onset disease.
Uniformity in the use of diagnostic criteria, and high degree of vigilance, even beyond 21 days, leading to early treatments may improve outcomes in VOD.
Disclosure: Nothing to declare
P194 Outcome of eculizumab treatment in stem cell transplantation - associated thrombotic microangiopathy in children: A single centre experience
David Bueno1, Yasmina Mozo1, Luisa Sisinni1, Blanca Rosich1, Pilar Nozal1, Alejandro Zarauza1, Antonio Pérez-Martínez1
1 La Paz University Hospital, Madrid, Spain
Background: HSCT-associated thrombotic microangiopathy (TA-TMA) affects 10-30% of patients receiving an allogenic SCT, with a high mortality up to 80-90% in severe cases. Endothelial injury mediated by complement activation has been atribuited a major role in the pathogenesis, and blockade of C5 with Eculizumab offers promising results.
Methods: We present our experience with 6 pediatric cases of TA-TMA treated with Eculizumab. The diagnosis of TA-TMA was stablished attending to Jodele et al criteria. Clinical data were collected retrospectively from medical records.
Results: All cases were diagnosed between August 2016 and April 2018, with a median age of 11 years (2.5 - 17) at time of diagnosis. Primary disease was acute leukemia in 2 cases (1 ALL and 1 AML), severe aplastic anemia in 3, and primary immunodeficiency in 1. They received their first SCT in all cases, 3 from MUD and 3 from MMRD (CD45RA+ depleted haploidentical grafts), with MAC regimen in 2 cases, and RIC in 4 cases. 3 of them received calcineurin inhibitors (cyclosporine) as GVHD prophylaxis. All patients developed aGVHD (grade 2 or higher in 3 cases). and 5 patients presented viral reactivation. Hypertension was present in 4 cases at TMA diagnosis, requiring 2 or more antihypertensive drugs in 3 of them. All patients had renal injury consisting of less-than-normal glomerular filtration rate (median of 41 (20-59)) and proteinuria, with urine protein-to-creatinine ratio higher tan 2 mg/mg in 2 cases (data not available in 2 patients). Serum haptoglobin was decreased in just 2 cases at diagnosis, and schistocytes were detected in 3 patients. Cutaneos signs were present in all cases, digestive symptoms in 2, neurological affection in 2, and notoriously all of them developed polyserositis. C3 and C4 were normal in all cases, with sC5b9 higher than 244 ng/mL in 2 patients and lower in 1 (data not available in 3 cases). All patients received defibrotide as treatment, and 4 cases received also rituximab, associated to therapeutical plasma exchange in 3. All of them received Eculizumab, as first line in 2 cases (median of 40 days between diagnosis and Eculizumab start). Treatment was correctly monitorized with CH50 levels in 3 cases (not available quick enough in other 3). Median number of doses needed in induction therapy was 8, and median interval between doses was 7 days. 2 patients required reduced interval and higher doses to maintain CH50 supressed. 2 patients did not respond, and died because of TMA. 4 patients had hematological response, with chronic renal injury in 3 of them and resolution of acute renal failure in 1 case. Nevertheless 1 patient responding to Eculizumab died because of TMA related complications, and 1 because of an invasive fungal infection. 2 patients are alive, with a median follow up of 6 months from treatment start.
Conclusions: Our experience supports promising results of Eculizumab based treatment for TA-TMA, highlighting the importance of an early treatment and a careful therapy monitoring by CH50 supression. Prospective studies are needed to achieve a better knowledge of this pathology and its treatment.
Disclosure: Nothing to declare
P195 AB0-mismatched allogeneic hematopoietic stem cell transplantation and associated complications
Yayra M Pichardo-Cepín1, Brenda Lizeth Acosta Maldonado1, Liliana M Rivera-Fong1, Andrea I Milan-Salvatierra1, Karen D. Pérez-Gómez1, Perla K Acosta-Maldonado1, Luis M Valero-Saldaña1
1 National Cancer Institute, México City, Mexico
Background: Approximately 40-50% of Allogeneic Hematopoietic Stem Cell Transplant (Allo-HSCT) are made with some sort of ABO blood group system incompatibility.
An HSCT ABO donor-recipient incompatibility implies risks of complications during the process of infusion as acute hemolytic anemia (AH), delayed graft and other later complications due to the presence of isohemaglutinins (Pure Red Cell Aplasia or passenger lymphocyte syndrome). Also, ABO incompatibility could impact on graft versus host disease (GVHD) incidence, and could be associated with Not Relapse Mortality (NRM) and overall survival (OS).
There are not concluded evidence about the ABO incompatibility impact, so the aim of this study was to identify complications and response associated with ABO incompatibility in patients undergoing Allogeneic Hematopoietic Stem Cell Transplantation.
Methods: A retrospective study was performed on patients who receive an allo-HSCT between January 2014 and August 2018. Two groups were performed according to the presences or not of ABO incompatibility. Demographic and clinical information was collected from physical and electronic medical records, and information was analyzed in SPSS v21
Results: Sixty-eight patients were enrolled in the study, 54% male, the median age was 34 years (19-61) with the following diagnoses: acute lymphoblastic leukemia 44%, acute myeloblastic leukemia 26.5%, granulocytic chronic leukemia 17.6%, myelodysplastic syndrome 4.4%, dendritic cell neoplasm 4.4%, aplastic anemia 2.9%. Ninety-one percent of the patients received a transplant from an identical HLA donor and 8.8% received a haploidentical transplant. Fifty-two patients (76%) were ABO-compatibility (G1) and 16 patients (24%) had ABO-incompatibility (G2). None patient with ABO-incompatibility received a haploidentical transplant.
The contrast between groups didn't show differences in fever, infections, bacterial isolation, presence and degree of acute or chronic GVHD and relapse of the disease. Graft failure was 6%(G1) vs 20%(G2) (p=0.27), intermediate risk CMV serostatus 79%(G1) vs 87(G2) (p=0.35). The most relevant characteristics and complications are described in table 1. Contrast analysis between G1 vs G2 showed that within the whole group there were 29 deaths (40% vs 50% respectively) (p=0.69), the overall survival 1-year was 74% vs 66% (p=0.58) with a median of 29 vs 34 months respectively; mortality associated with relapse was 68% vs 87% respectively, and mortality related with transplantation was 35% vs 13 % respectively.
|Characteristics||ABO compatibility n=52 n(%)||ABO incompatibility. n=16 n(%)||p|
|Mismatch ABO Major/minor||0||8(50)/8(50||-|
|R Male/D Female||11(21)||8(50)||0.13|
|Neutrophil recovery (days)||14±5||12±2||0.041*|
|Transfusion requirement of erythrocyte concentrates|
|Before HSCT >10||18(35.3)||2(14.3)||0.23|
|Acute complications (hemolytic anemia/delayed graft)||0 / 1(2)||1(6) / 1(6)||0.12|
|Acute complications (Pure Red Cell Aplasia)||0||1(6)||0.23|
|Chimerism day +100: incomplete(<94%)||3(6)||3(21)||0.22|
[ [P195 Table] 1 . Table1. Relevant characteristics and complications.]
