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Post-transplant Cyclophosphamide in Acute Leukemia Patients Receiving more than 5/10 HLA-Mismatched Allogeneic Hematopoietic Cell Transplantation from Related Donors: a Study on behalf of the ALWP of the EBMT
Wieczorek, M., Labopin, M., Castagna, L., Brissot, E., Socié, G., Raiola, A. M., Angelucci, E., Bermúdez Rodríguez, A., Yakoub-Agha, I., Aljurf, M., et al
American journal of hematology. 2022
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Should anti-thymocyte globulin be added in post-transplant cyclophosphamide based matched unrelated donor peripheral blood stem cell transplantation for acute myeloid leukemia? A study on behalf of the Acute Leukemia Working Party of the EBMT
Spyridonidis, A., Labopin, M., Brissot, E., Moiseev, I., Cornelissen, J., Choi, G., Ciceri, F., Vydra, J., Reményi, P., Rovira, M., et al
Bone marrow transplantation. 2022
Abstract
In this registry-based study which includes acute myeloid leukemia patients who underwent a matched unrelated donor allogeneic peripheral-blood stem cell transplantation in complete remission and received post-transplant cyclophosphamide (PTCY) as graft-versus-host disease (GvHD) prophylaxis, we compared 421 recipients without anti-thymocyte globulin (ATG) with 151 patients with ATG. The only significant differences between PTCY and PTCY + ATG cohorts were the median year of transplant and the follow-up period (2017 vs 2015 and 19.6 vs 31.1 months, respectively, p < 0.0001). Overall, 2-year survival was 69.9% vs 67.1% in PTCY and PTCY + ATG, respectively, with deaths related to relapse (39% vs 43.5%), infection (21.9% vs 23.9%) or GvHD (17.1% vs 17.4%) not differing between groups. On univariate comparison, a significantly lower rate of extensive chronic GvHD was found when ATG was added (9.9% vs 21%, p = 0.029), a finding which was not confirmed in the multivariate analysis. The Cox-model showed no difference between PTCY + ATG and PTCY alone with respect to acute and chronic GvHD of all grades, non-relapse mortality, relapse, leukemia-free survival, overall survival, and GvHD-free-relapse-free survival between study cohorts. Our results highlight that the addition of ATG in PTCY does not provide any extra benefit in terms of further GvHD reduction, better GRFS or better survival.
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ATG in HLA-matched, peripheral blood, hematopoietic cell transplantation in acute myeloid leukemia and myelodysplastic syndrome: a secondary analysis of a CIBMTR database
Arcuri, L. J., Kerbauy, M. N., Kerbauy, L. N., Santos, F. P. S., Ribeiro, A. A. F., Hamerschlak, N.
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
BACKGROUND Peripheral blood stem cells (PBSC) are the preferred grafts for hematopoietic cell transplantation (HCT), according to the CIBMTR. Donor recovery is faster with PBSC harvest, but PBSC is associated with higher chronic graft-versus-host disease (GVHD) and poorer quality of life. Anti-T cell globulin (ATG) is polyclonal IgG from rabbits or horses immunized with human thymocytes or a human T-cell line which may reduce graft-versus-host disease in HCT and improve outcomes. OBJECTIVE The objective of this study was to analyze the impact of ATG in HLA-matched Related (MRD) and matched (HLA 8/8) unrelated donor (MUD) HCT. STUDY DESIGN We used a freely available CIBMTR database published online for secondary analyses. The database included patients ≥ 40 y/o who have undergone their first PBSC MRD or MUD HCT for acute myeloid leukemia or myelodysplastic syndrome with or without ATG between 2008 and 2017. Patients who received posttransplant cyclophosphamide or alemtuzumab were excluded. RESULTS Overall survival was not different with ATG (HR = 1.09, 95CI 1.00-1.19, p = 0.06) compared with no ATG. Relapse rate was higher with ATG (HR = 1.29, 95CI 1.17-1.43, p < 0.001) and NRM was lower with ATG (HR = 0.84, 95CI 0.72-0.98, p = 0.03). Grades II-IV acute GVHD was significantly lower with ATG (HR = 0.77, 95CI 0.69-0.87, p < 0.001) but not grades III-IV acute GVHD (HR = 0.85, 95CI 0.69-1.04, p = 0.11). Both chronic GVHD (HR = 0.54, 95CI 0.48-0.60, p < 0.001) and moderate/severe chronic GVHD (HR = 0.45, 95CI 0.38-0.52, p < 0.001) were lower with ATG. There was an interaction between ATG and conditioning regimen for relapse rate and overall survival. Relapse rate was higher in those who received reduced-intensity (RIC) or non-myeloablative (NMA) conditioning regimens and ATG, compared with MAC ± ATG or RIC without ATG (interaction test, p = 0.003). Overall survival was also poorer with ATG and RIC or NMA conditioning regimens (interaction test, p = 0.03). CONCLUSION Our results show that ATG can mitigate the more severe forms of chronic GVHD without impairing overall survival in HLA-matched HCT with PBSC grafts and myeloablative conditioning regimen. ATG should be standard in this population.
