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The role of anti-thymocyte globulin in allogeneic stem cell transplantation (HSCT) from HLA-matched unrelated donors (MUD) for secondary AML in remission: a study from the ALWP /EBMT
Nagler, A., Labopin, M., Kröger, N., Schroeder, T., Gedde-Dahl, T., Eder, M., Franke, G. N., Blau, I. W., Salmenniemi, U., Socie, G., et al
Bone marrow transplantation. 2023
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Editor's Choice
Abstract
We compared outcomes, of 1609 patients with secondary acute myeloid leukemia (sAML) undergoing allogeneic transplantation (HSCT) in first complete remission (CR1) from matched unrelated donors (MUD) from 2010 to 2021, receiving or not receiving anti-thymocyte globulin (ATG) (ATG-1308, no ATG-301). Median age was 60.9 (range, 18.5-77.8) and 61.1 (range, 21.8-75.7) years, (p = 0.3). Graft versus host disease (GVHD) prophylaxis was cyclosporin-A with methotrexate (41%) or mycophenolate mofetil (38.2%), without significant differences between groups. Day 28, engraftment (ANC > 0.5 × 10(9)/L) was 92.3% vs 95.3% (p = 0.17), respectively. On multivariate analysis, ATG was associated with lower incidence of grade II-IV and grade III-IV acute GVHD (p = 0.002 and p = 0.015), total and extensive chronic GVHD (p = 0.008 and p < 0.0001), and relapse incidence (RI) (p = 0.039), while non-relapse mortality (NRM) did not differ (p = 0.51). Overall survival (OS), and GVHD-free, relapse-free survival (GRFS) were significantly higher in the ATG vs no ATG group, HR = 0.76 (95% CI 0.61-0.95, p = 0.014) and HR = 0.68 (95% CI 0.57-0.8, p < 0.0001), with a tendency for better leukemia-free survival (LFS), HR = 0.82 (95% CI 0.67-1, p = 0.051). The main causes of death were the original disease, infection, and GVHD. In conclusion, ATG reduces GVHD and improves LFS, OS, and GRFS in sAML patients without increasing the RI, despite sAML being a high-risk disease.
PICO Summary
Population
Adults with secondary acute myeloid leukemia (sAML) undergoing allogeneic HSCT) in first complete remission from matched unrelated donors and reported to the EBMT registry (n=1609)
Intervention
Anti-thymocyte globulin (ATG) included in GvHD prophylaxis (n=1308)
Comparison
No ATG included in GvHD prophylaxis (n=301)
Outcome
Day 28, engraftment (ANC > 0.5 × 10(9)/L) was 92.3% vs 95.3%, respectively. On multivariate analysis, ATG was associated with lower incidence of grade II-IV and grade III-IV acute GVHD, total and extensive chronic GVHD, and relapse incidence (RI), while non-relapse mortality (NRM) did not differ. Overall survival (OS), and GVHD-free, relapse-free survival (GRFS) were significantly higher in the ATG vs no ATG group, HR = 0.76 (95% CI 0.61-0.95) and HR = 0.68 (95% CI 0.57-0.8), with a tendency for better leukemia-free survival (LFS), HR = 0.82 (95% CI 0.67-1). The main causes of death were the original disease, infection, and GVHD.
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Higher cyclosporine-A concentration increases the risk of relapse in AML following allogeneic stem cell transplantation from unrelated donors using anti-thymocyte globulin
Lisak, M., Nicklasson, M., Palmason, R., Wichert, S., Isaksson, C., Andersson, P. O., Johansson, J. E., Lenhoff, S., Brune, M., Hansson, M.
Scientific reports. 2023;13(1):22777
Abstract
Cyclosporine-A (CsA) is used to prevent acute graft-versus-host disease (aGvHD). European Society for Blood and Marrow transplantation (EBMT) recommends a CsA target serum concentration of 200-300 µg/L during the first month after allogeneic hematopoietic stem cell transplantation (HSCT). With this study, we investigated whether a median CsA concentration > 200 µg/L (CsA(high)) the first month after HSCT, compared to ≤ 200 µg/L (CsA(low)), increased the relapse risk of acute myloid leukemia (AML), using unrelated donors (URD) and antithymocyte globulin (ATG). Data was collected from 157 patients with AML, transplanted 2010-2016. The cumulative incidence of relapse (CIR) at 60 months was 50% in the CsA(high) versus 32% in the CsA(low) group (p = 0.016). In univariate analysis, CsA(high) versus CsA(low) (p = 0.028), 10-unit increase of CsA as a continuous variable (p = 0.017) and high risk disease (p = 0.003) were associated with higher CIR. The results remained after adjusting for disease risk. Death following relapse occurred more frequently in the CsA(high) group (p = 0.0076). There were no significant differences in rates of aGvHD, chronic GvHD (cGvHD), EBV/CMV-infections or overall survival (OS) between the two groups. In conclusion, we found that a median CsA concentration > 200 µg/L, the first month after HSCT, results in higher CIR of AML when combined with ATG.