Conclusions: ABO incompatibility did not show association with complications related with the infusion, but there was a higher tendency of graft failure in the ABO incompatibility group. It has no statistical significance, but it is important to expand its study.
Disclosure: None declared
P196 Prevalence of metabolic syndrome following autologous stem cell transplantation for non-hodgkin lymphoma
Lerryn Edghill1, Naa Amua Quaye1, Sheridan Thompson2, Wendy Ingram2, Emma Kempshall2, Keith Wilson1,2
1 Cardiff University School of Medicine, Cardiff, United Kingdom, 2 University Hospital of Wales, Cardiff, United Kingdom
Background: Metabolic syndrome (MetS) is a well-recognised late effect of transplantation which has been largely overlooked in the autologous transplant setting. This service evaluation aimed to explore the prevalence of MetS in patients with Non-Hodgkin Lymphoma (NHL) treated with autologous stem cell transplantation (ASCT) within the South Wales Blood and Bone Marrow Transplant (SWBMT) Programme.
Methods: Retrospective data for 142 NHL patients who underwent ASCT between 1999 and 2017 was analysed. Patients were identified using the SWBMT database and data on MetS was collected using paper and electronic hospital records. Forty-eight patients were excluded due to loss of follow-up, inaccessible/incomplete records, or death. Cause of death was not determined. The NCEP-ATPIII definition of MetS was used. This requires ≥3 of 5 criteria to be met. A BMI of ≥30kg/m2 and HbA1c of ≥42mmol/L were used to replace central obesity and impaired fasting glucose, respectively. Other criteria include triglycerides (TGs) ≥1.7mmol/L or treatment, high density lipoprotein cholesterol (HDL-C) < 1.0mmol/L (male), < 1.3mmol/L (female) or treatment and blood pressure >130mmHg systolic or >85mmHg diastolic, or treatment.
Results: The prevalence of MetS in the cohort was 33% (n=31). Eighty-two percent of patients (n=77) met one or more criterion for MetS. Twenty-seven percent (n=25) fulfilled only one criterion, 23% (n=22) fulfilled two criteria, 20% (n=19) three criteria, 12% (n=11) four criteria, and 1% (n=1) five criteria.
The greatest prevalence of MetS was in the 60+ age group, accounting for 17 out of 31 (55%) patients with MetS. Overall prevalence decreased with declining age (Table 1). The number of patients aged < 20 years was too small to make any judgement on risk.
Raised triglycerides was the criterion most frequently met (61/94 patients), followed by hypertension (48), raised BMI (26), low HDL-C (23) and an increased HbA1c (15).
|Age Category (Years)||Total Number of Patients||Number of Patients with MetS||Prevalence of MetS per Age Category (%)||Prevalence of MetS per Cohort (n=31) (%)|
[ [P196 Table] 1 . Table 1. Prevalence of Metabolic Syndrome (MetS) by Age]
Conclusions: The prevalence of MetS in our cohort (33%) was higher than the estimated worldwide prevalence of 25%, with the majority in the 60+ age category. This is in keeping with other post-transplant studies, which show an increase in prevalence of MetS after transplantation. Moreover, the overall prevalence of MetS was greater in the older population, which could be associated with the cumulative effect of ageing on the decline of normal metabolic homeostatic mechanisms.
This study supports the need for late effects screening in survivors of autologous transplantation for NHL. Early recognition of aberrant parameters will allow for timely and targeted lifestyle and/or pharmacological treatment to help prevent diabetes and cardiovascular disease.
Clinical Trial Registry: None
Disclosure: Nothing to declare
P197 Incidence and prognostic significance of acute renal failure in myeloablative and non-myeloablative allogeneic stem cell transplant. single center experience
Marta Sitges1, Christelle Ferrà1, Jordi Soler2, Mireia Morgades1, María José Jimenez1, Inés Hernández1, Anna Torrent1, Marta Peña1, Georgina Gener1, Mireia Franch1, Mireia Santos1, Eloi Cañamero1, Martina Comes1, Andrea Espasa1, Montserrat Batlle1, Miriam Moreno1, Susana Vives1, Juan Manuel Sancho1, Blanca Xicoy1, Albert Oriol1, Laura Abril1, Gladys Ibarra1, Jose María Ribera1
1 Institut Català d'Oncologia-Hospital Germans Trias i Pujol, Josep Carreras Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain, 2 Hospital Germans Trias i Pujol, Badalona, Spain
Background: Acute renal failure (ARF) is a frequent complication in the early post-allogeneic hematopoietic stem cell transplant (alloHSCT) period with either myeloablative (MA) or non-myeloablative (NMA) conditioning regimens. The aim of this study was to compare the incidence of ARF in both types of HSCT and to evaluate its impact on overall survival (OS) and non-relapse mortality (NRM).
Methods: All alloSCT performed in one center between 2010 and 2018 were included in this study. AlloHSCT from cord blood and from haploidentical donors were excluded. The renal function and the incidence of the main complications after alloSCT from day 0 to day +90 were evaluated. ARF was defined according to KDIGO (Kidney Disease Improving Global Outcomes) classification; the relative increase of serum creatinine levels was considered a marker of kidney damage.
Results: Seventy-seven patients received a MA alloHSCT and 72 a NMA alloHSCT. Recipients of NMA alloHSCT had a higher median age (61 years [range: 18-69] vs. 41 years [15-55], p< 0.001), higher frequency of arterial hypertension (29% vs. 6%, p< 0.001) and showed most frequently active disease at alloSCT (42% vs. 18%, p=0.002). In both groups the most frequent graft-versus-host disease (GVHD) prophylaxis regimen was cyclosporine A and methotrexate. The median follow-up time was 2.3 years for the NMA group and 3.6 years for the MA group. Patients from the MA group had higher incidence of grade 3-4 mucositis (60% vs. 22%, p< 0.001) and acute GVHD of any grade (70% vs. 53%, p=0.029) than patients from the NMA alloHSCT. The incidence of ARF was similar in both groups (72% in NMA and 71% in MA). In the NMA group arterial hypertension (HR 2.05, p=0.018), obesity (HR 4.16, p< 0.001) and prior pneumonia (HR 3.19, < 0.001) were predisposing factors for ARF by multivariate analysis, whereas any factor was identified in the MA group. ARF had no impact on 2-year OS in both groups (28% vs. 35% p=0.406 for the NMA group and 45% vs. 40% p=0.623 for the MA group). However, worse OS were observed in patients with grade 2-3 ARF in the NMA group (18% vs. 43%, p=0.048) and in patients with grade 3 ARF in the MA group (25% vs. 59%, p=0.011). In turn, ARF had no influence on NRM in the MA group but was associated with a trend for higher NRM in the NMA group (59% vs. 35%, p=0.084).
Conclusions: ARF is a frequent complication in patients receiving alloHSCT irrespective of the intensity of the conditioning regimen. Moderate and severe ARF had negative impact on OS.