PICO Summary
Population
Adults over 40 years drawn from the CIBMTR database, undergoing first peripheral blood stem cell transplant from matched related donor or matched unrelated donor for acute myeloid leukemia or myelodysplastic syndrome with or without ATG (n=4320)
Intervention
Received Anti-T cell globulin (ATG) prophylaxis (n=1007)
Comparison
Received no ATG prophylaxis (n=3313)
Outcome
Overall survival was not different with ATG (HR = 1.09, 95CI 1.00-1.19) compared with no ATG. Relapse rate was higher with ATG (HR = 1.29, 95CI 1.17-1.43) and non-relapse mortality was lower with ATG (HR = 0.84, 95CI 0.72-0.98). Grades II-IV acute GVHD was significantly lower with ATG (HR = 0.77, 95CI 0.69-0.87) but not grades III-IV acute GVHD (HR = 0.85, 95CI 0.69-1.04). Both chronic GVHD (HR = 0.54, 95CI 0.48-0.60) and moderate/severe chronic GVHD (HR = 0.45, 95CI 0.38-0.52) were lower with ATG. Relapse rate was higher in those who received reduced-intensity (RIC) or non-myeloablative (NMA) conditioning regimens and ATG, compared with myeloablative conditioning with or without ATG or RIC without ATG. Overall survival was also poorer with ATG and RIC or NMA conditioning regimens.
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Graft-Versus-Host Disease Prophylaxis with Post-Transplantation Cyclophosphamide versus Cyclosporine A and Methotrexate in Matched Sibling Donor Transplantation
Nagler, A., Labopin, M., Dholaria, B., Wu, D., Choi, G., Aljurf, M., Ciceri, F., Gedde-Dahl, T., Meijer, E., Niittyvuopio, R., et al
Transplantation and cellular therapy. 2021
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Editor's Choice
Abstract
Cyclosporine A and methotrexate (CSA/MTX) is the standard graft-versus-host disease (GVHD) prophylaxis regimen for matched sibling donor (MSD) allogeneic hematopoietic cell transplantation (allo-HCT). Recently, post-transplant cyclophosphamide (PTCy) has been shown to be effective in GVHD prevention. In this registry-based study, we compared outcomes of 118 patients with PTCy and 1202 patients with CSA/MTX who underwent MSD allo-HCT for acute myeloid leukemia (AML). In a matched-pair analysis, PTCy was associated with a higher incidence of relapse at 2-year (41.1% versus 21.3%, p=0.039) compared to CSA/MTX. The incidence of day 180 grade II-IV acute GVHD (25.2% versus 25.4%, p=0.90) and 2-year chronic GVHD (42.6% versus 42.6%, p=0.84) were comparable between PTCy and CSA/MTX, respectively. Similarly, 2-year leukemia-free survival (LFS, 54.4% versus 74.32%, p=0.052), overall survival (OS, 70.6% versus 79.7%, p=0.15) and GVHD-free-relapse-free survival (GRFS, 38.1% versus 52.5%, p=0.49) were not statistically different between PTCy versus CSA/MTX. In conclusion, GVHD prophylaxis with PTCy is feasible, resulting in similar incidences of GVHD, GRFS, LFS, and OS compared to conventional CSA/MTX in patients undergoing allo-HCT from MSD. The higher relapse observed with PTCy needs further evaluation in a prospective study.
