Revised HLA-DP TCE-Core Permissiveness Model Better Defines Relapse Risk and Survival Following Haploidentical Transplant

Background The presence of an HLA-DPB1 non-permissive mismatch (NPMM) by the TCE-3 model has been associated with improved survival following haploidentical donor transplantation (HIDT) utilizing post-transplant cyclophosphamide (PTCy). A revised model (TCE-core) further separates TCE-3 “group 3” alleles into “core”(C) and “non-core” (NC) alleles has been recently developed, so that a formerly permissive mismatch (PMM) resulting from “group 3” alleles in both donor and recipient are now considered a C-NPMM if one or more of those alleles is NC. Objective We aimed to study the additional effect of HLA-DPB1 C-NPMM per the TCE-Core algorithm, as well as the directional vector of the mismatch, on transplant outcome following HIDT. Study Design To this end, 242 consecutive HIDT recipients with ALL, AML or MDS transplanted between 2005 – 2021 (median age 51 [19,80]) were analyzed. Median follow-up was 62 [23, 199] months. Of the 136 transplants classified as PMM by TCE-3, 73 were reclassified as a C-NPMM by the TCE-Core algorithm, of which 36 were in the GVH-vector (37 were HVG-only). Given comparable survival between conventional NPMM and C-NPMM GVH/bidirectional were analyzed together (nonpermissive). HVG-only C-NPMM were combined with HLA-DPB1 matched and PMM (permissive) due to similar outcomes. Results The presence of a TCE-Core-defined nonpermissive HLA-DP mismatch resulted in superior 5-year OS (66% vs. 47%) and DFS (60% vs. 43%). Compared to the conventional TCE-3 algorithm, TCE-Core identified a larger number of nonpermissive transplants (38% vs. 23%) and better discriminated outcomes between nonpermissive vs. permissive status (larger difference in survival outcome using TCE-Core vs. TCE-3, with OS Δ of 18.3% vs. 12.7%; DFS Δ of 16.5% vs. 8.5%). In multivariable analysis, a nonpermissive TCE-core mismatch led to improved OS (HR 0.54, p=0.003) and DFS (HR 0.62, p=0.013), due in large part to decreased relapse risk (HR 0.63, p=0.049). In contrast, NRM or GVHD outcomes were not significantly impacted. Conclusion In summary, the presence of nonpermissive TCE-Core HLA-DP mismatch strongly predicts survival following PTCy-based HIDT, due to a reduction in relapse risk without a corresponding increase in GVHD or NRM. As a donor selection tool, TCE-Core appears to better discriminate HIDT outcome while at the same time identifying a larger percentage of the potential donor pool.