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GVHD occurrence does not reduce AML relapse following PTCy-based haploidentical transplantation: a study from the ALWP of the EBMT
Baron, F., Labopin, M., Tischer, J., Raiola, A. M., Vydra, J., Blaise, D., Chiusolo, P., Stölzel, F., Fanin, R., Chevallier, P., et al
Journal of hematology & oncology. 2023;16(1):10
Abstract
The association between graft-versus-host disease (GVHD) occurrence and acute myeloid leukemia (AML) relapse in patients treated with HLA-haploidentical allogeneic hematopoietic stem cell transplantation (Haplo-HCT) with post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis has remained debated. Here, we addressed this issue in patients with active AML at transplantation. 2-year cumulative incidences of relapse and leukemia-free survival (LFS) were 49% and 32.3%, respectively. There were no associations between acute nor chronic GVHD of any grade and lower relapse incidence. However, grade I acute GVHD was associated with better LFS (HR = 0.71, 95% CI 0.51-0.99, P = 0.04). In contrast, grade III-IV acute (HR = 3.09, 95% CI 1.87-5.12, P < 0.0001) as well as extensive chronic (HR = 3.3, 95% CI 1.81-6.04, P = 0.0001) GVHD correlated with higher nonrelapse mortality leading to lower LFS (HR = 1.36, 95% CI 0.99-1.86, P = 0.056 and HR = 1.97, 95% CI 1.35-2.89, P = 0.0004, respectively). In conclusion, these data suggest a dissociation of graft-versus-leukemia effects from GVHD in patients with active AML treated with PTCy-based Haplo-HCT.
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Cyclophosphamide with cyclosporine A for graft-versus-host disease prophylaxis in adult patients with acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation from human leucocyte antigen-matched donors
Sharaf El-Deen, M. O., Soliman, M. M., Al-Azab, G., Samra, M., Shams, M. E. E.
International immunopharmacology. 2023;120:110374
Abstract
BACKGROUND Graft-versus-host disease (GVHD) is one of the most severe complications in patients with acute myeloid leukemia (AML) who underwent allogenic hematopoietic stem cell transplantation (HSCT). This study addressed the effectiveness and safety outcomes of high dose post-transplant cyclophosphamide (PT-CY) followed by cyclosporine A (CSA) as a GVHD prophylaxis protocol. PATIENTS AND METHODS From January 2019 to March 2021, AML patients who underwent HSCT, and received high-dose PT-CY followed by CSA were prospectively recruited, assessed, and followed up for one-year post-transplantation (PT). The cumulative incidences of both acute GVHD (aGVHD) at 100 days PT, and chronic GVHD (cGVHD) at one-year PT were assessed. RESULTS This study included 52 patients. The cumulative incidence (95% CIs) of aGVHD was 2.3% (0.3 - 15.4%), while the cumulative incidence of cGVHD was 23.2% (12.2-41.5%). The cumulative incidence of relapse and non-relapse mortality were 15.6%, and 7.9%, respectively. The median duration to reach neutrophil and platelet engraftment was 17 and 13 days, respectively. The overall, progression-free, and GVHD-free/relapse-free survival rates (95% CIs) were 89.6% (76.6 - 95.6%), 77.7% (62.1-87.5%), and 58.2% (41.6 - 71.7%) respectively. The cumulative incidences of the main transplant-related complications were; neutropenic sepsis (48.3%), cytomegalovirus reactivation (21.7%), pneumonia (13.8%), hemorrhagic cystitis (17.8%), septic shock (4.9%), and CSA toxicity (48.9%). CONCLUSION PT-CY followed by CSA was associated with low cumulative incidences of both aGVHD and cGVHD without increase in either the relapse or transplant-related complications; so, considered as a promising protocol to be widely applied in the settings of HLA-matched donors.
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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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Free full text
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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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Impact of the Addition of Antithymocyte Globulin to Post-Transplantation Cyclophosphamide in Haploidentical Transplantation with Peripheral Blood Compared to Post-Transplantation Cyclophosphamide Alone in Acute Myelogenous Leukemia: A Retrospective Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Battipaglia, G., Labopin, M., Blaise, D., Diez-Martin, J. L., Bazarbachi, A., Vitek, A., Chevallier, P., Castagna, L., Grillo, G., Daguindau, E., et al
Transplantation and cellular therapy. 2022;28(9):587.e1-587.e7
Abstract
The use of haploidentical hematopoietic cell transplantation (haplo-HCT) with peripheral blood stem cells (PBSCs) to treat acute myelogenous leukemia (AML) is increasing. We explored whether the addition of antithymocyte globulin (ATG) to post-transplantation cyclophosphamide (PTCy) allows better outcomes compared with PTCy alone in haplo-HCT with PBSCs (haplo-PBSCT). We included 441 adult patients undergoing a first haplo-PBSCT for AML in first or second complete remission; graft-versus-host disease (GVHD) prophylaxis contained either PTCy alone (n = 374) or ATG plus PTCy (n = 67), in addition to cyclosporine A (CsA) and mycophenolate mofetil (MMF) as other immunosuppressive agents. All transplantations were performed between 2011 and 2019. No major imbalances were observed between the 2 groups. For both groups, the median patient age was 56 years, and the median year of haplo-PBSCT was 2017. Most patients received a reduced-intensity conditioning regimen (57% in the PTCy group and 61% in the ATG+PTCy group; P = .54). The median follow-up was 19 months in the PTCy group versus 15 months in the ATG+PTCy group (P = .59), and the rate of neutrophil engraftment in the 2 groups was 97% and 98%, respectively. In univariate analysis, there were no statistical differences in transplantation outcomes between the 2 groups. In multivariate analysis, ATG+PTCy was associated with a lower risk of chronic GVHD compared with PTCy alone (hazard ratio, .46; 95% confidence interval, .23 to .93; P = .03). No between-group differences in the other transplantation outcomes were seen. In haplo-PBSCT, the addition of ATG to PTCy (with CsA and MMF) is feasible and better at preventing chronic GVHD and is associated with survival and transplantation outcomes comparable to those with PTCy alone, without increasing transplantation toxicity, mortality, or relapse incidence.
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Post-transplant cyclophosphamide and sirolimus based graft-versus-host disease prophylaxis after allogeneic stem cell transplantation for acute myeloid leukemia
Lazzari, L., Balaguer-Roselló, A., Montoro, J., Greco, R., Hernani, R., Lupo-Stanghellini, M. T., Villalba, M., Giglio, F., Facal, A., Lorentino, F., et al
Bone marrow transplantation. 2022
Abstract
Post-transplant cyclophosphamide (PTCy) has emerged as a promising graft-versus-host disease (GvHD) prophylaxis in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, no studies have reported the efficacy of a GvHD prophylaxis based on PTCy with sirolimus (Sir-PTCy) in patients with acute myeloid leukemia (AML). In this retrospective study, we analyze the use of sirolimus in combination with PTCy, with or without mycophenolate mofetil (MMF), on 242 consecutive adult patients with AML undergoing a myeloablative first allo-HSCT from different donor types, in three European centers between January 2017 and December 2020. Seventy-seven (32%) patients received allo-HSCT from HLA-matched sibling donor, 101 (42%) from HLA-matched and mismatched unrelated donor, and 64 (26%) from haploidentical donor. Except for neutrophil and platelet engraftment, which was slower in the haploidentical cohort, no significant differences were observed in major transplant outcomes according to donor type in univariate and multivariate analysis. GvHD prophylaxis with Sir-PTCy, with or without MMF, is safe and effective in patients with AML undergoing myeloablative allo-HSCT, resulting in low rates of transplant-related mortality, relapse/progression, and acute and chronic GvHD in all donor settings.