PICO Summary
Population
Patients who underwent matched sibling donor (MSD) allogeneic transplant for acute myeloid leukemia, (AML) reported to the EBMT registry (n=1320)
Intervention
Post-transplant cyclophosphamide (PTCy, n=118)
Comparison
Cyclosporine A and methotrexate (CSA/MTX, n=1202)
Outcome
In a matched-pair analysis, PTCy was associated with a higher incidence of relapse at 2-year (41.1% versus 21.3%) compared to CSA/MTX. The incidence of day 180 grade II-IV acute GVHD (25.2% versus 25.4%) and 2-year chronic GVHD (42.6% versus 42.6%) were comparable between PTCy and CSA/MTX, respectively. Similarly, 2-year leukemia-free survival (LFS, 54.4% versus 74.32%), overall survival (OS, 70.6% versus 79.7%) and GVHD-free-relapse-free survival (GRFS, 38.1% versus 52.5%) were not statistically different between PTCy versus CSA/MTX. In conclusion, GVHD prophylaxis with PTCy is feasible, resulting in similar incidences of GVHD, GRFS, LFS, and OS compared to conventional CSA/MTX in patients undergoing allo-HCT from MSD. The higher relapse observed with PTCy needs further evaluation in a prospective study.
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Post-transplant cyclophosphamide containing regimens after matched sibling, matched unrelated and haploidentical donor transplants in patients with acute lymphoblastic leukemia in first complete remission, a comparative study of the ALWP of the EBMT
Sanz, J., Galimard, J. E., Labopin, M., Afanasyev, B., Sergeevich, M. I., Angelucci, E., Kröger, N., Koc, Y., Ciceri, F., Diez-Martin, J. L., et al
Journal of hematology & oncology. 2021;14(1):84
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Editor's Choice
Abstract
BACKGROUND There is no information on the impact of donor type in allogeneic hematopoietic stem cell transplantation (HCT) using homogeneous graft-versus-host (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCy) in acute lymphoblastic leukemia (ALL). METHODS We retrospectively analyzed outcomes of adult patients with ALL in CR1 that had received HCT with PTCy as GVHD prophylaxis from HLA-matched sibling (MSD) (n?=?78), matched unrelated (MUD) (n?=?94) and haploidentical family (Haplo) (n?=?297) donors registered in the EBMT database between 2010 and 2018. The median follow-up period of the entire cohort was 2.2 years. RESULTS Median age of patients was 38 years (range 18-76). Compared to MSD and MUD, Haplo patients received peripheral blood less frequently. For Haplo, MUD, and MSD, the cumulative incidence of 100-day acute GVHD grade II-IV and III-IV, and 2-year chronic and extensive chronic GVHD were 32%, 41%, and 34% (p?=?0.4); 13%, 15%, and 15% (p?=?0.8); 35%, 50%, and 42% (p?=?0.01); and 11%, 17%, and 21% (p?=?0.2), respectively. At 2 years, the cumulative incidence of relapse and non-relapse mortality was 20%, 20%, and 28% (p?=?0.8); and 21%, 18%, and 21% (p?=?0.8) for Haplo, MUD, and MSD, respectively. The leukemia-free survival, overall survival and GVHD-free, relapse-free survival for Haplo, MUD, and MSD was 59%, 62%, and 51% (p?=?0.8); 66%, 69%, and 62% (p?=?0.8); and 46%, 44%, and 35% (p?=?0.9), respectively. On multivariable analysis, transplant outcomes did not differ significantly between donor types. TBI-based conditioning was associated with better LFS. CONCLUSIONS Donor type did not significantly affect transplant outcome in patient with ALL receiving SCT with PTCy.
