For patients with AML, the best alternative donor remains to be defined. We analyze outcomes of patients who underwent myeloablative umbilical cord blood or haploidentical hemopoietic stem cell transplantation (HSCT) in Spain. Fifty-one patients underwent single umbilical cord blood transplantation supported by a third party donor (Haplo-Cord) between 1999 and 2012, and 36 patients received an haploidentical HSCT with post-transplant cyclophosphamide (PTCY–haplo) between 2012 and 2014 in GETH centers. The Haplo-Cord cohort included a higher proportion of patients with high disease risk index and use of TBI in the conditioning regimen, and hematopoietic cell transplantation–age Comorbidity Age Index was higher in PTCY–haplo patients. Cumulative incidence of neutrophil engraftment was 97% in the Haplo-Cord and 100% in the PTCY–haplo group, achieved in a median of 12 and 17 days, respectively (P=0.01). Grade II–IV acute GvHD rate was significantly higher in the PTCY–haplo group (9.8% vs 29%, P=0.02) as well as chronic GvHD rates (20% vs 38%, P=0.03). With a median follow-up of 61 months for the Haplo-Cord group and 26 months for the PTCY–haplo cohort, overall survival at 2 years was 55% and 59% (P=0.66), event-free survival was 45% vs 56% (P=0.46), relapse rate was 27% vs 21% (P=0.79), and non-relapse mortality was 17% vs 23% (P=0.54), respectively. In this multicenter experience, Haplo-Cord and PTCY–haplo HSCT offer valid alternatives for patients with AML. Neutrophil engraftment was faster in the Haplo-Cord cohort, with similar survival rates, with higher GvHD rates after haploidentical HSCT.
In the absence of an HLA-matched donor, alternative donors may be considered for patients with AML in need of an allogeneic hemopoietic stem cell transplantation (HSCT). Alternative donor sources include unrelated umbilical cord blood (UCB) and mismatched family members (haploidentical donor). Unrelated UCB is considered one of the front-line stem cells sources for high-risk patients lacking access to a suitable adult donor.1 Cumulative experience in adult patients showed low rates of GvHD with potent GvL effects, especially in patients with minimal residual disease.2 The infusion of a single UCB unit together with a limited number of mobilized CD34+-selected peripheral blood (PB) stem cells from an HLA-mismatched third party donor (TPD), named dual or Haplo-Cord HSCT, has shown to significantly reduce the post-transplantation period of neutropenia compared to single UCB transplantation, mostly using units with relatively low cell content.3, 4, 5 Haplo-Cord HSCT has shown overall and leukemia-free survival rates comparable to those obtained with HLA-matched donors in adult patients.6, 7
Haploidentical donors represent a valid donor source for patients who may benefit from allogeneic HSCT. Several strategies have been developed in order to overcome the high rates of GvHD and graft failure obtained from early attempts at using T-cell replete grafts from haploidentical donors using conventional preparative regimens.8 However, T-cell depletion in adult patients is associated with slow immune reconstitution leading to a high frequency of infections and a high disease recurrence rate.9 More recently, strategies using T-cell replete grafts with reduced intensity conditioning (RIC) and post-transplant high-dose cyclophosphamide (PTCY) as GvHD prophylaxis have been developed.10 This approach has demonstrated promising results, especially for patients with lymphoproliferative disease.11, 12
Results of parallel phase 2 trials using partially HLA-mismatched-related bone marrow or unrelated double UCB grafts after reduced intensity conditioning showed higher relapse rates after haploidentical SCT and higher non-relapse mortality (NRM) after double UCB transplantation, with comparable survival rates.13 Other groups have introduced a myeloablative conditioning regimen in high-risk patients that may decrease the high relapse rate associated to haploidentical reduced intensity conditioning platforms.14
The objective of this study was to analyze toxicity and survival rates of adults with AML who underwent either Haplo-Cord HSCT or haploidentical HSCT with post-transplant cyclophosphamide (PTCY–haplo HSCT) using myloablative, busulfan-based, conditioning regimens in Spain.
Patients and methods
The study was approved by the institutional review board of each center and all donors and recipients gave written informed consent.
The study included adult patients with AML undergoing Haplo-Cord or PTCY–haplo HSCT with a minimum follow-up of 6 months after transplantation.