Disclosure: Supported by grants from: Asociación Española Contra el Cáncer, AECC (GC16173697BIGA), Instituto Carlos III (PI14/01971 FI), 2017-SGR288 (GRC), CERCA Program from Generalitat de Catalunya, and “La Caixa” Foundation.
P198 Treatment and risk factors of hepatic veno-occlusive disease after pediatric hematopoietic stem cell transplantation: A single-center experience
Barbaros Sahin Karagün1, Ilgen Sasmaz2, Ali Bülent Antmen1
1 Acibadem University, Pediatric Hematology and Oncology, Istanbul, Turkey, 2 Cukurova University, Pediatric Hematology and Oncology, Adana, Turkey
Background: Defibrotide emerged as a promising treatment option for hepatic veno-occlusive disease, a significant cause of mortality in recipients of HSCT. As VOD diagnosis is quite difficult even with the recently introduced EBMT 2017 criteria, studies which report treatment outcomes and response to prophylaxis are required. Our aim was to evaluate the efficacy of defibrotide prophylaxis in HSCT recipients at our center.
Methods: A total of 236 transplants in 210 patients from January 2013 to July 2018 were included in this study. All patients had factors that increased the risk of VOD and all received 25 mg/kg/day prophylaxis. Patients' coagulation, renal and liver function test were monitored daily and all clinical findings and complaints were recorded. Diagnoses were made via the EBMT 2017 VOD criteria and patients who developed VOD received treatment with increased DF dose (40 mg/kg/day) and supportive interventions. After complete remission of VOD findings, patients were returned to the prophylaxis dose. Close follow-up of patients was performed until 100 days.
Results: In total, 17 patients developed VOD (7.2%), none of the cases were severe (13 mild, 4 moderate). Median age was 8.5 (1-22) years and the most common clinical findings were weight increase, hepatomegaly, right upper quadrant pain and ascites development. In those with VOD, treatment with 40 mg/kg/day DF was initiated and average duration of treatment with this dosage was 7.4 (5-11) days. No adverse events were reported in any of the patients.
Conclusions: Our findings are consistent with previous studies on this topic, and we believe that the use of DF as a prophylactic agent for VOD is beneficial for pediatric patients with risk factors.
Disclosure: The authors report no conflicts of interest in this work.
P199 Donor-recipient major ABO-incompatibility might impact on the allo-HSCT outcome
Carmen González1, Montserrat Lozano1, Nerea Rodríguez1, Lourdes Aguirre1, Jose Javier Ferreiro1, Clara Lombardi1, Laida Ondarra1, María José Pizarro1, María Araiz1, Carlos Vallejo1
1 University Hospital Donostia, Donostia, Spain,
Background: Several factors might influence outcome of allo-HSCT. Analysis of the impact of donor-receptor blood group-incompatibility have been performed in different series not always showing the same results. As a consequence, its clinical impact remains controversial. Minor-mismatch is characterized by the ability of donor B lymphocytes to produce anti-recipient antibodies. In major-mismatch cases, antibodies against donor antigens are present in the recipient.
Methods: 343 pts underwent allo-HSCT between May 2011 and August 2018 in our center. Median age was 52 years (range: 7-69). 193 pts were male (56.3%) and 150 female (43.7%). Baseline diseases were: 138 AML, 76 LPD, 44 MDS, 41 ALL, 21 MPD, 16 MM, and 7 BMF. Donor was unrelated in 191, and related in 152 cases (including 36 haplo-identical). Donor-recipient ABO compatibility was as follows: 69 (20.1%) major-mismatched (including 11 bidirectional), and 274 (79.9%) nonmajor-mismatched (including 68 minor-mismatched and 206 matched). Donor-recipient Rh compatibility was as follows: 50 (15.6%) major-mismatched, and 293 (84.4%) nonmajor-mismatched (including 34 minor-mismatched and 259 matched). The impact of donor-recipient ABO and Rh compatibility on transfusion needs (PRBC and platelet concentrates) and survival by day +100 was analyzed.
Results: For the global series the median number transfusions by day +100 was: 4 (0-81) PRBC and 4 (0-92) platelets concentrates. Day +100 overall mortality was 9.3%. Rh-incompatible and nonmajor ABO incompatible cases showed no different results. However, major ABO-mismatched cases needed more PRBC transfusions (median: 6; range: 0-49) and more platelet transfusions (median: 7; range: 0-60), and had higher day +100 mortality (18.8%) (p < 0.05) (see table).
Conclusions: Our analysis showed: 1) Donor-recipient Rh-incompatibility, as well as minor ABO-incompatibility had no impact on PRBC and platelet concentrates transfusion needs nor on 100-day mortality; 2) Contrarily, donor-recipient major ABO-incompatibility had a significant adverse impact on PRBC and platelet concentrates transfusion needs and 100-day mortality. 3) Donor-recipient Rh-incompatibility and minor ABO-incompatibility.might be considered of marginal importance at the time to choose a potential donor. 4) Donor-recipient major ABO-incompatibility should probably be a factor to be considered, along with other features, to choose the best donor
|Platelets (median [range])||100-day mortality|
|Global||343||4 [0-81]||4 [0-92]||9,30%|
|-No||293 (85,4%)||4 [0-81]||4 [0-92]||9,60%|
|-Yes||50 (14,6%)||4 [0-81]||4 [0-92]||8%|
|-No||274 (79,9%)||3 [0-81]||4 [0-92]||6,90%|
|-Yes||69 (20,1%)||6 [0-49]||7 [0-60]||18,80%|
[ [P199 Table] 1 . Day +100 transfusion needs and overall mortality.]
Disclosure: "Nothing to declare"
P200 Incidence for arterial hypertension in adults following haematopoietic stem cell transplantation
Claudia Lucia Sossa Melo1,2, Claudia Marcela Chalela1, Sara Ines Jimenez1,2, Luis Antonio Salazar1,2, Maria Luna-Gonzalez1, Manuel Rosales2, Manuel Ardila-Báez1, Sergio Serrano1, Katherine Espinosa2, Julián Baez2, David Leonardo Reyes2, Angela María Peña1,2
1 Universidad Autónoma de Bucaramanga, Bucaramangaga, Colombia, 2 Clinica FOSCAL, Bucaramanga, Colombia
Background: Survivors of haematopoietic stem cell transplantation (HSCT) are at significant risk of developing treatment-related complications, including cardiovascular risk factors such as arterial hypertension, that could eventually lead to cardiovascular disease. The aim of this study is to evaluate the incidence and risk factors of hypertension following HSCT in a Colombian population.
Methods: A retrospective cohort study was conducted to assess the incidence and risk factors of hypertension in 220 consecutive adult HSCT recipients who underwent transplantation between 2009 and 2017 at a tertiary referral center in Colombia, South America. Blood pressure data, from two different measures, were collected at 7 time points: day of mobilization for autologous HSCT and day 0 before infusion for allogeneic transplantation, day 7, and months 1, 3, 6 and 12 post-transplantation. Hypertension was defined as having a systolic blood pressure >=140mmHg and/or a diastolic blood pressure >=90 mmHg. Patients with history of arterial hypertension were excluded.
