Impact of the Donor Recipient Sex Combination in Hematopoietic Stem Cell Transplantation: H-Y as a Model for the Interaction between Major and Minor Histocompatibility Antigens.
Authors: Gratwohl Alois , Stern Martin , Brand Ronald , de Witte Theo , Sureda Anna , Rocha Vanderson , Passweg Jakob , Baldomero Helen , Niederwieser Dietger 
Published: October 2019

Abstract
The importance of minor histocompatibility antigens (miHAg) on outcome in hematopoietic stem cell trans-plantation (HSCT) is well described. H-Y encoded miHAg’s were one of the first to be identified as clinically relevant genetic factors outside HLA. A higher risk of graft-versus-host disease (GvHD) in male recipients of female grafts, specific H-Y directed T-cell responses and antibody reactivity have been documented. As a beneficial effect, a reduced risk of relapse has been observed. Still, the role of H-Y miHAg’s has been disputed in some studies. We studied the effects of the donor recipient sex combination of 63′609 patients (59% male, 41% female, median age 33 years, range 0 to 77 years) with an allogeneic HSCT transplanted between 1980 and 2005 and reported to the EBMT. Main diagnoses were acute leukemias (32′671; 51%), chronic leukemias (15′167; 24%), lymphomas (3901; 6%), plasma cell disorders (1643; 3%), MDS/MPS (5′678; 9%) and aplastic anemia (4459; 7%). Patients were stratified by disease, disease stage (good (55%), intermediate (26%), high risk (19%)), stem cell source (bone marrow (62%), peripheral blood (36%), cord blood (2%)), age (<20 years (27%), 20–40 years (41%), >40 (32%) years), donor age (<20 (21%), >20 (79%) years), conditioning intensity (myeloablative (86%), RIC (14%) and year of transplant. Endpoints analysed were cumulative risks of transplant related mortality (TRM) or relapse (REL) and probability of survival. Results of multivariate analyses are presented. There was a 15% higher relative risk of TRM in male patients receiving a female donor (RMDF) transplant compared to all other gender combinations (RR 1.15; 1.12–1.19). Despite a 9% significant reduction in relapse (RR 0.91; 0.88–0.95), overall survival remained worse (RR 1.08; 1.05–1.11). A higher TRM for RMDF was seen over all calendar years, in all disease categories, disease stages, age classes and with all stem cell sources, with a few distinct exceptions: it was not seen in patients with donors <20 years (RR 0.98; 0.9–1.1), it was not observed in patients with lymphoma (RR 1.06; 0.93–1.20) and it was not observed in the cord blood cohort (RR 0.8; 0.62–1.04). In view of the discordant effects on TRM and REL, the relative impact on survival varied, depending on disease, disease stage and age; e.g., survival was similar in high risk patients for the RMDF and “other” group. Moreover, the higher TRM with RMDF was limited to HLA-identical sibling transplants (RR 1.22; 1.17–1.26) and matched unrelated transplants (RR 1.22; 1.13–1.32). It was neither observed in mismatched related (RR 0.97; 0.87–1.08) nor in mismatched unrelated HSCT (RR 1.03; 0.91–1.18). These data clarify the role of the donor recipient sex combination and form the basis for donor selection algorithms. In addition, they substantiate the close interaction between major and minor histocompatibility antigens: the higher the degree of matching for HLA-antigens, the higher the impact of H-Y difference. It is likely, that the same mechanisms will hold true for other miHAg’s as well.