Graft selection and processing
For Haplo-Cord transplants, UCB units a match of at least four out of six HLA loci considering low resolution for HLA-A and HLA-B and high resolution for HLA-DR was required. UCB units with a minimum of 2 × 107 total nucleated cells/kg and 1 × 105 CD34+ cells/kg were preferable. Donors of the HLA-mismatched CD34+ cells were sought among patients' first-degree relatives. If no relatives were available, an unrelated individual was selected as donor. Selection of mobilized CD34+ cells was performed by positive immunomagnetic procedures (CliniMACS, Miltenyi Biotec, Bergisch Gladbach, Germany) to obtain a final product with 2.5–3 × 106 CD34+ cells/kg and <1 × 104 CD3+ cells/kg of recipient body weight, as previously described.3
Within the PTCY–haplo HSCT cohort, potential first-degree family members were typed at the HLA-A, HLA-B, HLA-C and HLA-DRB1 loci at an intermediate resolution level. Donors were preferably excluded if anti-HLA antibodies against donor HLA antigens were present in the recipient.
Conditioning regimen and GvHD prophylaxis
The conditioning regimen for Haplo-Cord transplants has been previously described.7 Briefly, patients received fludarabine 30 mg/m2 (days −8 to −5), cyclophosphamide 60 mg/kg (days −4 and −3) and IV busulfan 3.2 mg/kg (days −6 and −5) or 10 Gy of fractionated TBI. Antithymocyte globulin 2 mg/kg on days −2 and −1. UCB cells were infused on day 0 followed by the TPD cells either the same day or on day +1. As GvHD prophylaxis, patients received cyclosporine A from day −5, and methylprednisolone 1–2 mg/kg from day −2, tapered until suspension on day +10 to +14. In the absence of GvHD manifestations, cyclosporine A was tapered when full cord blood (CB) engraftment was achieved or from day +50. G-CSF was administrated subcutaneously 5 mg/kg per day from day +1 until neutrophil recovery.
Conditioning regimen for haploidentical transplants included fludarabine 40 mg/m2 for 4 days and IV busulfan 3.2 mg/kg for 3 or 4 days. GvHD prophylaxis was performed with IV cyclosphosphamide 50 mg/kg on days +3 and +4 followed by cyclosporine A and mycophenolate mofetil from day +5. In the absence of GvHD manifestations, mycophenolate mofetil was stopped at day +35 and cyclosporine A was tapered from day +50. G-CSF was administrated subcutaneously 5 mg/kg/ per day from day +5 until neutrophil recovery.
Pre- and post-transplant evaluation
Response to therapy before and after transplantation followed the National Cancer Institute criteria, revised by the International Working Group in AML.15 Patients were stratified according to the disease risk index.16
Pre-transplant comorbidities were recorded using the hematopoietic cell transplantation–Comorbidity Age Index (HCT–CI).17 Chimerism was determined by quantitative analysis of informative microsatellite DNA polymorphisms as previously described.18 Acute GvHD was scored according to the published consensus criteria.19 Chronic GvHD (cGvHD) was scored according to the NIH Consensus Development Project.20
Myeloid engraftment was defined as an ANC of 0.5x109/L or greater for 3 consecutive days. Platelet engraftment was defined as a platelet count of 20x109/L or higher, without transfusion support, for 3 consecutive days. Patients who survived more than 30 days after transplantation and who failed to achieve myeloid engraftment were considered as graft failures. Diagnosis of disease recurrence was based on clinical and pathological criteria.
Quantitative variables were expressed as median and either range or interquartile range (25th and 75th percentiles). Qualitative variables were expressed as frequency and percentage. χ2 was used to test for the association between qualitative variables. Comparability of the two cohorts (Haplo-Cord and PTCY–haplo HSCT) for the main prognostic features was tested with t-test. NRM, disease relapse or progression, overall survival, and event-free survival were defined as primary end points. Relapse, toxic death and second transplant due to graft failure were considered events. Estimates of event-free survival and overall survival were calculated using the Kaplan–Meier method, including 95% confidence interval (95% CI). Cumulative incidence curves and competing risk regression were performed as alternatives to Cox regression for survival data in the presence of competing risks.21 In our case, competitor events were death and any other occurrence that prevents the appearance of the event under study. This model estimates the hazard ratio known as subdistribution hazard or subhazard ratio. For the cumulative incidence estimate of neutrophil recovery, death before day +30 was considered a competing event. For the cumulative incidence of platelet engraftment and full donor chimerism, death and retransplantation due to graft failure were considered competing events. NRM and relapse were considered competing events for each other, in addition to retransplantation for both of them. Except for the cumulative incidence, all calculations were made with SPSS (IBM, SPSS Statistics for Windows, Version 21.0. Armonk, NY, USA).