Results: One hundred and seventy-five patients were included, with a mean age of 44 years (range 15-67). Ninety-one patients (52%) were male. One hundred and sixteen patients (66.3%) underwent autologous HSCT and 59 (33.7%) allogeneic HSCT. The most common indication for HSCT was acute leukemia (26.3%), followed by non-Hodgkin lymphoma (23.4%) and multiple myeloma (22.9%). Twelve patients (6.9%) had medical history of type 2 diabetes mellitus (DM), 11 (6.3%) dyslipidemia, 24 (13.7%) alcohol consumption, and 25 (14.3%) tobacco smoking. Only two of the patients with history of tobacco smoking were active smokers at time of transplantation.
Twenty-four patients (13.7%) had developed hypertension by the end of the first year post-HSCT follow-up. Two patients (8.3%) had systolic and diastolic, 12 (50%) had only systolic, and 10 (41.7%) had only diastolic hypertension. Only one patient was hypertensive at more than two time points. The incidences of hypertension at each time point were 2.3% on day 7 post-HSCT, 6.9% at first month, 9.8% at three months, 12.1% at 6 months, and 13.8% at one-year post-transplantation. Allogeneic HSCT (P< 0.01), therapy with calcineurin inhibitors (P< 0.01), pre-HSCT fasting glucose levels (P< 0.05), acute GvHD (P< 0.05), chronic GvHD (P< 0.05), and media of diastolic blood pressure (P< 0.05) were significantly associated with the development of arterial hypertension. However, age, history of type 2 DM, history of tobacco consumption, volume of infusion, prophylactic treatment for GvHD with mycophenolate, chronic GvHD, serum creatinine level on day of HSCT, and being overweight or obese at time of transplantation were not significantly associated with the development of hypertension.
Conclusions: Arterial hypertension is a fairly common complication in HSCT recipients. Similar to findings reported in previous studies, association between allogeneic stem cell transplantation, therapy with calcineurin inhibitors, and acute and chronic GvHD, and post-HSCT hypertension was found in the present cohort. Further studies are needed to assess the link between HSCT and developing long-term cardiovascular complications.
Disclosure: Nothing to declare
P201 Tramadol-based pain management of oral and esophageal mucositis in pediatric HSCT recipients
Ekaterina Goncharova1,2, Portniagin Ivan3, Ilya Kazantsev3, Asmik Gevorgian3, Maxim Bogomolny3, Maxim Kucher3, Lyudmila Zubarovskaya3, Boris Afanasyev3
1 Pavlov First Saint Petersburg State Medical University/Raisa Gorbacheva Memorial Institute of Children's Oncology, St. Petersburg, Russian Federation, 2 Pavlov First Saint Petersburg State Medical University, Valdman Institute of Pharmacology, St. Petersburg, Russian Federation, 3 Pavlov First Saint Petersburg State Medical University/Raisa Gorbacheva Memorial Institute of Children's Oncology, St. Petersburg, Russian Federation
Background: Mucositis is one of the most common early HSCT complications seen in about 70% transplant recipients with 20% of patients developing Gr III-IV mucositis. Mucositis is characterized by painful gastrointestinal mucosa lesions impairing the solid and liquid foods intake and increased risk of infections, bleeding, and intestinal paresis. Thus, it greatly decreases the quality of life of a transplant recipient. According to WHO recommendations, the moderate pain control in pediatric patient is based on the use of low-dose morphine. However, there are some factors such as genetic polymorphisms causing variable morphine pharmacokinetics in children, side effects, and social factors (caregivers' general unwillingness to use narcotic analgesics), which cause the need for alternative pain relief options in pediatric practice. Tramadol, which has both opioid and non-opioid mechanisms of action, may be a feasible option in mild to moderate pain. It may be delivered via patient-controlled analgesia (PCA), although there is no consensus on its optimal parameters in pediatric practice.
Methods: A total of 69 pediatric patients with a median age of 8 (range 2 to 18) years receiving an autologous or allogeneic HSCT in our clinic as part of the treatment regimen for solid tumor (n=40), leukemia (n=24), acquired aplastic anemia (n=3) or inherited condition (n=2) were included. Conditioning regimens were myeloablative (MAC) in 54 and reduced-intensity (RIC) in 15 patients. All patients had oral and/or esophageal mucositis accompanied by moderate pain. The pain severity was assessed using the scales corresponding to patient's age and varied from 3 to 6 points. The pain control was based on intravenous tramadol administration using patient-controlled analgesia (PCA) approach. The following PCA parameters were used: loading dose of 0.5 mg / kg (not exceeding 25 mg), basal infusion rate of 0.25 mg / kg (not exceeding 12.5 mg), a bolus of 0.25 mg / kg (not exceeding 12.5 mg), lockout interval of 25 min. The maximal daily dose was 8 mg/kg/day. The pain control was considered adequate if a patient was satisfied or the basic and breakthrough pain score values were not higher than 3 and, accordingly. In case of inadequate pain control NSAIDs were added. Non-responders were switched to morphine. All patients were divided into 2 groups based on conditioning regimen intensity.
Results: As a whole, 46% of patients did not require pain control measures escalation. The tramadol pain control rate was slightly higher for RIC (n=9, 60%) compared to MAC (n=23, 47%) recipients. In most cases the inadequate pain control was due to progressive mucosal lesions. The PCA regimen used was characterized by very few complications. Drowsiness was observed in 4 (7%) of patients, in all cases the patients also had anemia. There was only 1 (7%) patients with severe nausea requiring switching to morphine.
Conclusions: Tramadol is an effective pain control option in transplant recipients with mild to moderate pain due to oral and esophageal mucositis without progressive mucosal lesions. The PCA allows achieving a very low complication rate. Therefore, this option may be considered for both MAC and RIC recipients.
P202 Immune reconstitution of lymphocyte subsets after allogenic stem cell transplant (SCT) and vaccination
Gala Vega1, Agustín Penedo1, Sara Martin1, Ines Martinez-Alfonzo1, Jose Luis López-Lorenzo1, Cristina Serrano1
1 Hospital Universitario Fundación Jiménez Díaz, Hematology, Madrid, Spain
Background: Infectious diseases are a major cause of morbidity and mortality after allogenic stem cell transplant (SCT).
Vaccines constitute an effective strategy to prevent infections but the optimal timing to start vaccinating is not well stablished.
In order to individualize the early vaccination schedule, we studied the lymphocyte subsets involved in generating enough response to produce protective serological levels.
Methods: We studied retrospectively 20 patients that had undergone allogenic SCT at our hospital.
Patient distribution - Age range: 21-68 years-old; diagnosis: acute leukaemia/myelodysplastic syndrome/chronic myeloid leukemia (16 patients), lymphoma (4 patients).
Analytic parameters: TCD4+, TCD8+, NK, total B and functional B lymphocyte subsets (naïve IgD+CD27-, memory IgD+CD27+ and IgD-CD27+, and effectors CD27++CD38++). Immunoglobulin levels (IgG, IgA, IgM) and specific IgG for pneumococcus, tetanus, HBV, chickenpox, measles, rubella and mumps.
Clinical parameters were collected from medical records.
