Department of Cancer Pharmacology and Pharmacogenomics, Atrium Health Levine Cancer Institute, Charlotte, North Carolina.
Department of Hematologic Malignancies and Blood Disorders, Atrium Health Levine Cancer Institute, Charlotte, North Carolina.
Clin Cancer Res. 2023 Dec 1;29(23):4941-4948. doi: 10.1158/1078-0432.CCR-23-0421.
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.
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.
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).
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.
接受伊布替尼治疗的慢性淋巴细胞白血病（CLL）患者存在发生心血管副作用（CVSE）的风险。CVSE 的分子决定因素尚未完全阐明。我们探讨了布鲁顿酪氨酸激酶（BTK）信号通路中的遗传多态性与伊布替尼相关 CVSE 的相关性。
我们对 50 例新诊断或复发的 CLL 患者进行了回顾性/前瞻性观察性药物遗传学研究，这些患者以 420mg 的起始日剂量接受伊布替尼治疗至少 6 个月。10 例（20%）患者出现 CVSE，主要为心房颤动和高血压，其中 4 例停止治疗。从所有 50 例患者的口腔拭子中提取 DNA，使用定制的下一代测序 panel 对 GATA4、SGK1、KCNQ1、KCNA4、NPPA 和 SCN5A 中的 40 个 SNP 进行基因分型。采用单变量和多变量逻辑回归分析确定与伊布替尼相关 CVSE 发生相关的遗传和临床因素。
GATA4 rs804280 AA（P=0.043）、KCNQ1 rs163182 GG（P=0.036）和 KCNQ1 rs2237895 AA（P=0.023）基因型与伊布替尼相关 CVSE 呈单变量相关。基于多变量分析，定义为至少存在这两种基因型的高遗传风险评分与 CVSE 的发生相关，风险比为 11.5 倍（P=0.019；95%置信区间，1.79-119.73）。
我们的研究结果表明 CLL 患者伊布替尼相关 CVSE 可能存在遗传决定因素。如果在更大的研究中得到证实，针对 GATA4 和 KCNQ1 多态性的治疗前药物遗传学检测可能是一种有用的临床工具，可用于对 CLL 患者进行个体化治疗选择和/或制定早期风险缓解策略。
