Work

New Polymorphic Antigen Binding Domain-Based HLA Evolutionary Divergence Score Independently Predicts AML Relapse after Haploidentical Stem Cell Transplantation

Year: 2025

Type: article

Abstract: Introduction HLA allelic diversity promotes the presentation of broader peptide repertoires to alloreactive T-cells, which facilitates the graft-versus-leukemia effect (GVL). Several studies have reported HLA evolutionary divergence (HED) as a predictor of clinical response to immune checkpoint inhibitors in solid tumors , yet the significance of HED in allogeneic stem cell transplantation (alloSCT) is not clearly defined. Grantham distances of antigen-binding domain amino acid sequences are conventionally used to calculate HED. However, the presence of conserved residues among these domains may underestimate clinically meaningful HLA divergence. Here, we explore a new HED score calculation approach focusing on polymorphic HLA residues to predict clinical outcomes in alloSCT. Methods We retrospectively analyzed acute myeloid leukemia patients who underwent alloSCT at the University of Pittsburgh between 2018-2023. HED scores of recipient HLA alleles were calculated by GranthamDist ( https://sourceforge.net/projects/granthamdist/ ). In order to improve sensitivity for measuring allelic divergence, we analyzed only polymorphic antigen-binding domain residues with an intra-allelic Simpson diversity index > 0.2. Cumulative incidence of relapse was compared among low- and high-HED scoring recipients, and multivariate analysis was performed using Cox proportional hazard models . Results We analyzed 92 alloSCT recipients of HLA-matched donors and 39 recipients of haploidentical donors (haplo-SCT). Across all HLA loci, HED scores calculated from polymorphic residues were higher than conventional scores from total antigen-binding domain residues (Figure A). HED scores did not correlate with any major clinical outcomes, overall survival , non-relapse mortality, or relapse in HLA-matched alloSCT, whereas in haplo-SCT, recipients with lower HED had a significantly increased risk of relapse (Figure B-C). In multivariate analysis , low HED was an independent risk factor for relapse in addition to age, disease risk index, and pre-transplant residual disease . Conclusion In our limited cohort, low recipient HED positively correlated with leukemic relapse in haploidentical alloSCT, consistent with what has been observed with loss of HLA heterozygosity in other studies, a well-known mechanism of GVL escape. Further validation of these results is needed with larger cohorts.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.jtct.2025.01.449

Authors: Padma Katikaneni, Emily Geramita, Kristine Cooper, Kevin Quann, Sawa Ito

Institutions: University of Pittsburgh, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center

Language: English

Topic: Hematopoietic Stem Cell Transplantation

Subfield: Hematology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,650