The Impact of Female-To-Male Allogeneic Hematopoietic Cell Transplantation on Survival Outcomes Varies by Recipient...

Sex-mismatched allogeneic hematopoietic cell transplantation (allo-HCT), particularly with female donors and male recipients (FtoM), is known to be associated with an increased risk of chronic graft-versus-host disease (GVHD) and nonrelapse mortality (NRM). This adverse effect of FtoM allo-HCT is considered to result from allo-immunity against Y-chromosome antigens. However, it has not been elucidated whether the adverse impact of FtoM allo-HCT varies by recipient age. This study aims to examine the effect of sex-mismatch on clinical outcomes in allo-HCT from human leukocyte antigen (HLA)-matched donors, stratified by recipient age group. Using a Japanese transplantation registry database, we analyzed 10392 patients (n = 2169, 2573, and 5650 in FtoM, MtoF, and sex-matched allo-HCT, respectively) with standard-risk hematological malignancies who had undergone their first allo-HCT from HLA-matched related or unrelated donors without in vivo T-cell depletion between 2008 and 2022. The impact of sex-mismatch on clinical outcomes was separately assessed by recipient age groups: ≤15, 16-39, and ≥40 years. The primary endpoint was overall survival (OS). Secondary endpoints included disease-free survival, NRM, and the cumulative incidences of acute and chronic GVHD. In recipients aged ≥40 years, OS and NRM at 5 years post-HCT were significantly worse in the FtoM group compared with the MtoF and sex-matched groups (5-year OS 49.5% versus 59.6% versus 57.1%, P < .001; 5-year NRM 27.9% versus 21.9% versus 23.0%, P < .001), while no differences were observed among the FtoM, MtoF, and sex-matched groups in recipients aged ≤ 15 years or 16-39 years. Multivariate analyses confirmed that FtoM allo-HCT was significantly associated with increased mortality only in recipients aged ≥ 40 years (hazard ratio [HR] for OS 1.31, P < .001; HR for NRM 1.44, P < .001). The FtoM group in recipients aged ≥ 40 years frequently experienced fatal infection and fatal noninfectious pulmonary complications. In addition, we confirmed that the adverse effect of FtoM allo-HCT on OS similarly appeared only in recipients aged ≥ 40 years in both sub-cohorts divided by a median of donor age (40 years). The adverse impact of FtoM allo-HCT on survival outcomes differed according to recipient age. Our findings suggest that female donors should be avoided, especially in older male recipients undergoing allo-HCT.