Reduced relapse in high risk acute myeloid leukemia and myelodysplastic neoplasms with permissive HLA-DPB1 mismatches and post-transplant cyclophosphamide

Disease progression, graft-versus-host disease (GVHD), and non-relapse mortality (NRM) are the main causes of failure after allogeneic hematopoietic cell transplantation (SCT) for myeloid neoplasms. T-cell epitope-based models classify HLA-DPB1 mismatches by permissiveness and have been associated with differential risks of GVHD, relapse, and NRM. However, most studies were conducted before the routine use of post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis for unrelated donor (UD) SCT. We retrospectively analyzed 541 adults undergoing 8/8 UD SCT with PTCy prophylaxis, categorized as DP-matched (DP-M, n = 176), permissive mismatch (DP-P, n = 219), non-permissive graft-versus-host (DP-NP-GVH, n = 82), or host-versus-graft (DP-NP-HVG, n = 64). Outcomes were compared across groups with stratification by disease risk and remission/MRD status. Two-year relapse incidence was lower with DP-P versus DP-M (18% vs 28%; HR 0.6, 95% CI 0.4-0.9, p = 0.03), most pronounced in high-risk AML/MDS, where relapse rates approached those of lower-risk disease. This effect persisted after adjustment for remission and MRD status. GVHD incidence was unaffected by DPB1 status. OS and PFS did not differ significantly; age and comorbidity were dominant predictors of NRM. In UD SCT with PTCy, DPB1-permissive mismatching reduces relapse in high-risk AML/MDS without increasing GVHD or NRM, supporting DP-P mismatching as an actionable donor-selection criterion.