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Post-transplant cyclophosphamide in one-antigen mismatched unrelated donor transplantation versus haploidentical transplantation in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the EBMT
Battipaglia, G., Galimard, J. E., Labopin, M., Raiola, A. M., Blaise, D., Ruggeri, A., Koc, Y., Gülbas, Z., Vitek, A., Sica, S., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
Whether to choose Haploidentical (Haplo) or one-antigen mismatched unrelated donor (1Ag-MMUD) hematopoietic cell transplantation (HCT) with post-transplant cyclophosphamide (PTCy) remains an unanswered question. We compared PTCy- Haplo-HCT to PTCy-1Ag-MMUD-HCT for acute myeloid leukemia (AML) in complete remission (three groups: 1Ag-MMUD using peripheral blood (1Ag-MMUD-PB; n = 155); Haplo using bone marrow (Haplo-BM; n = 647) or peripheral blood (Haplo-PB; n = 949)). Haplo-BM and Haplo-PB had a higher non-relapse mortality (NRM) compared to 1Ag-MMUD-PB (HR 2.28, 95% CI 1.23-4.24, p < 0.01; HR 2.65, 95% CI 1.46-4.81, p < 0.01, respectively). Haplo groups experienced a lower leukemia-free survival (LFS) compared to 1Ag-MMUD-PB (Haplo-BM: HR 1.51, 95% CI 1.06-2.14, p = 0.02; Haplo-PB: 1.47, 95% CI 1.05-2.05, p = 0.02); overall survival (OS) was also lower in Haplo-HCT (Haplo-BM: HR 1.50, 95% CI 1.02-2.21, p = 0.04; Haplo-PB: HR 1.51, 95% CI 1.05-2.19, p = 0.03). No differences were observed for graft-versus-host/relapse-free survival (GRFS) and relapse incidence (RI). Haplo-BM was associated with a lower risk of grade III-IV acute graft-versus-host disease (GVHD) (HR 0.44, 95% CI 0.24-0.81; p < 0.01), while no statistical differences were observed between groups for grade II-IV aGVHD and for cGVHD. Use of PTCy in 1Ag-MMUD-HCT is a valid alternative to consider when using alternative donors. Larger analysis of 1Ag-MMUD versus Haplo-HCT are warranted.
PICO Summary
Population
Adults with acute myeloid leukaemia, undergoing allo-HCT with post-transplant cyclophosphamide in first or second complete remission, identified from the EBMT database (n=1751)
Intervention
Haploidentical transplantation: Haplo using bone marrow (Haplo-BM, n = 647) or using peripheral blood (Haplo-PB, n = 949))
Comparison
One-antigen mismatched unrelated donor transplantation (1Ag-MMUD-PB, n = 155)
Outcome
Haplo-BM and Haplo-PB had a higher non-relapse mortality (NRM) compared to 1Ag-MMUD-PB (HR 2.28, 95% CI 1.23-4.24; HR 2.65, 95% CI 1.46-4.81, respectively). Haplo groups experienced a lower leukemia-free survival (LFS) compared to 1Ag-MMUD-PB (Haplo-BM: HR 1.51, 95% CI 1.06-2.14; Haplo-PB: 1.47, 95% CI 1.05-2.05); overall survival (OS) was also lower in Haplo-HCT (Haplo-BM: HR 1.50, 95% CI 1.02-2.21; Haplo-PB: HR 1.51, 95% CI 1.05-2.19). No differences were observed for graft-versus-host/relapse-free survival (GRFS) and relapse incidence (RI). Haplo-BM was associated with a lower risk of grade III-IV acute graft-versus-host disease (GVHD) (HR 0.44, 95% CI 0.24-0.81), while no statistical differences were observed between groups for grade II-IV aGVHD and for cGVHD.
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HLA-Matching with PTCy: A Reanalysis of a CIBMTR Dataset with Propensity Score Matching and Donor Age
Ambinder, A. J., Jain, T., Tsai, H. L., Horowitz, M. M., Jones, R. J., Varadhan, R.