Fifty-one adult patients with AML underwent a Haplo-Cord HSCT between 1999 and 2012 in GETH centers. Median weight of these patients was 71 kg (range 53–111). On the other hand, 36 patients with AML underwent a PTCY–haplo HSCT between 2012 and 2014. Characteristics of both groups are shown in Table 1. In the Haplo-Cord group 27 patients (53%) were transplanted in first CR (CR1) and 16 (31%) patients had active disease. Thirty-eight transplants (75%) were performed with the busulfan-based preparative regimen and 13 (25%) patients received TBI-based conditioning. Within the PTCY–haplo group, 28 patients (77%) were transplanted in CR1 and 5 (14%) had active disease. All patients received busulfan as part of conditioning regimen, 14 (39%) received busulfan 3.2 mg/kg per day for 3 days and 22 (61%) for 4 days.
There were significant differences between both the groups in disease risk index (higher in the Haplo-Cord patients, P=0.009), age hematopoietic cell transplantation–Comorbidity Age Index (higher in PTCY–haplo patients, P=0.01) and the use of TBI in the conditioning regimen (25% of Haplo-Cord patients, P=0.003).
In the Haplo-Cord group, the median numbers of post-processing CB total nucleated cells and CD34+ cells were 2.3 × 107/kg (range 1.3–6.0) and 1.5 × 105/kg (range 0.4–3.3), respectively (Table 1). The HLA-mismatched TPD was a sibling in 54%, another haploidentical relative (son in 16%, father in 5% and mother in 1 case) and an unrelated individual in 21%. The median number of the infused TPD CD34+ cells was 2.6 × 106/kg (range 0.8–11.6), with a median number of CD3+ cells of 0.25 × 104/kg (range 0.02–1.5).
For the PTCY–haplo group, the source of stem cells was mobilized PB in 97% and bone marrow in 3%. The haploidentical donor was a sibling in 36%, a son/daughter in 30%, the mother in 19% and the father in 14%.
Engraftment and chimerism
In the Haplo-Cord HSCT group, the cumulative incidence of myeloid engraftment at 30 days was 97% (Figure 1), with a median time to engraftment of 12 days (range 9–31). The cumulative incidence of platelet recovery at 60 days was 82% (95% CI, 72–94), with a median time of platelet engraftment of 35 days (range 12–105). All patients showed PB mixed chimerism on days +7 and +14, with variable percentages of UCB and TPD cells. The cumulative incidence of full UCB chimerism was 68% achieved in a median of 69 days (range 15–365). Five cases in the Haplo-Cord HSCT group showed cord blood graft failure with engraftment of third party cells only, three cases among them were due to poor viability of cord blood cells. All cases were rescued with a second transplant.
In the PTCY–haplo group, the cumulative incidence of myeloid engraftment at 30 days was 100% (Figure 1), with a median time to engraftment of 17 days (range 12–29), significantly slower compared to Haplo-Cord myeloid engraftment (P=0.01). The cumulative incidence of platelet recovery at 60 days was 72% (95% CI, 59–89), with a median time of platelet engraftment of 29 days (range 11–131). Cumulative incidence of full-donor chimerism was 97% in a median of 28 days (range 13–147). One patient from the PTCY–haplo cohort showed secondary graft failure rescued with a CD34+ cell boost performed on day +80 after transplantation.
The cumulative incidence of grades II–IV acute GvHD at day +180 was 9.8% (95% CI, 4–23) and 29% (95% CI, 17–50) for Haplo-Cord and PTCY–haplo groups (P=0.02), respectively (Figure 2). The 2-year cumulative incidence of cGvHD was 20% (95% CI, 9–42) and 38% (95% CI, 21–68), respectively (P=0.03), with a cumulative incidence of extensive cGvHD of 9% (95% CI, 3–26) and 16% (95% CI, 4–64), respectively (P=0.66). In addition, three patients from the PTCY–haplo group developed severe GvHD following donor lymphocyte infusion performed due to relapse.
