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HLA-haploidentical vs matched unrelated donor transplants with posttransplant cyclophosphamide-based prophylaxis
Gooptu, M., Romee, R., St Martin, A., Arora, M., Al Malki, M., Antin, J. H., Bredeson, C. N., Brunstein, C. G., Chhabra, S., Fuchs, E. J., et al
Blood. 2021;138(3):273-282
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Editor's Choice
Abstract
Posttransplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis has enabled haploidentical (Haplo) transplantation to be performed with results similar to those after matched unrelated donor (MUD) transplantation with traditional prophylaxis. The relative value of transplantation with MUD vs Haplo donors when both groups receive PTCy/calcineurin inhibitor/mycophenolate GVHD prophylaxis is not known. We compared outcomes after 2036 Haplo and 284 MUD transplantations with PTCy GVHD prophylaxis for acute leukemia or myelodysplastic syndrome in adults from 2011 through 2018. Cox regression models were built to compare outcomes between donor types. Recipients of myeloablative and reduced-intensity regimens were analyzed separately. Among recipients of reduced-intensity regimens, 2-year graft failure (3% vs 11%), acute grades 2 to 4 GVHD (hazards ratio [HR], 0.70; P = .022), acute grades 3 and 4 GVHD (HR, 0.41; P = .016), and nonrelapse mortality (HR, 0.43; P = .0008) were lower after MUD than with Haplo donor transplantation. Consequently, disease-free (HR, 0.74; P = .008; 55% vs 41%) and overall (HR, 0.65; P = .001; 67% vs 54%) survival were higher with MUD than with Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% vs 88%) was higher and grades 3 and 4 acute (HR, 0.39; P = .07) and chronic GVHD (HR, 0.66; P = .05) were lower after MUD than with Haplo donor transplantation. There were no differences in graft failure, relapse, nonrelapse mortality, and disease-free and overall survival between donor types with myeloablative conditioning regimens. These data extend and confirm the importance of donor-recipient HLA matching for allogeneic transplantation. A MUD is the preferred donor, especially for transplantations with reduced-intensity conditioning regimens.
PICO Summary
Population
Patients reported to the CIBMTR registry, undergoing transplantation for acute leukaemia or myelodysplastic syndrome (n=2320)
Intervention
Haploidentical transplantation with post-transplant cyclophosphamide (PTCy) (Haplo, n=2036)
Comparison
Matched unrelated donor transplantation with PTCy prophylaxis (MUD, n=284)
Outcome
Recipients of myeloablative and reduced-intensity regimens were analysed separately. Among recipients of reduced-intensity regimens, 2-year graft failure (3% vs 11%), acute grades 2 to 4 GVHD (hazard ratio [HR], 0.70), acute grades 3 and 4 GVHD (HR, 0.41), and nonrelapse mortality (HR, 0.43) were lower after MUD than with Haplo donor transplantation. Consequently, disease-free (HR, 0.74; 55% vs 41%) and overall (HR, 0.65; 67% vs 54%) survival were higher with MUD than with Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% vs 88%) was higher and grades 3 and 4 acute (HR, 0.39) and chronic GVHD (HR, 0.66) were lower after MUD than with Haplo donor transplantation. There were no differences in graft failure, relapse, nonrelapse mortality, and disease-free and overall survival between donor types with myeloablative conditioning regimens.
