Minor Histocompatibility Antigen Mismatches and Graft Versus Host and Relapse in High-Resolution HLA-Matched Allogeneic Hematopoietic Stem Cell Transplantation

In a fully molecular HLA-matched setting, the outcome of allogeneic stem-cell transplantation (allo-SCT) can be affected by mismatches in minor histocompatibility antigens (mHAs) that might impact on the risk of graft-versus-host (GvH) and graft-versus-leukemia (GvL) effects. The association between mHA disparities and outcome was investigated in 96 consecutive patients who underwent myeloablative HLA-matched allo-SCT (from 69 HLA-identical siblings and 27 HLA-matched unrelated donors, all typed and matched at both allelic levels for HLA-A, -B, -Cw, -DRB1, and -DQB1 loci) for standard-risk hematological malignancy (AML n = 41; ALL n = 29; MDS n = 12; CML n = 8; others n = 6). All patients but 9 received bone marrow graft. Allelic mHAg typing was performed by PCR with sequence-specific primers for 9 autosomally encoded mHA and H-Y (PCR-SSP; Spierings et al. PLoS ONE. 2006 Dec 20; 1:e42). The distribution of autosomal mHAs among donor and recipients conformed to the expected frequencies for this population. As expected, the prevalence of mHAg mismatches was higher in unrelated compared to related recipient/donor pairs (p < .003). In univariate analysis, patients who received a graft with more than 2 mHAg mismatches developed more often grade II-IV acute GvH disease (p = .01; HR=2.92 [1.28–6.64]). In multivariate analysis, HA2 mismatch emerged as an independent determinant of acute GvH disease (p = .05; HR = .42). When only mismatches in the GvL/GvH direction were considered, mismatch for HA-1, that is expressed mainly by the hematopoietic system, tended to influence the incidence of both acute and chronic GvH disease (p = .06; HR=1.47 [0.97–2.21] and p = .049; HR = 1.45 [1.00–2.10], respectively) but also to confer a reduced risk of relapse (p = .07; HR = .58 [0.32–1.05]). Mismatch for HA-8, that has a broad tissue distribution, emerged as an independent risk factor of grade II-IV acute GvH disease (p = .02; HR = 1.77 [1.08–2.89]). This study confirms the impact of mHAg mismatches on patients’ outcome after fully HLA-matched allo-SCT and highlights both the cumulative effect of mHAg disparities on outcome and the distinctive contribution of individual mHAs on GvH versus GvL effects of allo-SCT.