Impact of Previously Unrecognized HLA Mismatches Using Ultrahigh Resolution Typing in Unrelated Donor Hematopoietic Cell Transplantation

Abstract

PURPOSE Ultrahigh resolution (UHR) HLA matching is reported to result in better outcomes following unrelated donor hematopoietic cell transplantation, improving survival and reducing post-transplant complications. However, most studies included relatively small numbers of patients. Here we report the findings from a large, multicenter validation study. METHODS UHR HLA typing was available on 5,140 conventionally 10 out of 10 HLA-matched patients with malignant disease transplanted between 2008 and 2017. RESULTS After UHR HLA typing, 82% of pairs remained 10 out of 10 UHR-matched; 12.3% of patients were 12 out of 12 UHR HLA-matched. Compared with 12 out of 12 UHR-matched patients, probabilities of grade 2-4 acute graft-versus-host disease (aGVHD) were significantly increased with UHR mismatches (overall P = .0019) and in those patients who were HLA-DPB1 T-cell epitope permissively mismatched or nonpermissively mismatched (overall P = .0011). In the T-cell–depleted subset, the degree of UHR HLA mismatch was only associated with increased transplant-related mortality (TRM) (overall P = .0068). In the T-cell–replete subset, UHR HLA matching was associated with a lower probability of aGVHD (overall P = .0020); 12 out of 12 UHR matching was associated with reduced TRM risk when compared with HLA-DPB1 T-cell epitope permissively mismatched patients, whereas nonpermissive mismatching resulted in a greater risk (overall P = .0003). CONCLUSION This study did not confirm that UHR 12 out of 12 HLA matching increases the probability of overall survival but does demonstrate that aGVHD risk, and in certain settings TRM, is lowest in UHR HLA-matched pairs and thus warrants consideration when multiple 10 out of 10 HLA-matched donors of equivalent age are available.

HLA-DRB3/4/5 Matching Improves Outcome of Unrelated Hematopoietic Stem Cell Transplantation

“…Having said that, an additive effect of HLA-DRB4 E3 mismatches cannot be excluded ( 11 ), despite the common perception that mismatches not affecting the ARD have a low impact on alloreactivity ( 27 ). According to a recently published study, HLA mismatches outside the ARD that were newly detected after retrospective ultrahigh-resolution HLA genotyping of 5,140 10/10 HLA-matched transplant pairs did associate with a higher risk of aGvHD and TRM but no inferior survival ( 28 ). The fact that HLA-DRB3/4/5 incompatibility increased less the risk of aGvHD when compared to HLA-DRB1 or other single HLA incompatibility, as reported in this (i.e., HLA mismatch GvHD II–IV: HR 1.38, p < 0.001; Supplementary Table S4 ) but also in other studies conducted in Europe and the United States ( 21 , 24 , 29 – 31 ), indicates that the effect of HLA-DRB3/4/5 mismatch is more subtle and thus more difficult to detect.…”

The IPD-IMGT/HLA Database

“…Genomic sequences including introns were first added to the database for some HLA class I genes in October 2003 and have been included for more of the remaining genes as data has become available. The extension of these sequences has become more clinically relevant, as recent studies have shown that matching for intronic polymorphisms can improve clinical outcomes after Haematopoietic Cell Transplantation (HCT) ( 37 , 38 ).…”

Widespread non‐coding polymorphism in HLA class II genes of International HLA and Immunogenetics Workshop cell lines

“…Recent retrospective studies have demonstrated that there is a benefit to matching HCT donors and patients at ultra-high resolution. [21][22][23]66 Others have suggested that the increased use of NGS based HLA typing improves the chances of finding a wellmatched donor, because of reduced ambiguity in searches. 67 There is also potential to include other loci in the matching process to improve transplant outcomes, 68 define links between non-coding polymorphism and function, 59,69 and increase our understanding of human evolution and historical migration.…”