PBM Mismatches in Unrelated Donor HCT Associated With Lower Overall Survival and Increased Risk of GVHD

According to a trial recently published in the Journal of Clinical Oncology, bidirectional or unidirectional peptide-binding motif (PBM) mismatches in the graft-versus-host (GVH) direction were correlated with lower overall survival (OS) and a higher chance of transplant-related mortality and graft-versus-host disease in single class human leukocyte antigen (HLA)-mismatched unrelated donor hematopoietic cell transplantation (UD-HCT), compared to unidirectional PBM mismatches or PBM matches. 

These findings suggest that considering directional PBM-matching status may improve outcomes in single-class I HLA-mismatched unrelated donor HCT.

To find these results, Pietro Crivello, PhD, and colleagues observed HLA-A, -B, and -C allotype disparities after single class I HLA-mismatched UD-HCT to measure the role of immunopeptidome divergence. 

2,391 single-class I HLA-mismatched and 14,426 fully HLA-matched UD-HCT performed between 2008 and 2018 were analyzed for acute leukemia or myelodysplastic syndromes. 1,629/2,391 (68.9%) of the HLA-mismatched UD-HCT were classified as PBM-matched or PBM-mismatched after the use of hierarchical clustering of experimentally determined PBM as a proxy for immunopeptidome divergence of allotype disparities. Risks associated with PBM-matching status were assessed accordingly, with OS as the primary endpoint. 

Results found that the degree of mismatch between donor and recipient PBM was correlated with OS rates and various hazard risks. Specifically, when PBM mismatches occurred in the graft-versus-host direction, either bidirectionally or unidirectionally, OS rates were significantly lower (hazard ratio [HR], 1.48; P < .0001) than for fully matched transplants. In contrast, unidirectional PBM mismatches in the host-versus-graft direction, or PBM matches, did not significantly impact OS rates (HR, 1.13; P = .1017). 

Risks of transplant-related mortality and acute and chronic graft-versus-host disease increased from full HLA matches to single PBM-GVH matches and single PBM-GVH mismatches. To address this, Dr Pietro Crivello and co-authors developed a webtool for PBM-matching of single-class I HLA-mismatched donor-recipient pairs, which can help identify whether a PBM-matched or PBM-mismatched transplant will occur. 

As primary endpoints were met. Dr Crivello et al concluded, “PBM-GVH mismatches inform mortality risks after single class I HLA-mismatched UD-HCT, suggesting that prospective consideration of directional PBM-matching status might improve outcome,” adding, “these findings highlight immunopeptidome divergence between mismatched HLA as a driver of clinical tolerability in UD-HCT.”

“Prospective selection of donors without HLA class I PBM mismatches in the graft-versus-host direction may improve survival probability after HLA-disparate hematopoietic cell transplantation, which is particularly relevant for patient populations heavily dependent on mismatched donors,” added Journal of Clinical Oncology associate editor Charles F. Craddock, MD, “Validation of these data that identify HLA-restricted immunopeptidome divergence as a potentially important new driver of clinically relevant T-cell alloreactivity in an independent patient cohort will be important.” 

Source: 

Crivello P, Arrieta-Bolaños E, He M, et al. Impact of the HLA immunopeptidome on survival of leukemia patients after unrelated donor transplantation. J Clin Oncol. 2023: JCO2201229. doi:https://doi.org/10.1200/JCO.22.01229