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Post-transplant cyclophosphamide after HLA identical compared to Haploidentical donor transplant in Acute Myeloid Leukemia: a study on behalf of GETH-TC
Bailén, R., Pascual-Cascón, M. J., Guerreiro, M., López-Corral, L., Chinea, A., Bermúdez, A., Sampol, A., Heras, I., García-Torres, E., Torres, M., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Post-transplant cyclophosphamide (PTCY) effectively prevents graft-versus-host disease (GVHD) after unmanipulated HLA-haploidentical hematopoietic stem cell transplantation (HSCT) and achieves low rates of GVHD in HLA identical transplantation. OBJECTIVE To compare the outcomes of haploidentical versus HLA identical HSCT in patients undergoing HSCT for acute myeloid leukemia (AML) using PTCY. STUDY DESIGN We conducted a retrospective study of 229 patients undergoing first HSCT for AML using PTCY with additional immunosuppression, 99 from matched sibling or unrelated donor (MSD/MUD) performed in 3 hospitals and 130 from haploidentical donors (haplo group) performed in 20 hospitals within the Spanish Group of Hematopoietic Stem Cell Transplantation and Cellular Therapy (GETH-TC). RESULTS Peripheral blood stem cells were used as graft in 89% of patients; myeloablative conditioning was used in 56%. There were significantly more patients with active disease (5% vs. 20%, p = 0.001), high/very high DRI (32% vs. 67%, p = 0.000) and prior auto-HSCT (2% vs. 11%, p = 0.010) in the haplo group. Median follow-up was 27 and 62.5 months for MSD/MUD and haplo, respectively. At 2 years, no significant differences were observed in overall survival (OS) (72% vs. 62%, p = 0.07), event-free survival (EFS) (70% vs. 54%, p = 0.055), cumulative incidence of relapse (19% vs. 25%, p = 0.13), non-relapse mortality (14% vs. 19%, p = 0.145) and the composite endpoint of GVHD and relapse-free survival (GRFS) (49% vs. 42%, p = 0.249). Multivariate analysis identified only age and active disease as significant risk factors for OS and EFS; reduced intensity conditioning, high/very high DRI and haplo donor were nearly statistically significant for these outcomes. Grade II-IV acute GVHD was lower in MSD/MUD (14% vs. 47%, p = 0.000). Cumulative incidences of grade III-IV acute GVHD (4% vs. 9%, p = 0.14) and moderate-severe chronic GVHD (22% vs. 19%, p = 0.28) were similar. Limitations of our study include limited sample size, differences between haplo and MSD/MUD groups and heterogeneous additional immunosuppression and PTCY timing in MSD/MUD. CONCLUSIONS The use of a HLA identical donor with PTCY in patients with AML showed lower incidence of clinically significant grade II-IV acute GVHD compared to haplo donors. Further studies with larger sample size should be performed to establish a possible benefit of HLA identical donor on survival.
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Modified combination of anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) as compared with standard ATG protocol in haploidentical peripheral blood stem cell transplantation for acute leukemia
Barkhordar, M., Kasaeian, A., Janbabai, G., Kamranzadeh Fumani, H., Tavakoli, S., Rashidi, A. A., Mousavi, S. A., Ghavamzadeh, A., Vaezi, M.
Frontiers in immunology. 2022;13:921293
Abstract
In haploidentical peripheral blood stem cell transplantation (haplo-PBSCT), the combination of anti-thymocyte globulin and post-transplant cyclophosphamide (ATG/PTCy) has a synergistic impact in preventing graft-versus-host disease (GvHD). However, little is known about the long-term consequences of the new combination approach. Our goal is to evaluate the efficacy of ATG/PTCy versus a standard ATG regimen by focusing at long-term outcomes in a more homogeneous group of patients. We retrospectively included 118 adult patients up to 60 years with acute leukemia who underwent haplo-PBSCT at our single institution, following the same myeloablative conditioning regimen. From 2010 to 2020, 78 patients received a modified combination of ATG (2.5 mg/kg/day, on days -3, -2, and -1) and PTCy (40 mg/kg/day on days +3 and +4) compared to 40 patients who had a standard ATG-based regimen (2.5 mg/kg/day from days -4 to -1) from 2008 to 2015. The median follow-up time for all patients was 5.36 years, respectively. The cumulative incidence (CI) of neutrophil and platelet engraftment, as well as CMV reactivation, did not differ statistically between the two groups. The CI of the acute GvHD of grades II-IV and III-IV and extensive chronic GvHD were considerably lower in the ATG/PTCy (34.6%, 8.97%, and 13.63%) than in the ATG cohort (57.5%, 30%, and 38.23%) as validated by multivariable modeling. Additionally, compared to the ATG arm, the ATG/PTCy was a hazard factor associated with a higher risk of relapse (HR = 2.23, p = 0.039). The probability of 5-year overall survival, disease-free survival, and GvHD-free relapse-free survival in the ATG/PTCy group (53.34%, 49.77%, and 36.04%) was comparable with the ATG group (47.5%, 42.5%, and 22.5%), respectively. Our finding suggested that a modified ATG/PTCy combination resulted in a lower risk of acute and chronic GvHD and a higher risk of relapse than the standard ATG-based protocol but had no effect on long-term outcomes. However, certain adjustments in the immunosuppression protocol are warranted to improve the outcome.