Impact of HLA-b leader matching status on prognosis and underlying mechanism in patients with hematological malignancies following haploidentical hematopoietic stem cell transplantation

Abstract Background Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) represents a pivotal therapeutic approach for the treatment of hematological disorders, necessitating the identification of prognostic factors to enhance treatment efficacy. The leader peptide encoded by exon 1 of the HLA-B gene displays a dimorphism at position -21, which has the capacity to influence natural killer (NK) cell education through the NKG2A/CD94 receptor. The compatibility of the HLA-B leader has been shown to potentially influence the prognosis across various transplantation modalities. This study seeks to elucidate its specific impact on the prognosis of patients with hematological malignancies and to investigate the underlying mechanisms involved. Methods Analyses were conducted utilizing two retrospective cohorts of patients diagnosed with hematological malignancies, specifically acute myeloid leukemia (AML), acute lymphoblastic leukemia, and myelodysplastic syndrome, from Peking University People's Hospital. Cohort 1 comprised 1,245 patients who underwent haplo-HSCT between January 2020 and December 2022. Cohort 2 consisted of 91 patients who completed NK cell function tests post-transplantation between May 2016 and April 2017. Comprehensive HLA genetic data for both donors and recipients were available for all cases. Patients were categorized based on the matching status of the HLA-B leader between donors and recipients. Survival probabilities were assessed using the Kaplan-Meier method, while cumulative incidences were determined through a competing risks model. Inter-group comparisons were conducted using the Mann-Whitney U test. Results In Cohort 1, the median follow-up period for patients who survived was 1,468 days (range: 873-1,973 days). The 3-year cumulative relapse rate and overall survival (OS) were 15.8% (95% confidence interval [CI], 13.8-17.9%) and 81.9% (95% CI, 79.7-84.0%), respectively. No significant impact of HLA-B leader matching status on prognosis was identified across all patients with malignancies. In a multivariate analysis of a subgroup of patients with AML (n=577), it was observed that transplants mismatched at the HLA-B leader locus were associated with a significantly higher non-relapse mortality (hazard ratio [HR] 1.86; 95% CI, 1.05-3.28; P=0.032) compared to HLA-B leader matched transplants. Additionally, HLA-B leader mismatching was linked to a significantly reduced OS (HR 1.58; 95% CI, 1.08-2.31; P=0.020) and leukemia-free survival (HR 1.45; 95% CI, 1.02-2.04; P=0.037). Further analysis indicated a significant association between HLA-B leader mismatching and an increased risk of infection-related mortality (P=0.020). These associations were not observed in other disease categories. Data from Cohort 2 suggested that HLA-B leader matching may facilitate the functional recovery of NK cells post-transplantation in AML patients. Specifically, at one month post-transplantation, the proportion of interferon-γ (IFN-γ) expression in NKG2A+ NK cells was significantly higher in patients with HLA-B leader matching (P=0.045). At six months post-transplantation, there was a significant increase in the expression levels of both IFN-γ (P=0.043) and CD107a+ (P=0.027). Conclusion This study elucidates that the influence of HLA-B leader matching status on the prognosis of patients with hematological malignancies following haplo-HSCT is specific to the type of malignancy, with significant effects predominantly observed in AML. The matching of HLA-B leader enhances prognosis by facilitating the functional recovery of NK cells. These findings offer a critical reference for the precise selection of transplant donors and the optimization of clinical treatment strategies for individuals with AML.