Survival and relapse
With a median follow-up of 61 months (interquartile range 37–108) for the Haplo-Cord group and 26 months (interquartile range 16–43) for the PTCY–haplo group, estimated 2 years overall survival and event-free survival were 55% (95% CI, 41–69) vs 59% (95% CI, 42–76), and 45% (95% CI, 31–59) vs 56% (95% CI, 40–73), respectively (Figure 2). Differences in overall survival and event-free survival were found not statistically significant between both cohorts (Figure 2). The cumulative incidence of relapse at 2 and 3 years was 27% (95% CI, 17–43) and 29% (95% CI, 19–45) in the Haplo-Cord group, and 21% (95% CI, 11–41) and 30% (95% CI, 17–53) in the PTCY–haplo group (P=0.79; Figure 2).
NRM, infections and toxicity
Cumulative incidence of NRM at 1 and 2 years was 15% (95% CI, 8–30) and 17% (95% CI, 10–32) for the Haplo-Cord group, and 23% (95% CI, 12–42) for the PTCY–haplo group (P=0.54; Figure 2), respectively. In the Haplo-Cord group, non-relapse deaths were due to infections in six patients (two CMV, one bacteria, one non-documented, one trypanosomiasis, one toxoplasmosis), veno-occlusive disease in two patients and cGvHD in one patient. In the PTCY–haplo group non-relapse-related deaths were due to infections in six cases (two invasive fungal infection, two bacteria, one CMV, one viral hemorrhagic cystitis), severe intestinal hemorrhage in one case, and other in one patient.
More patients in the PTCY–haplo group showed CMV reactivation in the first 180 days after transplant compared to the Haplo-Cord cohort (23% vs 55%; P=0.04), with no differences in CMV disease rates (6%). The remaining infectious events showed similar incidence rates in the Haplo-Cord and PTCY–haplo groups, including bacterial infections (31% vs 20%; P=0.3), probable and proven fungal infections (10% vs 25%; P=0.1), EBV post-transplantation lymphoproliferative disease (0.2% vs 0.3%; P=0.8) and viral hemorrhagic cystitis (14% vs 19%; P=0.5), respectively. Similarly, there were no differences in the frequency of hepatic veno-occlusive disease between both cohorts (6% vs 10%; P=0.6).
For patients with AML in need of an allogeneic HSCT without a suitable HLA-identical donor, the choice of alternative stem cells remains controversial. Although alternative donors have advantages and drawbacks in terms of the rapidity of obtaining stem cells, efficacy and tolerability, the criteria for selecting one alternative donor over others are not well established. Unrelated UCB is considered one of the front-line stem cell sources for high-risk patients lacking access to a suitable adult donor.1 Advantages include rapid availability and less stringent HLA-match requirements than that for adult grafts. A major limitation when considering UCB transplantation in the adult setting is the prolonged neutropenia due to inadequate UCB total nucleated cell content. The infusion of a single UCB unit together with a limited number of mobilized CD34+-selected PB stem cells from an HLA-mismatched TPD provides the fastest neutrophil engraftment among the different strategies developed in order to reduce the post-transplant neutropenia period after UCB transplantation.3, 4, 5
On the other hand, advantages of haploidentical donors include immediate and almost universal availability, avoidance of unrelated donor search costs and the availability for potential post-transplantation cellular therapy. The strategy of using unmanipulated bone marrow from haploidentical-related donors followed by PTCY has been shown to offer adequate GvHD prophylaxis through a relative simple procedure.10 However, high relapse rates particularly in the reduced intensity conditioning regimen setting remain an issue.13
This is the first study comparing adult patients with AML undergoing Haplo-Cord HSCT and PTCY–haplo HSCT. All patients received a myeloablative conditioning regimen. Patient features were well balanced between both cohorts in terms of demographic features (Table 1). However, besides the different transplant periods, a significantly higher proportion of patients of the Haplo-Cord group was transplanted with higher-risk disease and a significant proportion received TBI in the conditioning regimen, whereas a higher proportion of patients in the PTCY–Haplo group showed higher comorbidity index before transplant.
With significantly longer median follow-up of the Haplo-Cord cohort (61 vs 26 months), survival results were comparable in both Haplo-Cord and PTCY–haplo HSCT groups. As previously reported, Haplo-Cord HSCT offered high rates of neutrophil engraftment in AML patients achieved in a short median time, comparable to those obtained from adult donors.7 ANC recovery rates were similar in both Haplo-Cord and PTCY–haplo groups, with significantly faster neutrophil engraftment for the Haplo-Cord transplants (12 vs 17 days). In the Haplo-Cord HSCT cohort, CB graft failure rate was 9%. Poor post-thaw CB viability has been most likely related to CB graft failure in the three out of the five cases. Of note, sustained TPD myeloid engraftment allowed salvage transplantation in all cases. This highlights the relevance of UCB selection criteria other than cellular content and HLA matching. Adequate units should be carefully selected taking into account various factors including colony forming units and bank of origin. In the PTCY–haplo HSCT group, using mainly PB as graft source, there were no primary graft failure cases despite the high degree of HLA mismatch, although one patient showed secondary failure rescued with a CD34+ cell boost.
