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BACKGROUND: HLA evolutionary divergence (HED) can be used as a surrogate for the degree of immunopeptidome diversity of HLA phenotypes. Different degrees of HED in the patient-donor pair may influence the presentation of peptides relevant for alloreactive responses involved in graft-versus-host and graft-versus-leukemia (GvL) effects, potentially impacting outcomes after hematopoietic cell transplantation (HCT).OBJECTIVE(S): To test whether higher HED scores (both class I and class II) correlate with improved GvL and survival after HLA-matched HCT.STUDY DESIGN: Pediatric and adult patients (N=9,231) reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) database who underwent a first HCT from 8/8 matched unrelated donors between 2008 and 2018 for the treatment of acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myeloid leukemia, or lymphoma were included. HED was calculated on the amino acid sequences at HLA-A, HLA-B, HLA-C, and HLA-DRB1, and class I (HLA-A, HLA-B, HLA-C), and HLA-DRB1 HED scores were assigned to each patient-donor pair. The association between increasing HED (top quartile vs lower three quartiles) and HCT outcome was evaluated with malignant disease relapse and disease-free (DFS) and overall survival (OS) as primary endpoints. Secondary enpoints were transplant-related mortality (TRM), acute and chronic graft-versus-host disease (GvHD), and engraftment.RESULTS: Greater HLA-DRB1 HED was associated with significantly decreased malignant disease relapse [HR 0.86; 95% CI, 0.79-0.94; P=0.0014], better disease free survival [HR 0.92; 95% CI, 0.86-0.98; P=0.0067] and improved OS [HR 0.91; 95% CI, 0.85-0.96; p=0.0019] in the total population after adjustment for other significant clinical variables. There was no significant association between HLA-DRB1 HED and TRM, or risk of acute or chronic GVHD. Conversely, higher (upper quartile) HLA class I HED did not significantly impact OS, DFS, TRM, relapse, or acute and chronic GVHD, compared with the lower three quartiles. In addition, neither class I nor HLA-DRB1 HED significantly impact neutrophil or platelet engraftment post transplant.CONCLUSION(S): Higher HLA-DRB1 HED scores are associated with reduced relapse, improved DFS and OS in patients undergoing matched unrelated donor transplantation for hematological malignancies. These findings contribute to the growing evidence supporting the importance of HED in post-transplant outcomes. However, further refinement and validation are required before incorporating HED into clinical transplant risk assessment.