Results: We distributed patients in two groups, based on the timing of lymphocyte analyses:
- Less than 12 months since SCT (5 patients)
No patient showed complete immune reconstitution, although 2 had enough T and functional B lymphocytes to generate response to vaccination. In these patients, vaccination for pneumococcus was completed and they generated sufficient protection antibody levels, despite being under immunosuppressive treatment.
- More than 12 months since SCT (15 patients)
Before the beginning of vaccination, we collected specific antibodies of 7 patients.
We compared the serological status before and after SCT and observed that protection against tetanus was the most frequently preserved (6 patients) and HBV the least frequent (2 patients).
Other than one patient treated with alemtuzumab, all patients in this group had minimum absolute count of TCD4+ (>200 cells/microl), TCD8+ (>200 cells/microl), NK (>100 cells/microl) and B cells (>100 cells/microl).
We also observed presence of B effector and B memory cells, with predominance of IgD-CD27+ memory cells. Immunoglobulin levels were within the normal range.
In this group, we registered vaccination in 13 patients. All of them were vaccinated against flu, and 11 against pneumococcus and HBV. The rest of vaccines administered were heterogeneous in type and timing.
6 patients were under immunosuppressive treatment at the time of vaccination and were able to generate enough specific antibodies for pneumococcus.
Immune reconstitution was not completed 12 months after SCT, although minimal immunological reconstitution was observed
TCD4+ and no-switching memory B lymphocytes were the last ones to reach minimum normal values according to patient age.
Some patients maintain serological protection after allogenic SCT.
Immunoglobulin levels were normal, suggesting no need for immunoglobulin administration to prevent infections.
Flu, pneumococcus and HBV vaccines were the most frequently administered.
Pneumococcus vaccination generated a much larger serological response than HBV. This seroconversion occurred in patients under immunosuppressive treatment.
The analysis of lymphocyte T, NK, B total and B functional subsets could be useful when programming an early vaccination schedule after SCT.
Completion of the vaccination schedule was heterogeneous despite giving specific indications. Therefore a more rigorous supervision of the process may be required.
Disclosure: No conflict of interests
P203 Metabolic syndrome is not uncommon complication post allogeneic stem cell transplantation: A single center experience
Panayotis Kaloyannidis1, Eshrak Al Shaibani1, Deia Awami1, Solaf Kanfar1, Khalid Bakhit1, Ashraf Suhebeh1, Belal Blowi1, Ahmed Bahrani1, Rabab Attas1, Hani Al Hashmi1, Khalid Al Anezi1
1 King Fahad Specialist Hospital, Dammam, Saudi Arabia
Background: The significant advances that have been achieved in the allogeneic transplantation (alloHCT) field, have resulted in better post-transplant outcome and therefore complications other than the Graft vs. Host disease (GvHD) or disease recurrence become increasingly important. The post transplant metabolic syndrome (PT-MS), which caused by several factors (i.e. immunosuppressive agents, chemo-radiotherapy, anti-viral, and biologic therapies) is a well known post transplant complication in pediatric allografted long-term survivors however, only few studies have evaluated the prevalence of the PT-MS in adults. In this retrospective study, we sought to evaluate the incidence, the risk factors and the impact of the PT-MS on the alloSCT outcome.
Methods: Since 2011, 42 patients (25 males and 17 females) with adequate clinical and laboratory data and a minimum follow-up of 6 months were included in the study. Their median age was 35.5 (17-62) years and after a myeloablative (n=28) or a reduced intensity (n=14) regimen they received either mobilized peripheral blood stem cells (n=34) or marrow graft (n=8), originated from full-matched siblings (n=35) or haploidentical donors (n=7). Calcineurin inhibitors plus either short-term Methotrexate or Mycophenolate Mofetil were given as GvHD prophylaxis. The diagnosis of PT-MS was based on the NCEP-ATPIII criteria; for patients with unknown data for abdominal circumference the body mass index (BMI) ≥25kg/m2 was consider as a criterion for PT-MS diagnosis. The independent T-test, logistic regression analysis and log-rank tests were used for the statistical analysis.
Results: Twenty (47.6%) patients (12 males, 8 females) assessed to have PT-MS within the first 6 months following the allograft. Seventeen diagnosed after the 1st trimester post alloSCT and additional 3 patients after 2nd trimester. Sixteen out of 20 patients had elevated glucose and BMI>25kg/m2, 13/20 elevated triglycerides levels, 12/20 low HDL levels and 10/20 hypertension. Four (20%) had already known history of MS before alloSCT (for 10 patients no data were available for MS diagnosis before alloSCT). Interestingly, for 7/20(35%) patients who had diagnosed with PT-MS either in the 1st or in the 2nd trimester the syndrome was reversible and did not fulfill the criteria for PT-MS beyond 6 months post alloSCT. Patients' gender, age, BMI, the type of conditioning regimen and GvHD co-existence evaluated as potential predisposing factors for PT-MS diagnosis. In univariate and multivariate analysis only the: BMI>25kg/m2 and age>35 years were detected as significant risk factors (p< 0.03). The PT-MS did not affected negatively the survival or the NRM incidence post alloSCT
Conclusions: In our study, in agreement with other publications, we demonstrated that the PT-MS is not an uncommon complication post in the early post transplant period however, for a significant number of patients the syndrome was a reversible. For patients with high risk features (BMI>25kg/m2, age> 35 years, known history of diabetes-mellitus, dyslipidemia, hypertension) apart of close monitoring, specific diet and encouragement for adequate exercise might help to reduce the incidence and the severity of PT-MS. Nevertheless, prospective and well design trials are warranted to determine the accurate incidence, severity and the impact of PT-MS on the alloSCT outcome.
Disclosure: No conflict ofinterest
P204 Experience of a single center in the humanization of the hospitalization process: Technology and team training impact on the QOL of the patient and family
Maria Claudia Moreira1, Marcia Rejane1, Marcia Garnica1, Andrea Ribeiro1, Paulo Cesar Dias1, Ilza Fellows1
1 CHN, Niteroi, Brazil
Background: Hematopoietic stem cell transplantation (HSCT) is one of the most aggressive therapeutic modalities of internal medicine, making it a highly stressful experience for the patient and his family. The duration of hospitalization can be prolonged by several intercurrences, frequently generating anxiety in the patient and their caregiver, which may lead to confinement and reactive depression. Interventions in the hospital environment, in addition to the continuous training of the multidisciplinary team, can have a positive impact in this process with improvement in the process of discharge and quality of life of the patient and his / her family.
Methods: The objective of this research was to evaluate the impact of a reformulation in the unit, completed in May 2018, which modified the facilities with availability of hermetic balconies in each room, with a view of an internal garden. There was also the addition of a screen in the corridor of the floor with images - technology known as videoowall, interconnected to motion sensors (kinects) that allow interaction between patients and families, besides facilitating physiotherapy and physical exercise. There was re-training of the multidisciplinary team with emphasis on the practice of humanization. The methodology consisted in the application of questionnaires of satisfaction to patients and their families during the period of hospitalization in a bone marrow transplant unit in the third quarter of 2018. The items evaluated ranged from the quality of the information provided by the medical team and nursing, to the cordiality and agility with which the patient and his patient were treated by the global team. The results were compared with a similar period of the same unit in the previous year and with the indices collected simultaneously in another unit of the same hospital (cardio-intensive).
