Genetic Variation in Donor CTLA-4 Regulatory Region is a Strong Predictor of Outcome after Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies

Abstract

Relapse remains a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). Graft-versus-tumor effect is primarily mediated by donor T cells. Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a critical inhibitor of T cell proliferation. Single nucleotide polymorphisms (SNPs) in CTLA-4 may affect immune responses. We hypothesized that CTLA-4 SNPs will be associated with disease control after allo-HCT. One hundred sixty-four adult patients with the availability of pretransplantation recipient and donor DNA samples were included in this analysis. Ten tagSNPs of the CTLA-4 gene were identified. Donor CTLA-4 SNP rs4553808 was associated with decreased relapse-free survival (RFS) (P = .019) and overallsurvival (OS) (P = .033). In multivariable analysis of an additive genetic model, genotype of CTLA-4 SNP rs4553808 was an independent risk factor for inferior RFS (hazard ratio [HR] = 1.73, 95% confidence interval [CI] 1.10-2.71, P = .017) and OS (HR = 1.84, 95% CI 1.13-3.0, P = .015). CTLA-4 SNPs can be used to identify high-risk patient subsets that may benefit from preemptive immunomodulation to decrease relapse rates and improve survival.