We conducted a single-arm prospective study in 50 patients who received the combination of an haploidentical stem cell graft and an unrelated umbilical cord blood unit for the treatment of hematological malignancies. The median time for neutrophil engraftment was 13 days (11–20 days), and for platelets was 15 days (11–180 days). All surviving patients attained complete haploidentical engraftment except three patients who presented a mixed engraftment with increasing cord blood and decreasing haplo mismatch chimerism during the first 4 months after transplantation. The cumulative incidence of grade II–IV acute GVHD was 20%±0.327% at day+100, and the incidence of chronic GVHD was 19.26%±1.0% at 1 year. The 1-year cumulative incidence of relapse was 19.78%±1%, and the TRM was 16.2%±0.54%. At 1 year, overall survival was 78.6%±7.6% and PFS 64.0%±11.0%. The BU/CY-based conditional regimen showed a significant superiority over TBI/CY on PFS (relative risk=5.012, 95% confidence interval, 1.146–21.927, P=0.032). In conclusion, the co-infusion of an unrelated cord blood unit may potentially improve the outcome of haploidentical allogeneic hematopoietic SCT.
Allogeneic hematopoietic SCT (HSCT) is the treatment of choice for many patients with high-risk or recurrent hematological malignancies, and an HLA-matched related or unrelated donor is considered to be the best choice.1, 2 However, despite the considerable development of the voluntary donor registry worldwide, >50% of patients lack a suitable donor. This situation is even worse for non-Caucasian people.3, 4, 5, 6 The paucity of available donors encourages research towards alternative sources of stem cells such as HLA-mismatched/haploidentical family donors or unrelated umbilical cord blood (UCB), which provide the advantages of easy procurement and immediate availability despite their respective drawbacks. In an effort to retain the advantages of both stem cell sources and bypass their drawbacks, we attempted to combine UCB and haploidentical sources for transplantation as a novel approach.
Patients and methods
Patients and donors
Fifty consecutive patients suffering from hematological malignancies received an haploidentical SCT combined with the co-infusion of an UCB unit between January 2011 and June 2012 in our transplant unit. The diagnoses were ALL: 20 cases, AML: 24 cases, CML: 3 cases, myelodysplastic syndrome: 1 case, and non-Hodgkin lymphoma: 2 cases. A total of 30% of patients (15 cases) had a karyotype associated with poor prognosis such as t(9;22), t(9;11), t(8;14), t(4;11), t(1;19), and complex karyotype with more than three abnormalities. Also, 36% of patients (18 cases) had advanced disease at the time of transplant (CR2 or subsequent CR or non-remission before transplantation). The donors of haploidentical stem cells were their parents, siblings or children, and the UCB units came from the cord blood banks in Shanghai, Beijing or Shandong Province in China. All patients and donors provided written informed consent for the protocol, which was approved by our hospital’s Ethics Committee. The baseline data of patients and donors are shown in Table 1.
HLA typing and donor selection
HLA-A, -B, and -DR typing of the recipients, haploidentical donors and UCB units was performed by low-resolution typing techniques, and results of the patients’ HLA typing were sent to the cord blood banks in Shanghai, Beijing and Shandong Province in China to look for ideal cord blood units. The HLA typing and cell doses infused were verified in our center after thawing the cord blood units. Haploidentical donors were selected on HLA typing, health conditions and willingness to donate. Cord blood units were selected based on the results of HLA typing and cell doses evaluated before freezing. Units with at least 4/6 matched HLA loci became the candidates, and HLA matching was prioritized over cell dose. At the same level of typing, the richest UCB units were chosen.
Two myeloablative regimens were used:
The BU/CY-based regimen consisted of Me-CCNU 250 mg/m2 (Day−10), cytarabine (Ara-C) 4 g/m2/day (Days−9 and −8), Bu 4 mg/kg/day p.o; (Days−7 to −5) and CTX 1.8 g/m2/day (Days−4 and −3).