Results: Overall and segmental satisfaction scores in the various items surveyed were higher when compared to the previous period of the same unit and were also higher in those obtained in a high complexity unit of the same hospital, composed of patients submitted to mental and psychological stress similar to onco- hematologicos.A reports of "free speech" were also obtained anonymously, in order to guarantee the authenticity and free expression of the subjects analyzed.
Conclusions: The results obtained allowed the validation of the technical and professional team initiatives, bringing indicators that will allow better monitoring and support of these patients and their relatives in this difficult time of treatment. They served as an initial tool in the continuous process of humanization and stimulated the multidisciplinary team to continuously improve this process.
Disclosure: No disclosures
P205 Bortezomib: Successful treatment of refractory pure red cell aplasia after ABO-incompatible stem cell transplantation
Stefan Lukic1, Helge Menzel1, Janka Benk1, Xenia Sitskaya1, Petra Drewniock1, Nadezda Basara1
1 St Franziskus Hospital, Akademical Hospital of UKSH, Internal Medicine, Flensburg, Germany
Background: Pure red cell anemia (PRCA) is a rare complication of ABO-incopatible hematopoetic stem cell transplantation characterized by anemia, reticulocytopenia and absence of erythroid precursors in patient's bone marrow. Most patients with PRCA resolve spontaneously within months, however a small number of patients requires continued red blood cell (RBC) transfusions. The treatment of this complication is difficult and not standardized. Different approaches has been used such as Rituximab, donor lymphocytes, plasma exchange with different outcome. Recently, a remarkable response to treatment with bortezomib has been described in a case of PRCA.
Methods: We reviewed 146 patients who received an allogeneic hematopoetic stem cell transplant (HCT) between Januar 2012 and August 2018 at our institution. Sixty eight patients received a major ABO-mismached HCT. PRCA was defined as a completely absence of erythroid precursors on day +30 bone marrow puncture, with absence of donor red cells and the recipient requiring RBC transfusion.
Results: Only one patient developed PRCA (1.5%). A 18 years old male received a myeloablative HLA-matched ABO-mismatched sibling donor transplant (brother, 12 years) for acute myeloid leukemia (AML), with t(8;21) CR1,MRD positive (RUNX1-RUNX1T1). The donor was blood type A Rh positive and the patient 0 Rh positive. The patient had no complication after transplant. The day +30 bone marrow puncture has shown only few erythroid precursors and day +100 puncture and biopsy no erythroid precursors, he had transfusion dependent anemia requiring a RBC transfusion every two weeks and retukulocytopenia. Parvo virus and cytomegalovirus were negative. Due to very high ferritin level (>4.000u/l) and increased luiver enzymes without signs of GvHD, the treatment with deferasirox has been started. The patient has achived CR1, MRD negative, and has evidence of complete chimerism. High titers of anti-A and anti-B issohemagglutinin was present.We started the treatment with Rituximab 375mg/m2 weekly, 4 weeks, however without response. The pathogenesis of the PRCA is thought to be due to the recipients plasma cells, bortezomib, a proteasome inhibitor inducing apoptosis of plasma cells has been given s.c. 1,3mg/m2 two times weekly, for two weeks. The patient responded to the treatment two weeks later with increase in Hb, which was 12,9 g/dl and increase in retikulocyte number. The patient has continued to be well at the last control.
Conclusions: PRCA aplasia is a rare but serious complication after ABO-incompatible HCT. Bortezomib is an effective treatment for this complication if mediated by residual host isohemeagglutinins after HCT and should be recommended as standard of care.
Clinical Trial Registry: no clinical trial
Disclosure: no disclosure
P206 Analysis of survival and mortality in patients undergoing hematopoietic stem cell transplant in solca guayaquil-ecuador
Julie Abifandi-Valverde1, María Santos-Bonilla1, Bella Maldonado-Guerrero2, Mayhua Lam-Rodriguez2, Fuad Huamán-Garaicoa3
1 Universidad Católica de Santiago de Guayaquil, Guayaquil, Ecuador, 2 Instituto Oncológico Juan Tanca Marengo, UTMO, Guayaquil, Ecuador, 3 Instituto Oncológico Juan Tanca Marengo, Anatomía Patológica, Guayaquil, Ecuador
Background: According to the World Health Organization (WHO), 50,000 TPH are carried out worldwide and this figure increases per year; however, this therapeutic approach is limited for Latin American countries. In Ecuador, there have been conducted since 2006 to nowadays about 200 hematopoietic stem cell transplants (HSCT), the 90% of them performed by SOLCA Institution. Due to the importance of this therapeutic technique and the lack of information about its development in our country; we consider relevant conduct this study in order to provide information needed for future research.
Methods: This work is retrospective, observational, cross-sectional and analytical. It included all patients who received HSCT at Stem Cell Transplantation Unit (UTMO, by its Spanish acronym) at SOLCA-Guayaquil, between the years 2009 -2016.We use the Kaplan-Meier method to analyze the survival rate between the autologous and allogeneic transplant. The information collected for this study was obtained from the database of the SOLCAy Institute and the review of the files of the patients included.
Results: At least, 150 patients have been undergoing to HSCT between 2009-2016 years. According to the type of HSCT, 42.1% received an autologous transplant and 57.9% received an allogeneic transplant, from which 79.3% were from a related donor. The main source of transplant was peripheral blood in 86.67%, followed by 12% obtained from umbilical cord blood and 1.33% by bone marrow aspiration. The most frequently reported pathologies were acute lymphoblastic leukemia (ALL) (34%), multiple myeloma (MM) (22%) and acute myeloid leukemia (AML) (13.33%). The overall survival was 68% (IC: 95%). The 82.53% of patients that were undergoing to autologous transplant have survive, meanwhile the patients that were undergoing allogeneic transplant only the 57.47% have survived (p< 0.05). The highest death rate occurred during the first year after HSCT, and decreased considerably after that period. The main cause of mortality related to transplant (MRT) was the graft-versus-host disease (GVHD) (8%); however, the main cause of mortality in the study population (n=150) was relapse in 12.66% of the patients, presented more frequently in ALL.
Conclusions: The results showed that 68% of patients undergoing to HSCT have survived. A high rate of deceased patients in this study, have died in the first year before the transplant (26.6 %%), due to relapse. The main cause of deceased in the study is not related to HSCT, and was the relapse in 12% of patients, in compare the GVHD was the main cause of MRT (8%). We consider that HSCT is a technique that is still under development in Ecuador, but despite the short time it has been taking and the institutional and medical limitations present in the health field, has presented excellent results comparable to studies conducted in developed countries.
