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

The goal of this study was to identify genetic polymorphisms associated with ibrutinib-related cardiovascular side effects (CVSEs). This is an observational non-interventional pharmacogenomic study of 50 patients with newly diagnosed or relapsed refractory chronic lymphocytic leukemia (NDCLL or RRCLL) receiving ibrutinib 420 mg for at least six months. The ibrutinib-related CVSEs included atrial fibrillation and hypertension, which occurred in 20% of patients. DNA obtained from buccal swabs was genotyped for 40 single nucleotide polymorphisms (SNPs) in GATA4, SGK1, KCNQ1, KCNA5, NPPA, and SCN5A using a customized next generation sequencing panel. It was found that GATA4 rs804280 AA (P =.043), KCNQ1 rs163182 GG (P =.036) and KCNQ1 rs2237895 AA (P =.023) were associated with the ibrutinib-related CVSEs. Patients with a high-risk score had at least two of the three significant risk genotypes identified in univariate analysis for GATA4 rs804280 A>C, KCNQ1 rs162182 G>C and KCNQ1 rs2237895 A>C, and patients with a low-risk score had either one or none of these genotypes. In multivariate analysis, 18 patients with at least two of the three high-risk genotypes had an 11.5-fold higher odds of CVSEs (P =.019; 1.79-119.73 at 95% CI). ]]>
This was a retrospective/prospective observational pharmacogenetic study of 50 patients with newly diagnosed or relapsed chronic lymphocytic leukemia who received ibrutinib at a starting daily dose of 420 mg for at least six months. Cardiovascular side effects (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, KCNA5, NPPA, and SCN5A using a customized next generation sequencing targeted panel. Univariate and multivariate logistic regression analysis were performed to determine genetic and clinical factors associated with the incidence of ibrutinib-related CVSEs.Newly diagnosed or relapsed refractory chronic lymphocytic leukemia (NDCLL or RRCLL) patients starting ibrutinib at the FDA approved dose of 420 mg daily. Patients had to remain on treatment for at least six months unless discontinued for toxicity, and provide written informed consent for specimen collection and analysis.]]>
Patients were consented between December 2019 and June 2020 at Atrium Health Levine Cancer Institute in Charlotte, NC, USA.]]>