Blood advances. 2022
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Editor's Choice
Abstract
Blood or marrow transplantation (BMT) outcomes using haploidentical donors (Haplo) and post-transplant cyclophosphamide (PTCy)-based graft versus host disease (GVHD) prophylaxis compare favorably to using HLA-matched donors with calcineurin inhibitor-based GVHD prophylaxis. A recent CIBMTR analysis of patients receiving homogenous PTCy-based prophylaxis found that, with reduced intensity conditioning, Haplo BMTs had worse outcomes than matched unrelated donor (MUD) BMTs. Due to significant differences in characteristics between the groups, we reanalyzed the dataset using propensity score matching and, additionally, added a donor age variable. MUD BMTs were matched to Haplo BMTs in a 1:5 ratio. After matching, no significant differences were found between groups across all measured baseline characteristics. Outcomes analyses demonstrated no significant differences in overall survival (HR of mortality with MUD vs Haplo [95% CI], 0.95[0.65-1.16], P=0.75), disease free survival (HR of relapse or death, 0.98[0.73-1.18], P=0.89), relapse rate (HR, 1.06[0.77-1.38], P=0.69), or non-relapse mortality (HR, 0.85[0.42-1.13], P=0.49) between the two groups. After stratification by conditioning intensity, MUD BMTs in the RIC cohort had a lower risk of NRM (HR, 0.56 [0.14-0.99], P=0.05), with no significant difference in other clinical outcomes. These results suggest that the effect of HLA matching on BMT outcomes with PTCy is less meaningful than previously reported and observed differences resulted in part from differences in donor age. Timely identification of a young, at least half-matched (related or unrelated) donor may be more important than finding a matched donor, if the latter leads to a substantial delay in BMT or use of an older donor.
PICO Summary
Population
Adults with acute myeloid leukaemia, acute lymphoblastic leukaemia in first or second complete remission, or myelodysplastic syndromes attending 111 bone marrow transplantation (BMT) centres across the USA and reported to the CIBMTR registry (n=837)
Intervention
BMT from haploidentical donors (Haplo, n=637, subset receiving reduced-intensity conditioning (RIC) n=341)
Comparison
BMT from matched unrelated donors (MUD, n=200, subset receiving RIC n=114)
Outcome
After matching, no significant differences were found between groups across all measured baseline characteristics. Outcomes analyses demonstrated no significant differences in overall survival (HR of mortality with MUD vs Haplo [95% CI], 0.95[0.65-1.16]), disease free survival (HR of relapse or death, 0.98[0.73-1.18]), relapse rate (HR, 1.06[0.77-1.38]), or non-relapse mortality (HR, 0.85[0.42-1.13]) between the two groups. After stratification by conditioning intensity, MUD BMTs in the RIC cohort had a lower risk of non-relapse mortality (HR, 0.56 [0.14-0.99]), with no significant difference in other clinical outcomes.
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A phase II study of post-transplant cyclophosphamide combined with tacrolimus for GVHD prophylaxis after HLA-matched related/unrelated allogeneic hematopoietic stem cell transplantation
Nakamae, H., Nakane, T., Okamura, H., Koh, H., Nakashima, Y., Hirose, A., Nakamae, M., Nishimoto, M., Kuno, M., Makuuchi, Y., et al
International journal of hematology. 2021
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Editor's Choice
Abstract
A combination of three post-transplant drugs, cyclophosphamide (PTCy), a calcineurin inhibitor, and mycophenolate mofetil, has long been used for prophylaxis of graft-versus-host-disease (GVHD) after HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT). Recently, this combination has been used following HLA-matched allo-HCT as well, but the optimal combination of drugs for GVHD prophylaxis in an HLA-matched setting remains unclear. This prospective phase II study evaluated the safety and efficacy of PTCy plus tacrolimus (TAC) for GVHD prophylaxis after allo-HCT from HLA-matched related donors (MRD) or HLA-matched unrelated donors (MUD). The cumulative incidences of grades II-IV and III-IV acute GVHD at 100 days post-transplantation were 18% and 5.9%, respectively, in the MRD group, and 18% and 9.1%, respectively, in the MUD group. The cumulative incidences of moderate to severe chronic GVHD at 1 year were 12% and 9.1% in the MRD and MUD groups, respectively. The 1-year overall survival rates in the MRD and MUD groups were 88% and 64%, respectively, and the 1-year GVHD-free, relapse free survival rates were 59% and 50%, respectively. These results suggest that GVHD prophylaxis with a less intensive double drug combination (PT/Cy and TAC) might be feasible after HLA-matched allo-HCT.Clinical Trial Notation This trial was a prospective single-center trial registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; identification number: UMIN000023890) and the Japan Registry of Clinical Trials (jRCTs051180143).
PICO Summary
Population
Patients undergoing allogeneic transplant at a single centre in Japan, with post-Transplant cyclophosphamide (PTCy) plus tacrolimus (TAC) for GVHD prophylaxis (n=39)
Intervention
Matched related donor (MRD) transplantation (n=17)
Comparison
Matched unrelated donor (MUD) transplantation (n=22)
Outcome
The cumulative incidences of grades II-IV and III-IV acute GVHD at 100 days post-transplantation were 18% and 5.9%, respectively, in the MRD group, and 18% and 9.1%, respectively, in the MUD group. The cumulative incidences of moderate to severe chronic GVHD at 1 year were 12% and 9.1% in the MRD and MUD groups, respectively. The 1-year overall survival rates in the MRD and MUD groups were 88% and 64%, respectively, and the 1-year GVHD-free, relapse free survival rates were 59% and 50%, respectively.
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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.