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HLA Haploidentical versus Matched Unrelated Donor Transplants with Post-Transplant Cyclophosphamide based prophylaxis
Gooptu, M., Romee, R., St Martin, A., Arora, M., Al Malki, M. M., Antin, J. H., Bredeson, C. N., Brunstein, C. G., Chhabra, S., Fuchs, E. J., et al
Blood. 2021
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Editor's Choice
Abstract
Post transplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis has allowed haploidentical (Haplo) transplantation to be performed with results similar to that after matched unrelated donor (MUD) transplantation with traditional prophylaxis. The relative value of transplantation with MUD versus Haplo donors when both groups receive PTCy/calcineurin inhibitor/mycophenolate containing GVHD prophylaxis is not known. We compared outcomes after 2036 Haplo and 284 MUD transplantations with PTCy GVHD prophylaxis for acute leukemia or myelodysplastic syndrome in adults between 2011 and 2018. Cox regression models were built to compare outcomes between donor types. Recipients of myeloablative and reduced intensity regimens were analyzed separately. Among recipients of reduced intensity regimens, 2-year graft failure (3% versus 11%), acute grade II-IV GVHD (HR 0.70, p=0.022), acute grade III-IV GVHD (HR 0.41, p=0.016) and non-relapse mortality (HR 0.43, p=0.0008) were lower after MUD compared to Haplo transplantation. Consequently, disease-free (HR 0.74, p=0.008; 55% versus 41%) and overall survival (HR 0.65, p=0.001; 67% versus 54%) were higher after MUD compared to Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% versus 88%) was higher and grade III-IV acute (HR 0.39, p=0.07) and chronic GVHD (HR 0.66, p=0.05) were lower after MUD compared to Haplo transplantation. There were no differences in graft failure, relapse, non-relapse mortality, disease-free and overall survival between donor types with myeloablative conditioning regimens. These data extend and confirm the importance of donor-recipient HLA matching for allogeneic transplantation. A MUD is the preferred donor, especially for transplantations with reduced intensity conditioning regimens.
PICO Summary
Population
Adults with acute leukaemia or myelodysplastic syndrome, undergoing transplantation with post-transplant cyclophosphamide (n=2320)
Intervention
Matched unrelated donor transplantation (n=284)
Comparison
Haploidentical transplantation (n=2036)
Outcome
Among recipients of reduced intensity regimens, 2-year graft failure (3% versus 11%), acute grade II-IV GVHD (HR 0.70), acute grade III-IV GVHD (HR 0.41) and non-relapse mortality (HR 0.43) were lower after MUD compared to Haplo transplantation. Consequently, disease-free (HR 0.74 55% versus 41%) and overall survival (HR 0.65, 67% versus 54%) were higher after MUD compared to Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% versus 88%) was higher and grade III-IV acute (HR 0.39) and chronic GVHD (HR 0.66) were lower after MUD compared to Haplo transplantation. There were no differences in graft failure, relapse, non-relapse mortality, disease-free and overall survival between donor types with myeloablative conditioning regimens.
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3.
The Effect of Donor Type on Outcomes in Adults with Acute Myeloid Leukemia after Reduced Intensity Hematopoietic Peripheral Blood Cell Transplant
Rashid, N., Slade, M., Abboud, R., Gao, F., DiPersio, J. F., Westervelt, P., Uy, G., Stockerl-Goldstein, K., Romee, R., Schroeder, M. A.
Transplant international : official journal of the European Society for Organ Transplantation. 2020
Abstract
We retrospectively analyzed outcomes in patients with acute myeloid leukemia (AML) receiving reduced intensity conditioning (RIC) hematopoietic stem cell transplants (HCT) from a peripheral blood (PB) source. We identified 46 haploidentical HCT (haplo), 59 matched unrelated donor HCT (MUD), and 40 matched related donor HCT (SIB) patients at a single institution. Haplo had improved overall survival (OS) when compared to MUD, HR 2.03 (p=0.01) but not SIB, HR 1.17, (p=0.61). There were no differences in relapse rates or treatment related mortality (TRM). Haplo had higher rates of acute graft versus host disease (GVHD) grade II-IV at day 180 than MUD (44% vs 25%, p=0.03) and SIB (44% vs 13% p<0.01). Rates of acute GVHD III-IV and chronic GVHD were similar among the groups. Haplo had slower engraftment rates compared to MUD with neutrophil engraftment at 87% vs 93%, (p<0.01) and platelet engraftment at 59% vs 86%, (p<0.01) at 28 days. Although patients receiving haplo had higher acute GVHD II-IV and slower engraftment, they did not have increased TRM. These data may suggest that patients receiving haplo have improved OS compared to MUD for AML patients receiving RIC transplants. This should be confirmed using a larger cohort.
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4.
