The HLA-B leader dimorphism informs survival after unrelated donor hematopoietic-cell transplantation.
The risks associated with HLA mismatching depend on the HLA-B leader genotype.
Hematopoietic-cell transplantation (HCT) from HLA-mismatched unrelated donors can cure life-threatening blood disorders but its success is limited by graft-versus-host disease (GVHD). HLA-B leaders encode methionine (M) or threonine (T) at position 2 and give rise to TT, MT or MM genotypes. The dimorphic HLA-B leader informs GVHD risk in HLA-B-mismatched HCT. If the leader influences outcome in other HLA-mismatched transplant settings, the success of HCT could be improved for future patients. We determined leader genotypes for 11872 patients transplanted between 1988 and 2016 from unrelated donors with one HLA-A -B,-C,-DRB1 or -DQB1 mismatch. Multivariate regression methods were used to evaluate risks associated with patient leader genotype according to the mismatched HLA locus and with HLA-A,-B,-C,-DRB1 or -DQB1 mismatching according to patient leader genotype. The impact of the patient leader genotype on acute GVHD and mortality varied across different mismatched HLA loci. Non-relapse mortality was higher among HLA-DQB1-mismatched MM patients compared to HLA-DQB1-mismatched TT patients (hazard ratio 1.35; P = .01). Grades III-IV GVHD risk was higher among HLA-DRB1-mismatched MM or MT patients compared to HLA-DRB1-mismatched TT patients (odds ratio 2.52 and 1.51, respectively). Patients tolerated a single HLA-DQB1 mismatch better than mismatches at other loci. Outcome after HLA-mismatched transplantation depends on the HLA-B leader dimorphism and the mismatched HLA locus. The patient's leader variant provides new information on the limits of HLA mismatching. The success of HLA-mismatched unrelated transplantation might be enhanced through the judicious selection of mismatched donors for a patient's given leader genotype.