PICO Summary
Population
Adults with acute lymphoblastic leukaemia (ALL) receiving allogeneic transplant in CR1 with prophylaxis with post-transplant cyclophosphamide (PTCy) prophylaxis (n=469)
Intervention
Haploidentical transplantation (n=297)
Comparison
Matched unrelated donor (MUD, n=94); matched sibling donor (MSD, n=78)
Outcome
Median age of patients was 38 years (range 18-76). Compared to MSD and MUD, Haplo patients received peripheral blood less frequently. For Haplo, MUD, and MSD, the cumulative incidence of 100-day acute GVHD grade II-IV and III-IV, and 2-year chronic and extensive chronic GVHD were 32%, 41%, and 34%; 13%, 15%, and 15%; 35%, 50%, and 42%; and 11%, 17%, and 21%, respectively. At 2 years, the cumulative incidence of relapse and non-relapse mortality was 20%, 20%, and 28% and 21%, 18%, and 21% for Haplo, MUD, and MSD, respectively. The leukemia-free survival, overall survival and GVHD-free, relapse-free survival for Haplo, MUD, and MSD was 59%, 62%, and 51%; 66%, 69%, and 62%; and 46%, 44%, and 35%, respectively. On multivariable analysis, transplant outcomes did not differ significantly between donor types. TBI-based conditioning was associated with better leukaemia free survival.
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Post-transplantation cyclophosphamide GvHD prophylaxis after hematopoietic stem cell transplantation from 9/10 or 10/10 HLA-matched unrelated donors for acute leukemia
Lorentino, F., Labopin, M., Ciceri, F., Vago, L., Fleischhauer, K., Afanasyev, B., Kroger, N., Cornelissen, J. J., Lovira, M., Meijer, E., et al
Leukemia. 2020
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Editor's Choice
Abstract
HLA-matching largely contributes to unrelated donor hematopoietic cell transplantation (UD-HCT) success but, due to the selective deletion of alloreactive T-cells, post-transplantation cyclophosphamide (PTCy) could modulate its negative impact on outcomes. We retrospectively compared acute leukemia patients receiving 10/10 or 9/10 HLA allele-matched UD-HCT with PTCy-GvHD prophylaxis between 2010 and 2017, reported to EBMT registry. The 100-day incidence of grade ≥2 and grade ≥3 aGvHD were comparable for 10/10 and 9/10 UD (28% versus 28%, p = 0.8 and 10% versus 8%, p = 0.5, respectively). The 2-year cGvHD and extensive cGvHD were similar between 10/10 and 9/10 UD (35% versus 44%, p = 0.2 and 21% versus 20%, p = 0.6, respectively). The 2-year nonrelapse mortality was 20% after 10/10 and 16% after 9/10 UD-HCT (p = 0.1). Relapse incidence at 2-year was 24% for 10/10 and 28% for 9/10 UD-HCT (p = 0.4). Leukemia-free survival at 2-year was the same for 10/10 and 9/10 UD (56 and 56%, p = 0.6, respectively), with comparable overall survival (62 and 59%, p = 0.9, respectively). Multivariate analysis showed no effect of HLA-matching on outcomes. An advanced disease status and patient disability remained the most important factors portending a worse survival. PTCy could alleviate the detrimental effect of HLA-allele mismatching in UD-HCT, potentially expanding the donor pool for acute leukemia patients.
PICO Summary
Population
Acute leukemia patients receiving unrelated donor HSCT with PTCy-GvHD prophylaxis between 2010 and 2017 reported to EBMT registry (n=464)
Intervention
10/10 allele-matched unrelated donor (n=305)
Comparison
9/10 allele-matched unrelated donor (n=159)
Outcome
The 100-day incidence of grade >/=2 and grade >/=3 aGvHD were comparable for 10/10 and 9/10 UD (28% versus 28% and 10% versus 8%, respectively). The 2-year cGvHD and extensive cGvHD were similar between 10/10 and 9/10 UD (35% versus 44%, and 21% versus 20%, respectively). The 2-year nonrelapse mortality was 20% after 10/10 and 16% after 9/10 UD-HCT. Relapse incidence at 2-year was 24% for 10/10 and 28% for 9/10 UD-HCT. Leukemia-free survival at 2-year was the same for 10/10 and 9/10 UD (56 and 56%, respectively), with comparable overall survival (62 and 59%, respectively). Multivariate analysis showed no effect of HLA-matching on outcomes. An advanced disease status and patient disability remained the most important factors portending a worse survival.
