Donor gender selection and its impact on acute graft-versus-host disease: a systematic review and meta-analysis

Abstract Acute graft-versus-host disease (aGVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Female donor-to-male recipient (F→M) transplantation has long been considered a potential risk factor for GVHD because of immune responses against H-Y antigens, but results from previous studies have been inconsistent, particularly in the era of post-transplant cyclophosphamide. We conducted a systematic review and meta-analysis of cohort studies evaluating grade II-IV aGVHD risk by donor-recipient sex combination. Hazard ratios (HRs) were pooled using random-effects models. Subgroup analyses were conducted based on donor type, PTCy use, and study design. Overall, F→M transplantation was associated with a significantly increased risk of grade II-IV aGVHD compared with other donor-recipient sex combinations (HR = 1.23, 95% CI:1.08–1.39, P = 0.001). Subgroup analysis demonstrated significant associations in matched sibling donor and matched unrelated donor transplantation, whereas no significant association was observed in the haploidentical donor subgroup. In the PTCy‑prophylaxis subgroup, the pooled HR for F→M mismatch was non‑significant (HR = 1.11, 95% CI: 0.90‑1.37, P = 0.33), while the non‑PTCy subgroup showed a significant association (HR = 1.25, 95% CI:1.09‑1.44, P = 0.002); however, the test for subgroup difference was non‑significant ( P = 0.34), providing no statistical evidence that PTCy modifies the association between F→M mismatch and grade II‑IV aGVHD risk. F→M transplantation is associated with a higher risk of grade II-IV aGVHD after allo-HSCT. Numerical differences in point estimates were observed across donor-type and prophylaxis subgroups. Nevertheless, formal subgroup-difference testing did not support effect modification by PTCy, and these subgroup findings should be interpreted cautiously. These findings support considering donor-recipient sex in selection and highlight GVHD prophylaxis’s immunomodulatory role.