Optimal donor for African Americans with hematologic malignancy: HLA-haploidentical relative or umbilical cord blood transplant
Solomon, S. R., Martin, A. S., Zhang, M. J., Ballen, K., Bashey, A., Battiwalla, M., Baxter-Lowe, L. A., Brunstein, C., Chhabra, S., Perez, M. A. D., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
While hematopoietic cell transplant from an HLA-matched unrelated donor is potentially curative for hematologic malignancy, survival is lower for African Americans compared to Caucasians. As only about 20% of African Americans will have an HLA-matched unrelated donor many of these patients undergo HLA-haploidentical relative or umbilical cord blood transplantation. Thus, the current analyses studied transplant-outcomes after HLA-haploidentical relative (n=249) and umbilical cord blood (n=118) transplants for African Americans with hematologic malignancy between 2008 and 2016. The predominant disease was acute myeloid leukemia for both donor types. Grade II-IV and III-IV acute graft versus host disease was higher after umbilical cord blood (56% and 29%, respectively) compared to HLA-haploidentical relative transplantation (33% and 11%), p<0.0001. The 2-year incidence of transplant-related mortality adjusted for age and conditioning regimen intensity was higher after umbilical cord blood compared to HLA-haploidentical relative transplantation (31% versus 18%, p=0.008). However, there were no differences in the 2-year adjusted incidence of relapse (30% versus 34%, p=0.51), overall survival (54% versus 57%, p=0.66), or disease-free survival (43% versus 47%, p=0.46). HLA-haploidentical and umbilical cord blood extend access to transplantation with comparable leukemia-free and overall survival for African Americans with hematologic malignancy.
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5.
The European Society for Blood and Marrow Transplantation (EBMT) consensus recommendations for donor selection in haploidentical hematopoietic cell transplantation
Ciurea, S. O., Al Malki, M. M., Kongtim, P., Fuchs, E. J., Luznik, L., Huang, X. J., Ciceri, F., Locatelli, F., Aversa, F., Castagna, L., et al
Bone marrow transplantation. 2019
Abstract
The number of HLA-haploidentical hematopoietic cell transplants continues to increase worldwide due to recent improvements in outcomes, allowing more patients with hematological malignancies and non-malignant disorders to benefit from this procedure and have a chance to cure their disease. Despite these encouraging results, questions remain as multiple donors are usually available for transplantation, and choosing the best HLA-haploidentical donor for transplantation remains a challenge. Several approaches to haploidentical transplantation have been developed over time and, based on the graft received, can be grouped as follows: T-cell depleted haploidentical transplants, either complete or partial, or with T-cell replete grafts, performed with post-transplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis, or G-CSF-primed bone marrow graft and enhanced GVHD prophylaxis. Carefully selecting the donor can help optimize transplant outcomes for recipients of haploidentical donor transplants. Variables usually considered in the donor selection include presence of donor-specific antibodies in the recipient, donor age, donor/recipient gender and ABO combinations, and immunogenic variables, such as natural killer cell alloreactivity or KIR haplotype. Here we provide a comprehensive review of available evidence for selecting haploidentical donors for transplantation, and summarize the recommendations from the European Society for Blood and Marrow Transplantation (EBMT) on donor selection for different transplant platforms.
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6.
Outcomes of haploidentical vs matched sibling transplantation for acute myeloid leukemia in first complete remission
Rashidi, A., Hamadani, M., Zhang, M. J., Wang, H. L., Abdel-Azim, H., Aljurf, M., Assal, A., Bajel, A., Bashey, A., Battiwalla, M., et al
Blood advances. 2019;3(12):1826-1836
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Abstract
HLA-haploidentical hematopoietic cell transplantation (Haplo-HCT) using posttransplantation cyclophosphamide (PT-Cy) has improved donor availability. However, a matched sibling donor (MSD) is still considered the optimal donor. Using the Center for International Blood and Marrow Transplant Research database, we compared outcomes after Haplo-HCT vs MSD in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Data from 1205 adult CR1 AML patients (2008-2015) were analyzed. A total of 336 patients underwent PT-Cy-based Haplo-HCT and 869 underwent MSD using calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis. The Haplo-HCT group included more reduced-intensity conditioning (65% vs 30%) and bone marrow grafts (62% vs 7%), consistent with current practice. In multivariable analysis, Haplo-HCT and MSD groups were not different with regard to overall survival (P = .15), leukemia-free survival (P = .50), nonrelapse mortality (P = .16), relapse (P = .90), or grade II-IV acute GVHD (P = .98). However, the Haplo-HCT group had a significantly lower rate of chronic GVHD (hazard ratio, 0.38; 95% confidence interval, 0.30-0.48; P < .001). Results of subgroup analyses by conditioning intensity and graft source suggested that the reduced incidence of chronic GVHD in Haplo-HCT is not limited to a specific graft source or conditioning intensity. Center effect and minimal residual disease-donor type interaction were not predictors of outcome. Our results indicate a lower rate of chronic GVHD after PT-Cy-based Haplo-HCT vs MSD using calcineurin inhibitor-based GVHD prophylaxis, but similar other outcomes, in patients with AML in CR1. Haplo-HCT is a viable alternative to MSD in these patients.