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Comparison of the clinical outcomes of hematologic malignancies after myeloablative haploidentical transplantation with G-CSF/ATG and posttransplant cyclophosphamide: results from the Chinese Bone Marrow Transplantation Registry Group (CBMTRG)
Tang, F., Xu, Y., Chen, H., Xu, L., Zhang, X., Wang, Y., Liu, Q., Wu, D., Huang, X.
Science China. Life sciences. 2019
Abstract
This study compared G-CSF/ATG and PTCy in myeloablative haploidentical hematopoietic stem cell transplantation (haplo-HSCT) for hematologic malignancies between January 2013 and March 2018 reporting to the Chinese Bone Marrow Transplantation Registry Group (CBMTRG). For each PTCy, G-CSF/ATG subjects (1:4) were selected using the nested case-pair method. In total, 220 patients including 176 in G-CSF/ATG group and 44 in PTCy group were analyzed. The incidences of 30-day neutrophil engraftment (88.6% vs. 96.6%, P=0.001), 90-day platelet engraftment (84.1% vs. 94.2%, P=0.04), the median time to neutrophil engraftment (17 days vs. 12 days, P=0.000) and platelet engraftment (22 days vs. 17 days, P=0.001) were significantly inferior in PTCy group. The incidences of grades 2-4 and 3-4 acute graft-versus-host disease (GVHD), chronic GVHD and severe chronic GVHD were comparable. Among G-CSF/ATG and PTCy groups, the 3-year progression-free survival, overall survival, cumulative incidences of nonrelapse mortality and relapse was 74.3% vs. 61% (P=0.045), 78.3% vs. 65.2% (P=0.039), 12% vs. 27.3% (P=0.008), and 14.9% vs. 11.7% (P=0.61), respectively. G-CSF/ATG can achieve better engraftment, PFS and OS, and lower incidence of NRM compared to PTCy in myeloablative haplo-HSCT for hematologic malignancies.
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Impacts of thymoglobulin in patients with acute leukemia in remission undergoing allogeneic HSCT from different donors
Wakamatsu, M., Terakura, S., Ohashi, K., Fukuda, T., Ozawa, Y., Kanamori, H., Sawa, M., Uchida, N., Ota, S., Matsushita, A., et al
Blood advances. 2019;3(2):105-115
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Abstract
Antithymocyte globulin (ATG) is widely used to reduce acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD). To clarify the different impacts of ATG for conditioning across different donor types, we retrospectively analyzed patients with acute leukemia (n = 6617) who underwent hematopoietic stem cell transplantation between 2008 and 2015 with ATG (n = 279) or without ATG (n = 6338). Because thymoglobulin is the only ATG drug approved for GVHD prophylaxis in Japan since September 2008, we included thymoglobulin alone in the present analysis. The survivors' median follow-up time was 1081 days. Patients were categorized into 5 groups: cord blood (CB; n = 1915), matched related donor (n = 1772), 1-antigen mismatched related donor (1-MMRD; n = 225), matched unrelated donor (MUD; n = 1742), and 1-allele mismatched unrelated donor (1-MMUD; n = 963). In multivariate analysis, ATG decreased overall survival (hazard ratio [HR], 1.403; P = .054) and GVHD-free/relapse-free survival (GRFS) (HR, 1.458; P = .053) in association with increased nonrelapse mortality (NRM) (HR, 1.608; P =03) with CB, whereas it improved GRFS (HR, 0.515; P < .01) and decreased grades II to IV aGVHD (HR, 0.576; P < .01), extensive cGVHD (HR, 0.460; P = .02), and NRM (HR, 0.545; P = .03) with 1-MMUD. ATG did not impact survival with 1-MMRD and MUD. The use of ATG in conditioning is beneficial due to the reduction in acute/chronic GVHD without increasing NRM or disease relapse only in 1-MMUD transplantation. On the other hand, ATG is not recommended for CB transplantation.
