Harnessing <scp>HLA</scp> Divergence for Improved Donor Selection in Haploidentical Haematopoietic Stem Cell Transplantation

Haploidentical haematopoietic stem cell transplantation (haplo-HSCT) with post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis is commonly used in patients without a fully matched donor. HLA evolutionary divergence (HED), a surrogate for the diversity of the immunopeptidome, can predict HLA-matched HSCT outcomes. Because of the peculiarities of HED measurement in haplo-HSCT, we designed a new HED_D->R metric to proxy the fraction of the recipient-specific immunopeptidome not recognised as self by the haplo-identical donor, and evaluated its predictive value on haplo-HSCT outcomes with the aim of providing help in choosing the best donor. We retrospectively studied 104 patients who underwent PTCy haplo-HSCT for haematological malignancy and calculated per-locus and per-class HED in the recipient (HED_R), the donor (HED_D), across mismatched haplotypes (HED_MM) as well as HED_D->R. Patients with low class 1 HED_R had worse OS (hazard ratio (HR) 2.16, 95% confidence intervals (CI) 1.06-4.40, p = 0.033), whereas no significant impact of HED_D or HED_MM at any HLA locus was observed. Moreover, in multivariate analysis of patients surviving at least 100 days, low class 1 HED_D->R was associated with inferior OS (HR 2.67, 95% CI 1.13-6.28; p = 0.025). In addition to strengthening the impact of recipient class 1 HED on HSCT outcomes regardless of donor type, our results suggest that our novel, publicly available, HED_D->R metric could help select the most appropriate donor among haploidentical candidates.