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7.
HLA-haploidentical vs matched-sibling hematopoietic cell transplantation: a systematic review and meta-analysis
Meybodi, M. A., Cao, W., Luznik, L., Bashey, A., Zhang, X., Romee, R., Saber, W., Hamadani, M., Weisdorf, D. J., Chu, H., et al
Blood advances. 2019;3(17):2581-2585
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Abstract
HLA haploidentical hematopoietic cell transplantation (haplo-HCT) using posttransplantation cyclophosphamide (PT-Cy) is an alternative strategy when a matched sibling donor (MSD) is not available. We performed a systematic review and meta-analysis to compare the outcomes of MSD vs haplo-HCT. Eleven studies (1410 haplo-HCT and 6396 MSD recipients) were meta-analyzed. All studies were retrospective and high quality, and 9 were multicenter. Haplo-HCT was associated with ~50% lower risk of chronic graft-versus-host disease (GVHD) (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.41-0.74), but higher risk of nonrelapse mortality (HR, 1.36; 95% CI, 1.12-1.66). Relapse, survival, acute GVHD, and GVHD-free relapse-free survival were not significantly different between the groups. Deciphering the relative contribution of PT-Cy and HLA disparity to the observed outcome differences between the groups requires further research.
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8.
HLA epitope mismatch in haploidentical transplantation is associated with decreased relapse and delayed engraftment
Rimando, J., Slade, M., DiPersio, J. F., Westervelt, P., Gao, F., Liu, C., Romee, R.
Blood advances. 2018;2(24):3590-3601
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Editor's Choice
Abstract
HLA disparity is traditionally measured at the antigen or allele level, and its impact on haploidentical hematopoietic cell transplantation (haplo-HCT) with high-dose posttransplant cyclophosphamide (PTCy) is unclear. To the best of our knowledge, the relationship between HLA eplet-derived epitope mismatch (EM) and clinical outcome has not been examined in haplo-HCT. We retrospectively analyzed 148 patients who received a peripheral blood, T-cell-replete haplo-HCT with PTCy at a single center. HLA EM was quantified using an HLAMatchmaker-based method and was stratified by class and vector. The primary outcome was incidence of relapse. The total number of mismatched epitopes (MEs) per patient-donor pair in our patient population ranged from 0 to 51 (median, 24) in the graft-versus-host (GVH) direction and 0 to 47 (median, 24) in the host-versus-graft (HVG) direction. Higher HLA class II EM in the GVH direction was associated with a significantly reduced risk of relapse (adjusted hazard ratio [HR], 0.952 per ME; P = .002) and improved relapse-free survival (adjusted HR, 0.974 per ME; P = .020). Higher HLA class II EM in the HVG direction was associated with longer time to neutrophil (adjusted HR, 0.974 per ME; P = .013) and platelet (adjusted HR, 0.961 per ME; P = .001) engraftment. In peripheral blood haplo-HCT patients, increased HLA EM was associated with a protective effect on the risk of relapse in the GVH direction but a negative effect on time to count recovery in the HVG direction. HLA EM based on the HLA Matchmaker represents a novel strategy to predict clinical outcome in haplo-HCT.