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A retrospective analysis of haplo-identical HLA-mismatch hematopoietic transplantation without posttransplantation cyclophosphamide for GVHD prophylaxis in patients with adult T-cell leukemia-lymphoma
Yoshimitsu, M., Utsunomiya, A., Fuji, S., Fujiwara, H., Fukuda, T., Ogawa, H., Takatsuka, Y., Ishitsuka, K., Yokota, A., Okumura, H., et al
Bone marrow transplantation. 2018
Abstract
Currently, allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only available curative modality for patients with adult T-cell leukemia-lymphoma (ATL). When used in conjunction with posttransplantation cyclophosphamide (PTCY) for graft-versus-host disease prophylaxis, allo-HCT from an HLA haplo-identical donor yields promising outcomes for many diseases other than ATL. However, appropriate comparisons with other donor sources, especially cord blood and conventional HLA haplo-identical donors, are needed to validate the safety and efficacy of this modality. In this study, we retrospectively evaluated the outcome of allo-HCT without PTCY in patients with ATL registered in the Japan Society for Hematopoietic Cell Transplantation TRUMP database between 1985 and 2015. During that period, 46 patients received allo-HCT without PTCY and survivors were followed for a median of 2316.5 days (range: 220-3884 days). Although the estimated 1- and 5-year overall survival rates of the entire cohort were 34.5% and 17.7%, respectively, the cumulative 1- and 5-year non-ATL mortality rates of 41.3% and 55.8%, respectively, were high. The results of our study will serve as a platform for discussions of the safety and efficacy of haplo-HCT for future clinical trials in patients with ATL.
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10.
Post-transplant cyclophosphamide versus anti-thymocyte globulin as graft- versus-host disease prophylaxis in haploidentical transplant
Ruggeri, A., Sun, Y., Labopin, M., Bacigalupo, A., Lorentino, F., Arcese, W., Santarone, S., Gulbas, Z., Blaise, D., Messina, G., et al
Haematologica. 2017;102(2):401-410
Abstract
Severe graft-versus-host disease is a major barrier for non-T-cell-depleted haploidentical stem cell transplantation. There is no consensus on the optimal graft-versus-host disease prophylaxis. This study compared the two most commonly used graft-versus-host disease prophylaxis regimens (post-transplant cyclophosphamide-based vs. the anti-thymocyte globulin-based) in adults with acute myeloid leukemia reported to the European Society for Blood and Bone Marrow Transplantation. A total of 308 patients were analyzed; 193 received post-transplant cyclophosphamide-based regimen and 115 anti-thymocyte globulin-based regimen as anti-graft-versus-host disease prophylaxis. The post-transplant cyclophosphamide-based regimen was more likely to be associated to bone marrow as graft source (60% vs. 40%; P=0.01). Patients in the post-transplant cyclophosphamide-based regimen group had significantly less grade 3-4 acute graft-versus-host disease than those in the anti-thymocyte globulin-based group (5% vs. 12%, respectively; P=0.01), comparable to chronic graft-versus-host disease. Multivariate analysis showed that non-relapse mortality was lower in the post-transplant cyclophosphamide-based regimen group [22% vs. 30%, Hazard ratio (HR) 1.77(95%CI: 1.09-2.86); P=0.02] with no difference in relapse incidence. Patients receiving post-transplant cyclophosphamide-based regimen had better graft-versus-host disease-free, relapse-free survival [HR 1.45 (95%CI: 1.04-2.02); P=0.03] and leukemia-free survival [HR 1.48 (95%CI: 1.03-2.12); P=0.03] than those in the anti-thymocyte globulin-based group. In the multivariate analysis, there was also a trend for a higher overall survival [HR 1.43 (95%CI: 0.98-2.09); P=0.06] for post-transplant cyclophosphamide-based regimen versus the anti-thymocyte globulin-based group. Notably, center experience was also associated with non-relapse mortality and graft-versus-host disease-free, relapse-free survival. Haplo-SCT using a post-transplant cyclophosphamide-based regimen can achieve better leukemia-free survival and graft-versus-host disease-free, relapse-free survival, lower incidence of graft-versus-host disease and non-relapse mortality as compared to anti-thymocyte globulin-based graft-versus-host disease prophylaxis in patients with acute myeloid leukemia.