Role of HLA-B exon 1 in graft-versus-host disease after unrelated haemopoietic cell transplantation: a retrospective cohort study

Effie W. Petersdorf*, Mary Carrington, Colm O'hUigin, Mats Bengtsson, Dianne De Santis, Valerie Dubois, Ted Gooley, Mary Horowitz, Katharine Hsu, J. Alejandro Madrigal, Martin J. Maiers, Mari Malkki, Caroline McKallor, Yasuo Morishima, Machteld Oudshoorn, Stephen R. Spellman, Jean Villard, Phil Stevenson, International Histocompatibility Working Group in Hematopoietic Cell Transplantation, Marcel Tilanus

*Corresponding author for this work

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Background The success of unrelated haemopoietic cell transplantation (HCT) is limited by graft-versus-host disease (GVHD), which is the main post-transplantation challenge when HLA-matched donors are unavailable. A sequence dimorphism in exon 1 of HLA-B gives rise to leader peptides containing methionine (Met; M) or threonine (Thr; T), which differentially influence natural killer and T-cell alloresponses. The main aim of the study was to evaluate the role of the leader dimorphism in GVHD after HLA-B-mismatched unrelated HCT.

Methods We did a retrospective cohort study of 33 982 patients who received an unrelated HCT done in Australia, Europe, japan, North America, and the UK between jan 1, 1988, and Dec 31, 2016. Data were contributed by participants of the International Histocompatibility Working Group in Hematopoietic Cell Transplantation. All cases were included and there were no exclusion criteria. Multivariate regression models were used to assess risks associated with HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 mismatching. Among the 33 982 transplantations, the risks of GVHD associated with HLA-B M and T leaders were established in 17 100 (50.3%) HLA-matched and 1457 (4.3%) single HLA-B-mismatched transplantations using multivariate regression models. Leader frequencies were defined in 2 004 742 BeTheMatch US registry donors.

Findings Between jan 20, 2017, and March 11, 2019, we assessed 33 982 HCTs using multivariate regression models for the role of HLA mismatching on outcome. Median follow-up was 1841 days (IQR 909-2963). Mortality and GVHD increased with increasing numbers of HLA mismatches. A single HLA-B mismatch increased grade 3-4 acute GVHD (odds ratio [OR] 1.89, 95% CI 1. 53-2.33; p

Interpretation The HLA-B leader informs GVHD risk after HLA-B-mismatched unrelated HCT and differentiates high-risk HLA-B mismatches from those with lower risk. The leader of the matched allotype could be considered to be as important as the leader of the mismatched allotype for GVHD. Prospective identification of leader-matched donors is feasible for most patients in need of a HCT, and could lower GVHD and increase availability of HCT therapy. These findings are being independently validated and warrant further research in prospective trials. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)E50-E60
Number of pages11
JournalThe Lancet Haematology
Issue number1
Publication statusPublished - Jan 2020



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