[ [P206 Image] 1 . Survival According HSCT's type]
|Age Group||Living Males||Living Females||Deceased Males||Deceased Females||Results|
|Children||16 (10.67%)||14 (9.33%)||12 (8%)||2 (1.33%)||44 (29.33%)|
|Teenagers||9 (6%)||6 (4%)||3 (2%)||3 (2%)||21 (14%)|
|Adults||33 (22%)||23 (15.33%)||16 (10.67%)||12 (8%)||84 (56%)|
|Elderly||1 (0.67%)||0 (0%)||0 (0%)||0 (0%)||1 (0.67%)|
[ [P206 Table] 1 . Survival and Mortality According to Age Group and Gender]
Disclosure: Nothing to declare
P207 Metastatic progression of pigmented epithelioid melanocytoma after stem cell transplantation in patient with fanconi anemia
Svetlana Radygina1, Dmitry Balashov1, Irina Kletskaya2, Konstantin Mitrakov1, Svetlana Kozlovskaya1, Nickolay Ershov1, Ilia Zakharov1, Irina Shipitsina1, Michael Maschan1, Alexey Maschan3
1 Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation, 2 Russian Children's Clinical Hospital, Moscow, Russian Federation
Background: Pigmented epithelioid melanocytoma (PEM, early known as 'Аnimal type' melanoma) is a rare tumor with unpredictable clinical behavior and metastatic potential. PEM generally has favorable prognosis. Involvement of regional lymph nodes is not rare. Extranodal and distant nodal metastases are extremely rare. We report about patient with Fanconi anemia (FA) and PEM with developed distant metastases in the early term after allogeneic hematopoietic stem cell transplantation (HSCT).
Methods: 10-years old boy with FA was hospitalized for HSCT. The blue-black painless nodulus 15х15 mm was noted on the left cheek. This lesion was observed from early childhood and during life only slightly increased in size.
There were no distant and regional metastases on computerized tomography (CT) and scintigraphy with 99mTc. The nodulus and regional lymph nodes were radically removed before HSCT. The resection margin was within the normal tissue. Microscopically the derma and subcutaneous fat were infiltrated with epithelioid and spindle cells with total expression of S100, MelanA, MHB45, CyclinD1. Ki-67 expression level was 15-20%. Histological structure was specific for PEM.
HSCT with TCRαβ+/CD19+ graft depletion from match unrelated donor was performed. The conditioning regimen included total lymphoid irradiation 2Gy, fludarabin 150 mg/m2, cyclophosphamide 40 mg/kg, rabbit ATG 5 mg/kg and rituximab 100 mg/m2.
Results: At +45 day after HSCT was detected the tumor on the left cheek and parotid region with a histological structure identical to the primary lesion. On CT in S6 segment of the left lung was detected focus 20x20 mm with a cavity. Invasive aspergillosis was suspected and empirical antifungal treatment was started. But in 15 days the lung lesion increased in size to 52x30x32 mm and penetrated in the bronchus. After bronchoscopy with biopsy, PEM metastasis was histologically confirmed. Moreover, the tumor on the face continued to grow.
Therapy with cobimetinib and vemurafenib was not effective and patient died from progression of PEM on +98 day after HSCT.
Conclusions: PEM was early described as indolent tumor with rare distant metastasis and favorable prognosis. We suspect that PEM may acquire an aggressive course in the absence of immunological control, especially in high immunocompromised patients after HSCT.
Disclosure: Nothing to declare
P208 Abstract withdrawn
P209 B-cells reconstitution after autologous stem cell transplantation
Lidia Gartcheva1, Antoaneta Mihova1, Penka Ganeva1, Margarita Guenova1, Branimir Spassov1
1 Specialized Hospital for Active Treating of Haematological Diseases, Sofia, Bulgaria, Laboratory of haematopathology and immunology, Sofia, Bulgaria
Background: The main objective of the study is to assess the dynamics of quantitative and qualitative changes in the parameters of the B cell population and the production of immunoglobulins in patients after autologous transplantation of hematopoietic stem cells in the course of recovery of the immune system.
Methods: 56 patients with hematological neoplasms undergoing autologous transplantation were included in the study: 30 women and 26 men, with an average age of 31 years. Patients were diagnosed with lymphoma (n = 30), multiple myeloma (n=7), leukemia (n = 7) and solid tumors (n = 12). At the time of transplantation, 16 patients were in complete clinical remission or at least with very good partial response, 30 patients were in partial remission and 10 patients - with progression. All patients were evaluated in nine time points through 356 examinations by clinical-laboratory, flow cytometric and immunochemical methods.
Results: The percentage of CD19 (+) B cells reached the minimum values one month after transplantation then began to increase in the second month reaching a plateau around the mean values in the period 6-12 months after transplantation. The absolute number remained low during the entire period of observation. The amounts of IgG and IgM serum immunoglobulins gradually increased within the reference range throughout the entire period, while the IgA level varied around the lower reference range.
Conclusions: Implementation of an adequate humoral immune response is hampered by the reduction of circulating B cells, suppressed proliferative potential and functional deficits. Restoration of B-cell function occurs over a period of 6 months to 2 years after autologous transplantation.
Clinical Trial Registry: no clinical trials
Disclosure: Nothing to declare
P210 Incidence and general outcome of allogeneic stem cells transplantation in infants
Justyna Miśkiewicz - Bujna1, Zofia Szmit1, Jowita Frączkiewicz1, Małgorzata Salomonowicz1, Izabella Miśkiewicz1, Monika Mielcarek1, Krzysztof Kałwak1, Marek Ussowicz1, Ewa Gorczyńska1
1 Wroclaw Medical University, Wrocław, Poland
Background: Allogeneic hematopoietic stem cells transplantation (allo-HSCT) is a life-saving and well established therapy for wide range of diseases. However, it is still uncommon treatment for infants less than 12 months of age. The data about indications and outcome of allo-HSCT in the youngest group of patients is sparse.
The primary objective of this study was to assess the incidence, indications, post- HSCT complications and general outcome of allo-HSCT among infants not older than 12 months. Latter sequelae of HSCT such as physical and cognitive development were secondary aim of this study.
Methods: We retrospectively analyzed data of 63 patients who underwent allo-HSCT before 1 year of age in Department of Pediatric Hematology, Oncology and Bone Marrow Transplantation in Wrocław during years 1999-2017. Clinical and epidemiological features as well as indications for transplantation, early and late complications and general outcome were assessed.
Results: Infants who underwent HSCT in our Department comprise 8.2% of all patients undergoing HSCT in analyzed period of time. Thirty-one (49.2%) patients received stem cells from matched unrelated donor (MUD), 26 (41.3%) from mismatched (haploidentical) related donor (MMRD) and 6 (9.5%) from a sibling donor (MSD). Non-malignant disorders were indication for transplant in 49 (77.8%) patients and malignant diseases in 14 (22.2%). Acute graft versus host disease (aGvHD) occurred in 33 (52%) infants, chronic graft versus host disease (cGvHD) in 15 (24%). Majority of graft rejections were seen in infants transplanted from MMRD 7(63.6%), whereas the rest 4 (36.4%) was associated with MUD. Median follow-up in study cohort was 860 days, 1148 days for alive patients (range 72 days-19.5 yrs) and 72 days for those deceased (range 3 days-341 days). Overall survival (OS) in study cohort was 0.682 and transplant related mortality (TRM) was 0.317. In children with malignancy 5 (35.2%) patients died comparing to 15 (30.6%) patients in non-malignant group respectively. Main cause of death in analyzed group of infants was infection (60%).
