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Immunoglobulin Gene Sequence Analysis In Chronic Lymphocytic Leukemia: From Patient Material To Sequence Interpretation
Published on: November 26, 2018
Genetic Predictors of Ibrutinib-related Cardiovascular Side Effects in Patients with Chronic Lymphocytic Leukemia
Issam S Hamadeh1, Jai N Patel1, Ryan Jacobs2
1Department of Cancer Pharmacology and Pharmacogenomics, Atrium Health Levine Cancer Institute, Charlotte, North Carolina.
Insights
Genetic variations in GATA4 and KCNQ1 are linked to cardiovascular side effects (CVSE) in chronic lymphocytic leukemia (CLL) patients treated with ibrutinib. Pharmacogenetic testing may personalize treatment and mitigate risks.
Area of Science:
- Pharmacogenomics
- Oncology
- Cardiology
Background:
- Patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib face risks of cardiovascular side effects (CVSE).
- The underlying genetic factors contributing to these CVSEs remain largely unknown.
- Investigating genetic polymorphisms within the Bruton tyrosine kinase (BTK) signaling pathway is crucial for understanding ibrutinib-related CVSEs.
Purpose of the Study:
- To identify genetic polymorphisms associated with the development of cardiovascular side effects (CVSE) in patients with chronic lymphocytic leukemia (CLL) undergoing ibrutinib treatment.
- To explore the role of the Bruton tyrosine kinase (BTK) signaling pathway in mediating ibrutinib-induced CVSEs.
- To establish a potential genetic risk score for predicting CVSEs in CLL patients.
Main Methods:
- A retrospective/prospective observational pharmacogenetic study involving 50 CLL patients treated with ibrutinib.
- DNA isolation from buccal swabs and genotyping for 40 single nucleotide polymorphisms (SNPs) in genes including GATA4, SGK1, KCNQ1, KCNA4, NPPA, and SCN5A using next-generation sequencing.
- Univariate and multivariate logistic regression analyses to determine associations between genetic factors and CVSE incidence.
Main Results:
- Ten patients (20%) developed CVSEs, primarily atrial fibrillation and hypertension.
- Specific genotypes, including GATA4 rs804280 AA, KCNQ1 rs163182 GG, and KCNQ1 rs2237895 AA, showed univariate association with ibrutinib-related CVSEs.
- A high genetic risk score, defined by the presence of at least two specific genotypes, was significantly associated with an 11.5-fold increased odds of developing CVSEs (P = 0.019).
Conclusions:
- Genetic variations in GATA4 and KCNQ1 may be significant determinants of ibrutinib-related cardiovascular side effects in CLL patients.
- Pretreatment pharmacogenetic testing for these polymorphisms could aid in personalizing treatment strategies.
- Future larger studies are warranted to validate these findings and implement early risk mitigation strategies for CLL patients treated with ibrutinib.
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.
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