Abstract
•In an 8/8 matched transplant cohort, several HLA Class I alleles were predicted to have strong binding to mutated NPM1 peptides•Presence of predicted strong binding alleles was associated with a lower risk of post-transplant relapse
Mutation-bearing peptide ligands from mutated nucleophosmin-1 (NPM1) protein have been empirically found to be presented by HLA Class I in acute myeloid leukemia (AML).
We hypothesized that HLA genotype may impact allogeneic hematopoietic stem cell transplantation (allo-HCT) outcomes in NPM1-mutated AML due to differences in antigen presentation. We evaluated the effect of the variable of predicted strong binding to mutated NPM1 peptides using HLA Class I genotypes from matched donor:recipient pairs on transplant recipient overall survival (OS) and disease free survival (DFS) as part of primary objectives, and relapse risk (CIR) and non-relapse mortality (NRM) as part of secondary objectives. Study Design: Baseline and outcome data reported to the Center for International Blood and Marrow Transplant Research from a study cohort of adult patients (N=1020) with NPM1-mutated de novo AML in first (71%) or second (29%) complete remission undergoing 8/8 matched related (18%) or matched unrelated (82%) allo-HCT were retrospectively analyzed. Class I alleles from donor:recipient pairs were analyzed for predicted strong HLA binding to mutated NPM1 using netMHCpan 4.0.
429 (42%) of donor:recipient pairs were classified as having predicted strong binding HLA alleles (SBHA) to mutated NPM1. In multivariable analyses adjusting for clinical covariates, the presence of predicted SBHA was associated with a lower risk of relapse (HR 0.72, 95% CI 0.55-0.94, p=0.015). Overall survival (HR 0.81, 95% CI 0.67-0.98, p=0.028) and DFS (HR 0.84, 95% CI 0.69-1.01, p=0.070) had a suggestion towards better outcomes if predicted SBHA were present but did not meet prespecified p<0.025. Non-relapse mortality did not differ (HR 1.04, p=0.740).
These hypothesis generating data support further exploration of HLA genotype:neoantigen interactions in the allo-HCT context.
