Refined HLA-DPB1 mismatch with molecular algorithms predicts outcomes in hematopoietic stem cell transplantation

Abstract

HLA-DPB1 mismatches between donor and recipient are commonly seen in allogeneic hematopoietic stem cell transplantation (HSCT) from an unrelated donor. HLA-DPB1 mismatch, conventionally determined by the similarity of the T-cell epitope (TCE), is associated with an increased risk of acute graft-versus-host disease (aGVHD) and a decreased risk of disease relapse. We investigated the clinical impact of HLA-DPB1 molecular mismatch quantified by mismatched eplets (ME) and Predicted Indirectly Recognizable HLA Epitopes score (PS) in a cohort of 1,514 patients receiving HSCT from unrelated donors matched at HLA-A, -B, -C, -DRB1/3/4/5, and -DQB1 loci. HLA-DPB1 alloimmunity in the GVH direction determined by high GVH ME/PS was associated with a reduced risk of relapse (HR 0.83, P= .05 for ME) and increased risk of grade 2-4 aGVHD (HR 1.44, P< .001 for ME), whereas high HVG ME/PS was only associated with an increased risk of grade 2-4 aGVHD (HR 1.26, P= .004 for ME). Notably, in the permissive mismatch subgroup classified by TCE grouping, high HVG ME/PS was associated with an increased risk of relapse (HR 1.36, P= .026 for ME) and grade 2-4 aGVHD (HR 1.43, P= .003 for PS-II). Decision curve analysis showed GVH ME outperformed other models and provided the best clinical net benefit for the modification of aGVHD prophylaxis regimen in patients with high risk of developing clinically significant aGVHD. In conclusion, molecular assessment of HLA-DPB1 mismatch enables separate prediction of HVG or GVH alloresponse quantitatively and allows further refinement of HLA-DPB1 permissiveness as defined by conventional TCE grouping.

SIRPα Mismatch Is Associated With Relapse Protection and Chronic Graft-Versus-Host Disease After Related Hematopoietic Stem Cell Transplantation for Lymphoid Malignancies

“…Unlike allorecognition mediated by T cells that express rearranging receptors, allorecognition by the innate system appears to be independent of major histocompatibility complex (MHC) mismatch and possibly initiated by the mismatching signal from non-MHC genomic loci ( 17 ). In the allo-HSCT setting, it is believed that the host antigens, especially antigens from HLA molecules, are processed and presented to donor T cells by either host or donor Antigen-presenting Cells (APC)s ( 18 ), the direction of alloreactivity (GVH or HVG) derived from the HLA mismatch affect the outcomes differently ( 19 ). In the present study, all the SIRPα mismatches, regardless of the alloreactive vector or the presence of a specific genotype, are associated with cGVHD and relapse protection.…”

Molecular disparity of HLA‐DPB1 is associated with the development of subsequent solid cancer after allogeneic hematopoietic stem cell transplantation

“…These in silico mismatch methods not only provide a measurable assessment of alloreactivity between donor and recipient but also enable evaluation of a specific HLA locus in a particular direction (GVH or host‐versus‐graft [HVG]) 18 . We recently investigated the clinical impact of HLA‐DPB1 alloreactivity quantified by mismatched eplets (MEs) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) score (PS) in a cohort of patients receiving allo‐HSCT from an unrelated donor matched at HLA‐A, ‐B, ‐C, ‐DRB1/3/4/5, and ‐DQB1 loci 19 . ME analysis by HLAMatchmaker reveals specific structural disparities that elicit the immune response, whereas PS reflects the polymorphic HLA‐derived peptides recognized by T cells, in which PS‐I represents CD8 + T‐cell alloreactivity and PS‐II represents CD4 + T‐cell alloreactivity 20,21 .…”

Not all mismatches are equal: importance of alloreactivity direction

“… 4 HLA-DPB1 mismatch in otherwise matched donors is common, yet our ability to predict GVHD severity based on this mismatch is limited. In this issue, Zou et al 5 present data supporting HLA-DPB1 mismatch associated risks of acute GVHD while using clinical correlation to investigate the clinical impact of HLA-DPB1 molecular mismatch.…”

“…This quantification, when combined with the PIRCHE score (PS), a predictor of TCE alloreactivity, has been shown to predict immunogenicity and clinical outcomes in haploidentical transplant recipients. 8 Zou et al 5 present novel data on the use of molecular algorithms for HLA-DPB1 mismatch in a cohort of more than 1,500 patients who received an unrelated donor transplant between 2005-2018 at The University of Texas MD Anderson Cancer Center. The primary question in this study is whether molecular matching offers superior prognostic guidance than the traditional TCE model.…”

“…Zou et al 5 present an important novel approach to assessment of HLA-DPB1 mismatch permissibility. The authors acknowledge that confirmation of their findings with multi-center data is needed before refinement of algorithms can be considered.…”