The TBI/CY-based regimen consisted of Me-CCNU 250 mg/m2/day (Day−8), TBI with a total dose of 8–8.5 Gy (Days−7 and −6), Ara-C 4 g/m2/day (Days−6 and −5) and CTX 1.8 g/m2/day (Days−4 and −3).
The choice of the preparative regimen was primarily based on diagnosis and age: the BU/CY-based regimen was first considered for patients with myeloblastic malignancies and younger patients, while patients with lymphoid malignancies and patients with extramedullary localizations received TBI/CY.
GVHD prophylaxis strategy
CsA at 3 mg/kg/day was given by continuous infusion over 24 h from day−10 until patients could switch to oral intake (PO), with a target blood concentration ranging from 200 to 300 ng/mL. MTX was given at 15 mg/kg/day on day+1 and 10 mg/kg/day on days+3, +6 and +11. Mycophenolate mofetil 1.0 g PO twice a day was given from day−10 to day+30, then gradually tapered until day+60. Rabbit antithymocyte globulin (r-ATG, Genzyme, Cambridge, MA, USA) was administrated in vivo at 2.5 mg/kg on days −5 to −2. Promethazine hydrochloride and methylprednisolone, as well as dexamethasone were given to prevent r-ATG reactions. The first-line treatment for acute GVHD II–IV consisted of the administration of methylprednisolone 2 mg/kg/day.
Graft collection and infusion
Stem cell mobilization of haploidentical donors were performed by G-CSF subcutaneously 5 μg/kg/day daily from day−5. BM grafts were collected by BM aspiration at day 0 in the operation room. If the counts of cells was <2 × 106/kg, PBSCs were additionally collected by apheresis using a COBE SPECTRA device (Gambro BCT, Lakewood, CO, USA) from day+1 and if needed on the following day until a target number of 2 × 106/kg of CD34+ cells was attained. Haploidentical grafts were infused on day 0, 8 h after the infusion of the cord blood or on day+1.
Supportive care and post-transplantation surveillance
All the patients were in sterile rooms with strict reverse isolation from the beginning of the preparative regimen. Patients started selective gut decontamination with levofloxacin (200 mg twice a day), albendazole (200 mg once a day for 3 days) and fluconazole (200 mg twice a day) before conditioning. Prophylactic antibiotics, antifungal (voriconazole or micafungin) and antivirus (acyclovir) therapies were administrated during the conditioning and immnosuppressive period. Trimethoprim/sulfamethoxazole was given at four tablets daily twice a week for the prevention of Pneumocystis carinii infection. G-CSF was administered subcutaneously at a dose of 5 mg/kg/day from day+7 until stable neutrophil recovery. Heparin and prostaglandin E1 was given to prevent veno-occlusive disease. Prophylactic i.v. Ig was used once a week. Irradiated and leukodepleted blood products were administered to maintain a Hb level above 60 g/L and platelet count over 20 × 109/L.
From the time of neutrophil recovery, chimerism of donor cells was assessed by multiplex fluorescent STR analysis in the peripheral blood weekly during hospital stay, as well as CMV and EBV viremias using a real-time PCR-based method. In order to evaluate the remission status and chimerism, BM aspirations were performed every month for the first 6 months after transplant, and thereafter every 3 months until at least 1-year post-transplantation. They were also repeated when clinically indicated. Ganciclovir or foscarnet was delivered as pre-emptive therapy if CMV DNA viremia was positive.
Definitions and post-transplantation evaluations
Neutrophil engraftment was defined as the first day when the ANC was >0.5 × 109/L for 3 consecutive days. Platelet engraftment was defined as the first day when the platelet count was >20 × 109/L without transfusion support for 7 consecutive days. Primary graft failure was defined as failure to achieve a neutrophil engraftment after SCT until day+100 post-transplantation. Secondary graft failure was defined as the development of an absolute nucleated count of <0.5 × 109/L after achievement of initial engraftment.
