Genetic Predictors of Ibrutinib-Related Cardiovascular Side Effects in Patients with Chronic Lymphocytic Leukemia

Purpose: Patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib are at risk of developing cardiovascular side effects (CVSEs). The molecular determinants of CVSEs have not been fully elucidated. We interrogated genetic polymorphisms in the Bruton Tyrosine Kinase (BTK) signaling pathway for their association with ibrutinib-related CVSEs. Experimental Design: We conducted a retrospective/prospective observational pharmacogenetic study of 50 patients with newly diagnosed or relapsed CLL who received ibrutinib at a starting daily dose of 420 mg for at least six months. CVSEs, primarily atrial fibrillation and hypertension, occurred in ten patients (20%), of whom four discontinued therapy. DNA was isolated from buccal swabs of all 50 patients and genotyped for 40 single nucleotide polymorphisms in GATA4, SGK1, KCNQ1, KCNA4, NPPA, and SCN5A using a customized next generation sequencing panel. Univariate and multivariate logistic regression analysis were performed to determine genetic and clinical factors associated with the incidence of ibrutinib-related CVSEs. Results: GATA4 rs804280 AA (P =.043), KCNQ1 rs163182 GG (P =.036) and KCNQ1 rs2237895 AA (P =.023) genotypes were univariately associated with ibrutinib-related CVSEs. Based on multivariate analysis, a high genetic risk score, defined as the presence of at least two of these genotypes, was associated with 11.5-fold increased odds of CVSEs (P =.019; 95% CI, 1.79-119.73). Conclusions: Our findings suggest possible genetic determinants of ibrutinib-related CVSEs in CLL. If replicated in a larger study, pre-treatment pharmacogenetic testing for GATA4 and KCNQ1 polymorphisms may be a useful clinical tool for personalizing treatment selection for CLL and/or instituting early risk-mitigation strategies.