Impact of HLA Molecular Mismatch on Haploidentical Hematopoietic Stem Cell Transplantation: A Center for International Blood and Marrow Transplant Research Study
Authors: Zou Jun , Wang Tao , Bolon Yung-Tsi , Gadalla Shahinaz M. , Marsh Steven G.E. , Kuxhausen Michelle , He Meilun , Paczesny Sophie , Spellman Stephen R. , Lee Stephanie J. , Ciurea Stefan O. 
Published: November 2021

Abstract
ABSTRACT
BACKGROUND
The number of haploidentical hematopoietic stem cell transplantations (haplo-HSCT) being performed has substantially increased in recent years. Single-center studies have previously used in silico algorithms to quantitively measure HLA disparity and shown an association of the number of HLA molecular mismatches with relapse protection and/or increased risk of acute graft-versus-host disease (GVHD) in haplo-HSCT. However, inconsistent results from small studies have made it difficult to understand the full clinical impact of molecular mismatch in haplo-HSCT.
OBJECTIVE
In the current study, we investigated the potential of the HLA class I and II mismatched eplet (ME) score measured by HLAMatchmaker, as well as ME load at a specific locus to predict outcomes in a registry-based cohort of haplo-HSCT recipients.
STUDY DESIGN
We analyzed data from patients (n= 1,287) who underwent their first haplo-HSCT for acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndrome between 2013 and 2017, as reported to the Center for International Blood and Marrow Transplant Research database. ME load at each HLA locus and total Class-I and -II were scored using the HLAMatchmaker module incorporated in HLA Fusion software v4.3, which identifies predicted eplets based on the crystalized HLA molecule models and identifies ME by comparing donor and recipient eplets.
RESULTS
In the cohort studied, ME scores derived from total HLA Class I or Class II loci or individual HLA loci were not associated with overall survival, disease-free survival, non-relapse mortality, relapse, acute or chronic GVHD (P&lt; .01). An unexpected strong association was identified between total class II ME load in the GVH direction and slower neutrophil engraftment (HR 0.82; 95% CI, 0.75 - 0.91; P &lt; .0001) and platelet engraftment (HR 0.80; 95% CI, 0.72 - 0.88; P &lt; .0001). This was likely attributable to ME load at the HLA-DRB1 locus, which was similarly associated with slower neutrophil engraftment (HR 0.82; 95% CI, 0.73 - 0.92; P = .001) and slower platelet engraftment (HR 0.76; 95% CI, 0.70 - 0.84; P &lt; .0001). Additional analyses suggested that this effect is attributable to matched vs. mismatched in the GVH direction and not to ME load, as there was no dose effect identified.
CONCLUSION
These findings contradict those of prior relatively small studies reporting that ME load, as quantified by HLAMatchmaker, was associated with haplo-HSCT outcomes. As the study failed to demonstrate the predictive value of ME from HLA molecules for major clinical outcomes, other molecular mismatch algorithms in haplo-HSCT settings should be tested.

Disclosures
Lee: Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Janssen: Other; Takeda: Research Funding; Syndax: Research Funding; AstraZeneca: Research Funding; Kadmon: Research Funding; Amgen: Research Funding.