Impact of HLA-B Leader Mismatching on Outcomes after Haploidentical Transplantation with Antithymocyte Globulin

Abstract

Objective Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is increasingly used to treat hematologic diseases in the last 10 years. Continuous effort has been made to identify a high-risk HLA mismatch pattern to avoid detrimental factors to HSCT outcomes. However, whether HLA-B leader could be used to optimize donor selection in haplo-HSCT with antithymocyte globulin (ATG) is unknown. We thus sought to evaluate the role of HLA-B leader in haplo-HSCT with ATG which may help to optimize donor selection. Method We conducted a single-center retrospective analysis of 570 patients who received haplo-HSCT for the treatment of hematological malignancies between Sep, 2012 and May, 2021 in our institution to test a series of hypotheses for a better understanding of the significance of HLA-B leader in haplo-HSCT with ATG. HLA-B leader genotype and shared HLA-B leader was determined using HLA-B Leader Assessment Tool. Probabilities of survival were estimated by the Kaplan-Meier method. Cumulative incidences of competing risk outcomes were estimated by competing risk model. The Cox proportional hazard regression and the Fine-Gray competing risks regression model was used to define hazard ratio (HR) and conduct multivariate analysis. All statistical analysis was performed with R version 4.0.5. Results All patients received myeloablative conditioning regimen with ATG for graft-versus-host-disease prevention. Median follow-up was 649 days (interquartile range [IQR] 398-965 days) for surviving patients.Relative to HLA-B leader matched transplantation, HLA-B leader mismatched transplantation had lower overall-survival (OS) (HR, 1.44; 95% CI, 1.02-2.01; P=0.04; Figure 1A) and higher non-relapse mortality (NRM) (HR, 1.56; 95% CI, 1.04-2.35, P=0.03; Figure 1B). These results were further demonstrated by multivariable analysis. With respect to specific causes of NRM, leader mismatch group had a higher risk of infection-related death (HR, 2.30; 95% CI, 1.25-4.23; P=0.01). Additionally, we found that relapse was adversely affected by a shared M relative to a shared T allotype in the leader matched subgroup (HR, 1.92; 95% CI, 1.07-3.47, P=0.03; Figure 1C). In terms of disease-free-survival (DFS) and OS, no significant differences were identified between shared M and shared T in both leader matched subgroup and leader mismatched subgroup (Figure 1D; Figure 1E). Notably, patients benefited from HLA-B leader match with a shared T, which was associated with superior OS (HR, 0.71; 95% CI, 0.51-0.98; P=0.035) and modestly increased DFS (HR, 0.74; 95% CI, 0.55-1.00; P=0.051) when compared with the other three groups. Additionally, in the subgroup with shared T, HLA-B leader mismatch had a non-statistically significant trend of higher NRM (HR, 1.50; 95% CI, 0.97-2.31, P=0.07; Figure 1F). Similar association was observed in multivariable models that relative to leader match with shared T, leader match with shared M was associated with higher relapse (HR, 1.85; 95% CI, 1.02-3.36; P=0.045) and leader mismatch with shared T was associated with inferior OS (HR, 1.57; 95% CI, 1.08-2.28; P=0.017). Conclusion Our findings suggested that mismatched HLA-B leader informed increased risk of NRM and lower OS. Furthermore, patients benefited from HLA-B leader matched donors with shared T. A paradigm inclusive of HLA-B leader might help to optimize donor selection and improve clinical outcomes of haplo-HSCT with ATG. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal