Comparison of post‐transplant cyclophosphamide and low‐dose anti‐thymocyte globulin with dose‐dependent effects in mismatched unrelated donor transplantation

Comparison of post-transplant cyclophosphamide and low-dose anti-thymocyte globulin with dose-dependent effects in mismatched unrelated donor transplantationTo the Editor, Human leucocyte antigen (HLA)-mismatched unrelated donor (MMUD) transplantation is an important therapeutic option for patients with haematological malignancies who lack a suitable related donor.Although rabbit anti-thymocyte globulin (ATG) has been widely used to reduce graft-versushost disease (GVHD) and non-relapse mortality (NRM) in MMUD transplantation, 1-3 the optimal ATG dose remains unclear.Recently, post-transplant cyclophosphamide (PTCY) has been increasingly adopted because of its favourable outcomes in the MMUD setting.4,5 Retrospective studies have suggested that PTCY-based prophylaxis is associated with lower incidences of GVHD and NRM, as well as superior GVHD-free, relapse-free survival (GRFS), compared with ATG-based prophylaxis.[6][7][8][9][10][11][12] However, these studies evaluated ATG doses ranging from 4.5 to 10 mg/kg, and no study has directly compared PTCY with low-dose ATG in the MMUD setting.Furthermore, the impact of ATG dose on transplantation outcomes has not been well established.Therefore, we used a nationwide registry database to compare outcomes between PTCY-based prophylaxis and low-dose ATG-based prophylaxis and to investigate the dose-dependent effects of ATG in MMUD transplantation.We analysed data from the registry database of the Japan Society for Transplantation and Cellular Therapy and the Japanese Data Center for Hematopoietic Cell Transplantation.13,14 Adult patients (age ≥16 years) who underwent allogeneic haematopoietic stem cell transplantation HSCT between 2015 and 2022 for haematological malignancies from unrelated donors with at least one HLA mismatch among HLA-A, -B, -C and -DR were included.Eligible patients received GVHD prophylaxis with either PTCY or rabbit ATG (Thymoglobulin®).Patients who received both PTCY and ATG or underwent in vivo T-cell depletion other than Thymoglobulin® were excluded.The study end-points included cumulative incidence of acute and chronic GVHD, relapse, NRM, infectious events, GRFS and overall survival (OS).Outcomes were compared between the PTCY and ATG groups using multivariable analyses in the overall cohort and a propensity scorematched analysis.Details of the statistical analyses are provided in the Supporting Information.A total of 1228 patients were included in the analysis (PTCY group, n = 53; ATG group, n = 1175) (Table S1).Compared with the ATG group, patients in the PTCY group had significantly older donors, more frequent peripheral blood stem cell (PBSC) grafts and less frequent use of total body irradiation (TBI) ≥8 Gy-containing regimens.Significant differences were also observed between the two groups in cytomegalovirus (CMV) prophylaxis strategies, concomitant GVHD prophylaxis regimens, transplant year and follow-up duration.The median total dose of PTCY was 100 mg/kg, whereas the median total dose of ATG was 2.5 mg/kg.Among patients who received ATG, higher dose groups were characterized by younger patient age, more frequent use of bone marrow (BM) grafts and HLA ≤6/8 allelematch donors (Table S2).Multivariable analyses were conducted in the overall cohort after stratifying patients into four groups: PTCY (n = 53), ATG <2.0 mg/kg (n = 262), ATG 2.0-2.5 mg/kg (n = 706) and ATG >2.5 mg/kg (n = 74).All ATG dose groups were associated with a significantly higher risk of grade II-IV and grade III-IV acute GVHD compared with the PTCY group (Figure 1A,B and Table 1).ATG dose was not associated with the incidence of acute GVHD.In contrast, an ATG dosedependent trend was observed for chronic GVHD, with a lower incidence at higher ATG doses.The 1-year cumulative incidences of chronic GVHD were 16%, 34%, 25% and 15% in the PTCY, ATG <2.0 mg/kg, ATG 2.0-2.5 mg/kg and ATG >2.5 mg/kg groups respectively (p < 0.001).In multivariable analyses, the ATG <2.0 mg/kg group was associated with a significantly higher risk of chronic GVHD compared with the PTCY group.However, the risk of chronic GVHD in the ATG >2.5 mg/kg group was comparable to that in the PTCY group (Figure 1C,D, and Table 1).There were no significant differences among the groups in relapse, NRM, GRFS or OS (Figure 1E-H and Table 1).The ATG >2.5 mg/kg group showed a trend towards higher NRM, whereas the ATG