1. Allo-HSCT is rarely performed in children less than 12 months of age.
2. Majority of those patients receive stem cells due to non-malignant disorder.
3. Among youngest HSCT recipients, haploidentical transplant are more common than in general pediatric transplant population.
4. Graft rejection is a significant problem in infants transplanted from MMRD.
Disclosure: nothing to declare
P211 Unusual non-infectious lung complication after allogeneic haematopoietic stem cell transplantation
Claudia Lucia Sossa Melo1,2, Manuel Rosales2, Francisco Fernando Naranjo Junoy1,2, Sara Inés Jiménez1,2, Luis Antonio Salazar1,2, Angela María Peña1,2, María Angélica Chacón Manosalva3, Maria Luna-González1, Claudia Marcela Chalela1, Manuel Ardila-Báez1
1 Universidad Autónoma de Bucaramanga, Bucaramanga, Colombia, 2 Clinica FOSCAL, Bucaramanga, Colombia, 3 Universidad Industrial de Santander, Bucaramanga, Colombia
Background: Pulmonary Alveolar Proteinosis (PAP) is a very low incidence disease characterized by an accumulation of pulmonary surfactant at the alveoli, which can produce an alteration in gas exchange. Three types of this disease have been described: autoimmune, secondary and congenital. Secondary PAP can occur posterior to a haematopoietic stem cell transplantation (HSCT) as a non-infectious complication, or associated with Pneumocystis jirovecii infections, viral infections or Nocardia. We describe the case of a patient with Acute Lymphoblastic Leukemia (ALL) diagnosis with PAP associated to a HSCT and pulmonary pneumocystis.
Methods: A 55-year-old Colombian female patient diagnosed with B-precursor ALL of high-risk in January 2017, positive Philadelphia chromosome, positive BCR / ABL in February 2017, infiltration to the Central Nervous System (CNS), 2.53% of lymphoblasts, and karyotype without legible metaphases. Refractory to induction according to the PETHEMA protocol (Vincristine, Daunorubicin, Prednisone, L-asparaginase) with presence of 13.9% blasts at the end of the induction. Re-induction was performed with the FLAG-IDA protocol (Idarubicin, Fludarabine, Cytarabine) achieving complete remission, obtaining Minimum Residual Disease (MRD) < 0.01. Dasatinib was initiated by BCR / ABL expression and CNS involvement at the time of diagnosis.
An allogeneic HSCT was performed, from a male brother donor, with low intensity conditioning TT BUFLU and prophylaxis of Graft-versus-Host Disease (GVHD) with Tacrolimus and Sirolimus. Patient showed early post-transplant complications, given the reactivation of cytomegalovirus and hemorrhagic cystitis grade I due to adenovirus. Late complications such us GVHD at the cutaneous level and subsequent hepatic and gastrointestinal involvement were seen too, for which immunosuppressive therapy was administered with high doses of systemic corticosteroid.
Results: Patient was hospitalized on day +270 post-transplantation due to febrile neutropenia and respiratory symptoms, with normal chest CT, and CT of paranasal sinuses with acute pansinusitis, for which she received Meropenem 1gr intravenously every 8 hours plus Vancomycin 1gr intravenously every 12 hours during 14 days with symptom resolution.
She remained hospitalized for cytopenias with normal bone marrow and 100% chimerism. On day +291 post-transplant she presented fever and leukocytosis, with acute respiratory failure with chest CT that showed bilateral alveolar occupation, "crazy-paving" pattern and frosted glass (see image), so diagnostic fibro-bronchoscopy was performed, reporting postoperatively for Pneumocystis jirovecii.
She received 21 days of Trimethoprim-sulfamethoxazole, with a torpid evolution requiring mechanical ventilation and tracheostomy, persisting with hypoxemia. The report of cultures for fungi, mycobacteria, and respiratory panel of FilmArray were negative. A pathology report was obtained with 30% neutrophils, as well as PAS staining with acellular pink material and elevated serum LDH, with a diagnosis of secondary PAP.
The patient continued with poor general condition, refractory hypoxemia, high ventilatory parameters and hemodynamic instability, due to which she was not able to be a candidate for treatment with total pulmonary lavage; leading to multi-organ failure and later death.
[ [P211 Image] 1 . High resolution chest CT. Sample opacification in frosted glass (A) and pattern ''Crazy-paving'' (B)]
Conclusions: The importance of considering the diagnosis of PAP as a noninfectious pulmonary complication in patients with allogenic HSCT despite its low incidence is recognized.
Disclosure: Nothing to declare
P212 Blood samples for monitoring of trough levels can be drawn from the PICC line in patients with intravenous tacrolimus
M. José Pizarro1, Lourdes Aguirre1, Carmen Tejado1, Maider Rojo1, Itxaso Muguruza1, Nerea Caminos1, Esther Pérez1, Naiara Manzanares1, Maider Valencia1, Carlos Vallejo1
1 University Hospital Donostia, Hematology, San Sebastián, Spain
Background: Monitoring of calcineurin inhibitors [cyclosporin A (CsA) and tacrolimus (Tac)] blood levels are critical to assure effectiveness and to avoid toxicity in patients undergoing allogeneic HSCT. However, it is not clear if samples have to be drawn from a peripheral site (through venipuncture) or can be obtained from the central line. Blood draws from central line are preferred by the patients, but there are doubts related to accuracy of the value. We aimed to check if there were differences in the blood levels of Tac in samples drawn through a PICC line compared to those obtained by venipuncture.
Methods: Once the project was approved by the Clinical Trials and Ethics Committee, 154 pairs of blood samples were drawn (154 from PICC line and 154 from venepuncture) from 33 voluntary allo-HSCT recipients who were receiving continuous infusion tacrolimus from February through August 2018. The pts had inserted a double-lumen polyurethane PICC. Tacrolimus was always administered through the red line, and the blood draw always performed through the purple line. All of the patients signed the informed consent. 22 were male and 11 women. Median age was 55 years (30-68). 24 of the venepunctures were carried out in the arm where the PICC was set, and the other 130 from the contralateral arm. A limited group of nurses performed the extractions of the samples.
Results: As shown in the table, tacrolimus trough levels determined in blood from venepuncture were similar to those in blood drawn through the PICC (median: 10.7 vs 11.1 ng/mL). When comparing one by one in the individual patients, the differences were not significant, and changed the dosing prescription in no cases.
Conclusions: In our experience, there are not significant differences in tacrolimus levels draw from the PICC line, compared with a peripheral site. So, in our opinion, if the line for tacrolimus infusion is properly identified and the one used for the sample draw is the alternative one, venepunctures to obtain sample from peripheral sites are not justified for tacrolimus levels measurements.
|Venipuncture (N=154)||PICC (purple line) (N=154)||P|
|Tacrolimus trough blood level [median (range)]||