Disease relapse was defined as disease progression from the best response. The diagnosis of disease recurrence was based on clinical and pathological criteria. Death without disease progression was considered transplantation related. Acute GVHD was scored according to the criteria proposed by the 1994 Consensus Conference on Acute GVHD Grading.7 Chronic GVHD was scored according to the NIH Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: Diagnosis and Staging Working Report.8
PFS and OS were calculated using the Kaplan–Meier method and expressed as probabilities with a s.e. Cumulative incidence of relapse with TRM as the competing risk and cumulative incidence of neutrophil and platelet recovery with death before recovery as the competing risk were also calculated. The incidence of acute GVHD and chronic GVHD were calculated using the cumulative incidence function, with death and graft failure as competing risks.
Univariate comparisons and multivariate analyses of the significance of presenting and transplantation-related covariates affecting OS and PFS were determined using the Cox proportional hazard model. For multivariate analysis, variables with a P-value<0.1, as determined by univariate analysis, were considered for entry into the model selection procedure. Parameters calculated in the univariate analysis included age, gender of patients and haploidentical donors, diagnosis, risk classification of cytogenetics at diagnosis, active disease, the source and type of haplograft, conditional regimen, typing of cord blood unit and cell dose both in haplograft and cord blood unit. Factors were considered statistically significant if they had an associated P-value of <0.05 as determined by the likelihood ratio test using the two-tailed significance testing. Statistical analyses were performed using the SPSS 16.0 (SPSS, Chicago, IL, USA), except for the cumulative incidence analyses, which were carried out with R functions from competing-risks analysis libraries (R version 2.15.1, R Foundation for Statistical Computing, Vienna, Austria).
As described in Table 2, the median values of absolute nucleated cell counts were 10 × 108/kg in the haploidentical grafts and 1.8 × 107/kg in the cord blood units. The median doses of CD34+ cells infused were 3.31 × 106/kg and 0.948 × 105/kg, respectively. The recovery of neutrophils and platelets is shown in Figure 1. The median time to neutrophil recovery was 13 days (range from 11 to 20 days), and the median time to platelet recovery was 15 days (range from 11 to 180 days). Two patients died before engraftment from severe infection. All other 48 patients engrafted on neutrophils within 20 days after transplantation. In two patients, platelet recovery was significantly prolonged; these two patients are still supported with platelet transfusion. No relationship was found between engraftment and the doses of cells infused of either the haploidentical graft or the cord blood unit.
All surviving patients achieved complete haploidentical chimerism (>95%) except three patients with aberrant engraftment patterns in whom early haploidentical engraftment tended to be replaced by cord blood, with a progressive increased mixed cord blood chimerism (Figure 2). Case 1 died of infection at day+126 post-transplantation, and the other two cases showed stable engraftment of the cord blood unit. The HLA typings of the UCB units were 5/6, 4/6 and 5/6 match, respectively. Neither the haplograft nor the cord blood cell dose in these three patients differed from the doses received by the other patients.
GVHD, relapse, TRM and cause of death
The cumulative incidence of acute GVHD (grade II–IV) was 20%±0.3% at day+100 (Figure 3a), and grade III–IV acute GVHD occurred in only five cases. Cumulative incidence of chronic GVHD was 19.3%±1.0% at 1 year (Figure 3b), and extensive chronic GVHD occurred in two cases. Neither acute nor chronic GVHD resulted in death directly in the whole cohort. There were six relapses, including three in the central nervous system, leading to death. The 1-year cumulative incidence of relapse was 19.8%±1.0% (Figure 3c). Multivariate analysis did not identify any risk factor affecting the relapse rate. There were six cases of TRM for a cumulative incidence of 16.2%±0.5% at 1 year (Figure 3d). Of the six patients, five patients died from severe infection and the other one from thrombotic thrombocytopenia purpura.
OS and PFS
Overall survival at 1 year was 78.6%±7.6% (Figure 4a), and PFS at 1 year was 64.0%±11.0% (Figure 4b). During the analysis of risk factors affecting OS and PFS, the age of the patient, active disease status and the nature of the conditioning regimen were significant in univariate comparisons, but only the nature of the conditioning regimen showed a significant influence on PFS in multivariate analysis: the BU/CY regimen was superior to the TBI/CY regimen (RR=5.012, 95% confidence interval, 1.146–21.927, P=0.032). No other predictor of outcome could be identified in multivariate analysis.