PICO Summary
Population
Population 148 patients who received a peripheral blood, T-cell-replete haplo-HCT with high-dose posttransplant cyclophosphamide
Intervention
Intervention Measurement of epitope mismatch
Comparison
Comparison N/A
Outcome
Outcome Higher HLA class II EM in the GVH direction was associated with a significantly reduced risk of relapse and improved relapse-free survival. Higher HLA class II EM in the HVG direction was associated with longer time to neutrophil and platelet engraftment. In peripheral blood haplo-HCT patients, increased HLA EM was associated with a protective effect on the risk of relapse in the GVH direction but a negative effect on time to count recovery in the HVG direction
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Related donor transplants: has posttransplantation cyclophosphamide nullified the detrimental effect of HLA mismatch?
Robinson, T. M., Fuchs, E. J., Zhang, M. J., St Martin, A., Labopin, M., Keesler, D. A., Blaise, D., Bashey, A., Bourhis, J. H., Ciceri, F., et al
Blood advances. 2018;2(11):1180-1186
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Abstract
We sought to identify whether posttransplantation cyclophosphamide (PT-Cy) reduces or eliminates the detrimental impact of HLA mismatching on outcomes of HLA-haploidentical related donor transplantation for acute leukemia. Data from 2143 donor-recipient pairs (n = 218 haploidentical sibling; n = 218 offspring; n = 1707 HLA-matched sibling) with acute myeloid or lymphoblastic leukemia were studied. All received a calcineurin inhibitor for graft-versus-host disease (GVHD) prophylaxis while high-dose PT-Cy was also given to recipients of haploidentical transplant. Patient age correlated with donor-recipient relationship: haploidentical siblings donated to patients aged 18 to 54 years whereas offspring donated to patients aged 55 to 76 years. Therefore, transplant outcomes were examined separately in the 2 patient age groups. In patients aged 18 to 54 years, there were no significant differences in outcomes except chronic GVHD, which was lower after haploidentical sibling compared to HLA-matched sibling transplant (hazard ratio [HR], 0.63; P < .001). In patients aged 55 to 76 years, despite lower chronic GVHD (HR, 0.42; P < .001), graft failure (14% vs 6%; P = .003), nonrelapse mortality (HR, 1.48; P = .02), and overall mortality (HR, 1.32; P = .003) were higher after transplant from offspring compared with an HLA-matched sibling. These data demonstrate a superior outcome in older recipients when using an HLA-matched sibling instead of offspring, although there were differences in transplant platforms (GVHD prophylaxis and graft type) between the 2 groups. Validation of these findings requires a prospective randomized trial wherein the transplant platforms can be closely matched.
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10.
Effect of donor characteristics on haploidentical transplantation with posttransplantation cyclophosphamide
McCurdy, S. R., Zhang, M. J., St Martin, A., Al Malki, M. M., Bashey, A., Gaballa, S., Keesler, D. A., Hamadani, M., Norkin, M., Perales, M. A., et al
Blood advances. 2018;2(3):299-307
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Abstract
We studied the association between non-HLA donor characteristics (age, sex, donor-recipient relationship, blood group [ABO] match, and cytomegalovirus [CMV] serostatus) and transplant outcomes after T-cell-replete HLA-haploidentical transplantation using posttransplantation cyclophosphamide (PT-Cy) in 928 adults with hematologic malignancy transplanted between 2008 and 2015. Siblings (n = 358) and offspring (n = 450) were the predominant donors, with only 120 patients having received grafts from parents. Although mortality risks were higher with donors aged 30 years or older (hazard ratio, 1.39; P < .0001), the introduction of patient age to the Cox regression model negated the effect of donor age. Two-year survival adjusted for CMV seropositivity, disease, and disease risk index was lower in patients aged 55 to 78 years after transplantation of grafts from donors younger than 30 years (53%) or aged at least 30 years (46%) compared with younger patients who received grafts from donors younger than 30 years (61%) and at least 30 years (60%; P < .0001). Similarly, 2-year survival in patients aged 55 to 78 years was lower after transplantation of grafts from siblings (45%) or offspring (48%) compared with patients aged 18 to 54 years after transplantation of grafts from siblings (62%), offspring (58%), and parents (61%; P < .0001). Graft failure was higher after transplantation of grafts from parents (14%) compared with siblings (6%) or offspring (7%; P = .02). Other non-HLA donor characteristics were not associated with survival or graft failure. The current analyses suggest patient and disease, rather than non-HLA donor characteristics, predominantly influence survival in adults.