Using a myeloablative conditioning regimen based on IV busulfan, PTCY–haplo HSCT seem to offer similar relapse rates in patients with AML compared to Haplo-Cord HSCT. However, a significant shorter follow-up in the PTCY–haplo HSCT group and the inclusion of higher-risk patients in the Haplo-Cord HSCT cohort compels to take these results cautiously.
The PTCY–haplo HSCT approach using mainly PB as graft source showed acute grades II–IV GvHD and cGvHD rates comparable to those reported by other series using myloablative conditioning and bone marrow.22 However, compared to the Haplo-Cord HSCT cohort, acute and cGvHD rates were significantly higher in the PTCY–haplo group, and extensive cGvHD rates showed a higher tendency. Furthermore, as previously reported, Haplo-Cord HSCT offer significant less morbidity derived from GvHD symptoms and its therapy compared to adult donors, maintaining disease control in long-time surviving patients.7
Early toxicity, mainly due to infectious complications were not significantly different between both procedures, except for CMV reactivation rates, significantly lower in the Haplo-Cord group. The use of prophylaxis with ganciclovir in the main recruiting center could account for this result.2, 4
This multicenter study confirms the utility of single UCB supported by third party HLA-mismatched donor and haploidentical donors as alternative donor sources in adult patients with high-risk AML using myeloablative conditioning regimens. Survival and NRM rates so far do not benefit one procedure over the other. However, results should be taken cautiously due to significant differences in follow-up. Moreover, a significant proportion of Haplo-Cord procedures was performed from 1999 to 2004 when supportive care and preemptive approaches were poorer or less standardized. A randomized prospective comparison is needed in this setting to confirm these results.
Other factors and outcomes should be also taken into account in order to select the appropriate source for each case in the setting of AML. The higher upfront costs of cord blood HSCT may be decreased by an appropriate selection of UCB units in order to avoid graft failure of cord blood cells. Furthermore, costs may be counterbalanced by the costs derived from treatment and support of significant acute and cGvHD in the haploidentical setting.23 GvHD is a major complication after allogeneic HSCT resulting in variable degrees of morbidity and quality-of-life compromise after transplantation in patients with long-term survival as well as higher rates of NRM.24 Therefore, the impact of significant GvHD in the short and long term should be taken into account in the alternative transplant procedure selection process for each particular case.25 Further prospective studies should address this important issue, taking into account events occurring beyond the immediate post-transplant period such us GvHD and relapse.
In conclusion, UCB supported by TPD cells should remain in the front-line stem cells sources for patients with AML in need of an allogeneic HSCT, especially in patients with high- or very-high-risk AML. On the other hand, haploidentical HSCT using a myeloablative busulfan-based conditioning regimen together with high-dose post-transplant cyclophosphamide is a feasible and valuable alternative for those patients without a suitable donor. Further studies in the AML setting are needed to address thoroughly the advantages of one procedure over the other in terms of cost-effectiveness.
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We thank the staff and nurses of all the hematology and transplant units for their care and contributions to making this work possible. We thank Jose Maria Bellón from the Instituto de Investigación Sanitaria Gregorio Marañon for data analysis. This work was partially supported by the Ministry of Economy and Competitiveness ISCIII-FIS grants PI08/1463, PI11/00708, PI14/01731 and RD12/0036/0061, co-financed by ERDF (FEDER) Funds from the European Commission, 'A way of making Europe', as well as grants from the Fundación LAIR, Asociación Madrileña de Hematología y Hemoterapia (AMHH) and Asociación Española Contra el Cáncer (AECC).
Conception and design: MK, GB, JG and PB.
Provision of study materials or patients: all authors.
Collection and assembly of data: MK, GB, JG and PB.
Data analysis and interpretation: all authors.
Manuscript writing: MK, GB and PB.
Final approval of the manuscript: all authors.
The authors declare no conflict of interest.
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