Allogeneic HSCT is the best therapy for patients with severe hematopoietic diseases of unfavorable prognosis, such as refractory/relapse hematological malignancies, and acute leukemias with poor prognostic factors at diagnosis. Matched sibling donor remain the ideal source of hematopoietic stem cells, but only 25–30% patients can finally find a HLA-identical sibling donor. Although the expansion of the worldwide unrelated donor registry elevates the probability of finding a matched unrelated donor, many patients, especially patients of diverse racial and ethnic backgrounds, may not be able to rapidly benefit from the finding of a suitably matched unrelated donor. Besides, potential recipients have to wait for about 4 months because of the complicated process of searching and acquisition to the donation of hematopoietic stem cells.9 Patients with advanced malignancies may experience disease progression or even death during the waiting time.
Haploidentical family donors and UCB are currently considered as alternative hematopoietic stem cell sources owing to the easy acquisition of stem cells. However, each of them has its own inherent advantages and disadvantages. Despite mismatching, UCB stem cells transplantation causes little GVHD, and some data suggest less disease recurrence than transplantation from adult donors,10 but the limited cell numbers result in delayed and unpredictable hematopoietic recovery.11 Delayed engraftment and slow immune reconstitution predispose to lethal infections and hemorrhages, as well as increased transfusion requirements, prolonged length of hospital stay, and high early mortality.12, 13, 14, 15 Although considerable effort has been devoted to address the problem, such as using double units of cord blood, intrabone infusion or co-infusion of expanded cord blood progenitors,15, 16, 17, 18, 19 none has been shown to clearly overcome the obstacles so far.20, 21, 22, 23 In order to speed up hematopoietic recovery, the team from Universidad Autonoma de Madrid has pioneered a transplantation strategy of myeloablative cord SCT combined with related haploidentical stem cells as a third-party donor support. Several reports have revealed some encouraging results both in myeloablative and non-myeloablative conditioning, which proved the feasibility of this approach.4, 11, 20, 24, 25, 26, 27 The Spanish group recently updated the data with a long-term follow-up, which demonstrated outcomes comparable to the outcome achieved with HLA-identical related donors in acute leukemia and myelodysplastic syndromes.20 The median times to neutrophil and platelet recovery were 11 days and 37 days, respectively. Cumulative incidence of Grade II–IV acute GVHD was 22.4%, and incidence of relapse was 11.6%. In all, 35.7% of patients died of transplanted-related complications. The study group of Dr van Besien reported the results with reduced-intensity conditioning: 45 patients received a transplantation of UCB and CD34+ stem cells from an haploidentical family member after a fludarabine/melphalan-based conditioning. Neutrophil engraftment occurred at 11 days and platelet engraftment at 19 days. Cumulative incidence of acute and chronic GVHD was 25% and 5%, respectively. Survival at 1 year was 55%, PFS was 42%, TRM was 28% and the relapse incidence was 30%.11 Of note is that all these combined transplantation studies performed CD34+ cell enrichment and/or T-cell depletion for the purpose of overcoming the HLA barrier to ensure engraftment and reduce the risk of GVHD. However, in addition to the workload involved by these approach, the use of manipulated graft has been shown to be complicated by a high TRM due to delayed hematopoietic and immune reconstitution.
