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

Author:

Hamadeh Issam S.1ORCID,Patel Jai N.1ORCID,Jacobs Ryan2ORCID,Zeng Hang3ORCID,He Jiaxian3ORCID,Hu Bei2ORCID,Moyo Tamara Kay2ORCID,Soni Amy2ORCID,Park Steven2ORCID,Copelan Ed2ORCID,Avalos Belinda2ORCID,Hamilton Alicia4ORCID,Steuerwald Nury4ORCID,Ghosh Nilanjan2ORCID

Affiliation:

1. 1Department of Cancer Pharmacology and Pharmacogenomics, Atrium Health Levine Cancer Institute, Charlotte, North Carolina.

2. 2Department of Hematologic Malignancies and Blood Disorders, Atrium Health Levine Cancer Institute, Charlotte, North Carolina.

3. 3Department of Cancer Biostatistics, Atrium Health Levine Cancer Institute, Charlotte, North Carolina.

4. 4Molecular Biology and Genomics Core Facility, Atrium Health Levine Cancer Institute, Charlotte, North Carolina.

Abstract

Abstract Purpose: Patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib are at risk of developing cardiovascular side effects (CVSE). 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 6 months. CVSEs, primarily atrial fibrillation and hypertension, occurred in 10 patients (20%), of whom 4 discontinued therapy. DNA was isolated from buccal swabs of all 50 patients and genotyped for 40 SNPs 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 = 0.043), KCNQ1 rs163182 GG (P = 0.036), and KCNQ1 rs2237895 AA (P = 0.023) genotypes were univariately associated with ibrutinib-related CVSEs. On the basis of 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 = 0.019; 95% confidence interval, 1.79–119.73). Conclusions: Our findings suggest possible genetic determinants of ibrutinib-related CVSEs in CLL. If replicated in a larger study, pretreatment 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.

Funder

Leon Levine Foundation

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

Reference37 articles.

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