HLA‐DRB3/4/5 mismatches are associated with increased risk of acute GVHD in 10/10 matched unrelated donor hematopoietic cell transplantation

Abstract

Matching for HLA-A, -B, -C, and -DRB1 loci (8/8 match) is currently the gold standard for unrelated donor hematopoietic cell transplantation (HCT). In Europe, patients are also matched at the HLA-DQB1 loci (10/10 match). However, there is increasing evidence that matching at HLA-DRB3/4/5 loci may help to lower transplant-related morbidity and mortality. We therefore investigated the impact of HLA-DRB3/4/5 mismatches on outcomes in 1975 patients who received a first 10/10 matched unrelated donor (MUD) HCT in France from 2000 to 2012 for a hematological malignancy. High-resolution typing was performed at HLA-A, -B, -C, -DRB1, -DQB1, -DPB1, and -DRB3/4/5 loci for all donor/recipient pairs. Compared with DRB3/4/5-matched pairs, patients who received a MUD HCT from a DRB3/4/5 mismatched donor had a significantly increased risk of grade II-IV acute graft-versus-host disease (aGVHD) (Adjusted Hazard Ratio (HR) 1.43 (1.07 to 1.90)) associated with lower graft-versus-host disease-free and relapse-free survival (GRFS) (Adjusted HR 1.20 (1.02 to 1.42)). Conversely, we observed no differences in terms of chronic GVHD, nonrelapse mortality, relapse and overall survival. However, we believe that patients stand to benefit from DRB3/4/5 loci being considered for unrelated donor selection to improve GRFS and then quality of life after unrelated HCT.

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

“…An impact of HLA-DRB3/4/5 mismatch on OS has not yet been described in other studies ( 11 , 12 ). This might be attributed to the relatively high percentage of older patients included in this study (i.e., 30% >60 years and 54 years median age), given that HLA-associated risk increases with age particularly with regard to transplant-related morbidity ( 26 ).…”

“…Although statistical significance was not reached in the aGvHD models including only HLA-DRB3/4/5 ARD-mismatched cases, the analysis in a model encompassing all types of HLA-DRB3/4/5 mismatches revealed a statistically significant higher risk of aGvHD II–IV in the complete cohort (HR 1.21, 95% CI 1.02–1.43, p = 0.027). The inability to clearly identify this effect in the HLA-DRB3/4/5 ARD-mismatched cases alone is more likely due to a lack of statistical power rather than lack of association, considering that previous studies have already shown a significantly higher risk of aGvHD in patients receiving HLA-DRB3/4/5- mismatched grafts ( 10 , 11 ). 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 ).…”

“…The inability to clearly identify this effect in the HLA-DRB3/4/5 ARD-mismatched cases alone is more likely due to a lack of statistical power rather than lack of association, considering that previous studies have already shown a significantly higher risk of aGvHD in patients receiving HLA-DRB3/4/5- mismatched grafts ( 10 , 11 ). 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 ).…”

“…Due to the strong linkage between HLA-DRB1 and HLA-DRB3/4/5 , mismatches at the HLA-DRB3/4/5 loci have been reported in only a fraction of transplant pairs ( 10 , 11 ) with frequencies between 9.5% and 12.8% in different retrospective cohorts ( 10 – 12 ). The relevance of HLA-DRB3/4/5 discrepancies on outcome of uHSCT is still controversial.…”

BSHI guideline: HLA matching and donor selection for haematopoietic progenitor cell transplantation

“…A retrospective multicentre French study of 1,975 patients with haematological malignancies who received 10/10 matched unrelated donor transplant showed significant increased risk of grade II‐IV aGvHD in pairs with HLA‐DRB3, DRB4, DRB5 mismatches when compared with those with no mismatch at these loci. There was no difference in cGvHD, NRM, relapse and OS between these two groups (Ducreux et al., 2018).…”