Effect of Heterozygosity of Human Leukocyte Antigen on Outcomes Following Allogeneic Hematopoietic Cell Transplant for Myeloid and Lymphoid Malignancies

Abstract

Background A recent study demonstrated that heterozygosity at HLA class I loci is associated with improved survival in patients with advanced solid tumors treated with immune checkpoint inhibitors when compared to patients homozygous in at least one HLA class I locus (Chowell et al. Science 2018). HLA heterozygosity allows for greater diversity of peptide presentation to T-cells and activation of a diversified immune response. In HCT, we hypothesize that HLA heterozygosity impacts disease control and survival in patients with myeloid and lymphoid malignancies. Design Patients who underwent 8/8 HLA-matched first allogeneic HCT for AML, MDS, ALL, or NHL between 2000 – 2015 were identified from CIBMTR database. Patients who received non-myeloablative and reduced intensity conditioning were excluded from analysis, except for those with NHL. HLA zygosity was characterized to the allele level as either heterozygous at all HLA class I loci or homozygous in at least one HLA class I locus. Primary outcomes of overall survival (OS) and relapse were analyzed. Secondary outcomes included transplant-related mortality (TRM) and acute graft-versus-host disease (aGVHD). Multivariate analysis using Cox proportional hazards model was performed with factors violating the proportional hazards assumptions adjusted through stratification. Results A total of 7,474 patients received 8/8 HLA-matched allogeneic HCT according to our selection criteria. 5,775 patients were heterozygous at all HLA class I loci, while 1,699 patients were homozygous in at least one HLA class I locus. OS was not statistically different with HLA homozygosity when compared to heterozygosity (HR=0.98, P=0.6849). When analyzed in disease-specific cohorts, there were no differences in OS with homozygosity when compared to heterozygosity: AML (HR=0.99, P=0.8315), MDS (HR=0.88, P=0.3198), ALL (HR=0.97, P=0.6398), and NHL (HR=0.99, P=0.8862). Relapse was not associated with HLA homozygosity when compared to heterozygosity (HR=0.93, P=0.1028). This remained consistent when evaluated by diseases: AML (HR=0.89, P=0.0891), MDS (HR=0.89, P=0.5106), ALL (HR=0.97, P=0.7669), and NHL (HR=0.91, P=0.3413). There were also no differences in TRM (HR=1.05, P=0.3110) and aGVHD grade 2-4 (HR=1.06, P=0.2213). Conclusions Zygosity of HLA class I loci was not associated with outcomes following allogeneic transplants for myeloid and lymphoid malignancies. Alloreactivity of T-cells in conjunction with presence of minor MHC antigens may possibly override the effect of HLA zygosity seen in an autologous setting with immune checkpoint inhibitors. Our findings may be limited by small sample sizes in the disease subgroups. Future analysis into differential expression and epitope presentation of HLA may help reveal the effect of HLA zygosity on antigen presentation to T-cells and impact on outcomes.