In recent years, interest in T-cell-replete haploidentical transplantation has been regenerated by the development of new transplant strategies or GVHD prophylaxis, such as the use of G-CSF-primed grafts and the use of high dose CY post transplant and/or other combined immunosuppressive agents. A much lower incidence of GVHD has been reported, and several reasons may explain this observation,9 including the hyporesponsiveness of T cells after mixture of BM and PBSCs, the use of ATG before transplantation, the improvements in the use of immunosuppressive agents post transplant and the application of G-CSF to both donors and recipients.28, 29, 30, 31, 32 A recent report from the MD Anderson Cancer Center has obtained similar results using a T-cell-replete haploidentical graft followed by an effective post-transplantation immunosuppressive agent.33
With this understanding, we infused unmanipulated haploidentical graft in our study, and we used the cord blood as the third-party donor support. We observed an improved outcome when compared with the historical data of our center during 2003–2008,34 especially for GVHD. In our past experience, the cumulative incidences of acute and chronic GVHD were 41% and 48%, respectively, with haploidentical transplantation without co-infusion of cord blood, and 33% and 32%, respectively, with matched unrelated transplantation. Further, our results suggest that the co-infusion protocol has yielded at least a non-inferior prevention against GVHD when compared with current studies, including T-cell depletion grafts and reduced-intensive preparative regimen.9, 12, 35, 36, 37, 38, 39, 40 Several large-scale studies using these approaches have resulted in a cumulative incidence of 8–34% for Grade II–IV acute GVHD and 7–14% for chronic GVHD.41, 42, 43 The results of our study indeed are in favor of a superiority of unmanipulated haploidentical transplantation co-infused with UCB over haploidentical HSCT alone or even matched unrelated HSCT.
UCB was rejected in all our patients except three, which differs from other observations where in the majority of patients early haploidentical engraftment has been replaced by durable engraftment of UCB cells over time.11, 20, 25, 26 Competition between grafts of various sources is commonly observed after double UCB transplantation, which induces the elimination of one of the grafts. A probable explanation is an immunological graft-versus-graft effect.44, 45 We attribute the preferential engraftment of the haploidentical graft in our patients to the absence of T-cell depletion, which results in a stronger engraftment ability. However, although no UCB chimerism could be detected via STR in our study, we cannot rule out an effect of the UCB, which could result in GVHD prevention, and possibly in anti-leukemia effect, thus explaining at least in part the encouraging 1-year-OS and PFS. Modification of cytokines and microenvironment induced by infusion of UCB cells may also participate in the immune mechanism.
Several randomized studies, as well as retrospective registry data comparing the two types of preparative regimens, report conflicting results concerning outcomes and toxicities.46, 47, 48, 49, 50 Although TBI-based regimens are widely used in HSCT, excellent outcomes of BU-based regimens were also reported by several single institution trials. We observed a superiority of BU/CY-based regimen over TBI/CY-based regimen on 1-year PFS in this co-infusion approach. However, the conclusion needs to be confirmed by long-term follow-up.
In conclusion, we report here the transplantation of unmanipulated haploidentical HSCT combined with the infusion of UCB in 50 patients. The encouraging results observed suggest that this promising approach deserves further evaluation. It is regretful that no further risk factors on the outcomes were identified besides the preparative regimen, probably due to the limited numbers of cases. Besides, a longer follow-up remains necessary to estimate the long-term outcome. Well-designed prospective research with controls is needed to confirm the superiority of this approach, as well as experimental research to reveal the probable mechanism of the observed improvement.
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We thank all of the physicians, nurses, and support personnel for their unevaluated contribution to this study, and we also extend our gratitude to all the patients in this study. This study was supported by a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions, as well as Jiangsu Province’s Key Medical Center (ZX201102).
The authors declare no conflict of interest.
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Cite this article
Chen, J., Wang, RX., Chen, F. et al. Combination of a haploidentical SCT with an unrelated cord blood unit: a single-arm prospective study. Bone Marrow Transplant 49, 206–211 (2014). https://doi.org/10.1038/bmt.2013.154
- haploidentical SCT
- cord blood transplantation
- mobilized hematopoietic stem cells
- unmanipulated graft
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Combining haplo-identical and cord blood stem cell grafts – might the whole be greater than the sum of its parts?
Leukemia & Lymphoma (2020)
Haploidentical stem cells combined with a small dose of umbilical cord blood transplantation exert similar survival outcome of HLA-matched stem cells transplantation in T-cell acute lymphoblastic leukemia
Bone Marrow Transplantation (2020)
Impact of donor and recipient characteristics on graft-versus-host disease and survival in HLA-matched sibling hematopoietic stem cell transplantation
Transfusion and Apheresis Science (2020)