The Degree of HLA-DPB1 Mismatch Predicted By Evolutionary Divergence Scoring Informs the Risk of Chronic Graft-Versus-Host Disease after Haploidentical Transplantation with Post-Transplant Cyclophosphamide
Authors: Solh Melhem M. , Bashey Asad , Aubrey Michael T , Freed Brian , Roark Christina , Morris Lawrence E , Holland H Kent , Bachier-Rodriguez Lizamarie , Zhang Xu , Solomon Scott R. 
Published: December 2024

In the context of haploidentical donor transplantation (HIDT) utilizing post-transplant cyclophosphamide (PTCY), our group has previously demonstrated that mismatch at HLA-DPB1 predicts a higher incidence of chronic GVHD, regardless of permissiveness by the TCE algorithm or directionality of the mismatch. HLA Evolutionary Divergence (HED) can predict the quantify of divergence between two alleles of the same HLA locus. The divergent allele advantage hypothesis proposes that diversity between HLA alleles of the same locus will increase the capacity of peptide antigen presentation, resulting in increased protection against pathogens and malignancy. As higher divergence may also increase the presentation of self-peptides resulting in autoreactive T cells, we hypothesized that higher divergence in recipient HLA-DPB1 alleles may better inform the association of HLA-DP mismatch with chronic GVHD.
To that end,
we studied 322 consecutive recipient/donor pairs who received HIDT with PTCY at our center between 2005-2020 with a median follow up of 57.2 months. In addition to HLA-DPB1 matching and vector, we calculated HED using the GRAHAM distance score within the recipient HLA-DPB1 loci. HLA-DPB1 mismatch vector was bidirectional (n=167), graft vs host (GVH only, n=49), host vs graft (HVG only, n=39) and matched (n=67). The median HED score in the HLA-DPB1 recipient was 4.06 (range 0-10.68). Recipients were grouped into 4 different cohort based on the direction of HLA-DPB1 mismatch and the HED score (high &gt;4.06 vs low): matched (n=67), HLA-DPB1 mismatched GVH/bidirectional low divergence (n=104), HLA-DPB1 mismatched GVH/bidirectional high divergence (n=112) and HLA-DPB1 mismatch HVG (n=39).
Patient's characteristics were median age 49.5 (19,80) years, male sex 58%, disease ( AML 38%, ALL 21%, MDS 12%, NHL 10%, other 19%); Cell source (PBSC 80%); regimen intensity ( myeloablative 49%); HCT-CI comorbidity index ≥3 in 50%; disease risk ( high/very high 35%); donor male sex 61% and female donor to male recipient (21%). Donor was a child, sibling/half sibling or parent in 47%, 38% and 14% respectively. In univariate analysis, high HED score in recipient HLA-DPB1 had no impact on OS, DFS, Relapse or NRM but was significant for all grade ( HR 2.10, p=0.005) and moderate-severe (HR 1.86, p=0.04) cGVHD compared to patients with low HED score. A subgroup analysis comparing cGVHD cumulative incidences based on vector and divergence score showed that HLA-DPB1 MM in GVH/bidirectional with high HED had higher all grade and moderate-severe cGHVD compared to matched recipients (P=0.01 and 0.004). Additionally, patients with HLA-DPB1 MM in GVH/bidirectional high HED score had higher all grade and moderate-severe cGVHD compared to MM in GVH/bidirectional with low HED score (p=0.005 and 0.013)
A multivariable analysis using cox model was performed on moderate-severe cGVHD and showed that in addition to black race and being transplanted in earlier years ( 2005-2013 vs later), patients with HLA-DPB1 mismatched in GVH/bidirectional with high divergence score had higher risk of mod-severe cGVHD ( HR 2.20, CI 1.09-4.43, p=0.028) than matched HLA-DPB1. Similarly, patients with HLA-DPB1 MM in the HVG direction had higher risk of mod-severe cGVHD compared to matched (HR 2.57, CI 1.15-5.74, p=0.002).
In conclusion, our analysis shows that in the context of PTCY-based HIDT, recipient with more divergent HLA-DPB1 alleles are at significantly higher risk of moderate-to-severe chronic GVHD when a HLA-DPB1 mismatch is present in the GVH/bidirectional direction, a result predicted by the divergent allele advantage hypothesis. Furthermore, the presence of an HLA-DPB1 mismatch in the HVG-only direction also resulted in more chronic GVHD, a finding requiring further mechanistic study. In recipients with more divergent HLA-DPB1 alleles by HED scoring, care will need to be taken in donor selection to balance the detrimental effects of HLA-DPB1 mismatch on chronic GVHD with the known beneficial effects of a TCE non-permissive HLA-DPB1 mismatch in terms of relapse reduction.