Multinational study of donor selection and HLA loss leukemia relapse after hematopoietic cell transplantation

For patients with hematologic malignancies, relapse is the leading cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). Frequently, relapses are explained by immune evasion through alteration of human leukocyte antigens, but determinants and clinical consequences are poorly defined. In a retrospective study by the HLALOSS Consortium at 27 centers worldwide, 533 relapses of hematologic cancers after allo-HCT from different donor types were analyzed. Genomic loss of mismatched HLA (HLA loss) was assesed using a newly developed next-generation sequencing pipeline. Using HLA data from approximately 5 million individuals, a web-based tool to infer HLA incompatibility phasing was developed. HLA loss occurred in 15.6% of relapses, with significant variation according to donor type: 28.7% haploidentical family, 7.2% unrelated adult, 2.7% cord blood (p<0.0001). The distribution of HLA mismatches across the patients’s haplotypes, predicted through the phasing tool, was strongly associated with HLA loss, with an incidence of 27.6% when HLA mismatches were in the same haplotype, compared with 5.4% if present on different haplotypes (p<0.0001). HLA loss affected postrelapse outcomes, abrogating the efficacy of original donor lymphocyte infusions, with significant survival advantage by second allo-HCT from a different donor. The authors conclude that the likelihood of HLA loss varies significantly according to the number and positioning of HLA mismatches between patient and donor; the newly developed phasing tool enables reliable prediction of its risk, supporting informed donor selection. xtagstartz/p>