Cardiac arrhythmias of BCR-ABL inhibitors with or without triazole antifungal agents: A real-world pharmacovigilance study based on the food and drug administration adverse event reporting system database.

OBJECTIVES

Breakpoint Cluster Region (BCR)-Abelson tyrosine kinase (ABL) inhibitors are widely used in the treatment of blood cancers, particularly chronic myelogenous leukemia and are often combined with triazole antifungal agents to prevent fungal infections. However, the cardiac arrhythmia risks associated with BCR-ABL inhibitors in combination with triazole antifungal agents in real-world settings remain poorly understood. To address this gap, we conducted a pharmacovigilance study to evaluate and compare the cardiac arrhythmia profiles of BCR-ABL inhibitors when used with and without triazole antifungal agents in clinical practice.

METHODS

A disproportionality analysis was performed using the Food and Drug Administration Adverse Event Reporting System database (2004Q1-2024Q2). To identify potential signals of cardiac arrhythmias associated with BCR-ABL inhibitors, with or without triazole antifungal agents, we calculated reporting odds ratios and 95% confidence intervals. Comparisons were made between BCR-ABL inhibitor monotherapy and all other drugs in the Food and Drug Administration Adverse Event Reporting System database, as well as between BCR-ABL inhibitors combined with triazole antifungal agents and BCR-ABL inhibitor monotherapy. Additionally, the Weibull shape parameter test was also used to evaluate time-to-onset.

RESULTS

From 2004Q1 to 2024Q2, the Food and Drug Administration Adverse Event Reporting System database reported 21,433,114 cases, including 2666 and 68 cases of cardiac arrhythmias linked to BCR-ABL inhibitor monotherapy and its combination with triazole antifungal agents, respectively. The reporting odds ratios and their 95% confidence intervals for BCR-ABL inhibitor monotherapy, asciminib, nilotinib, and ponatinib were 1.31 (1.27-1.36), 2.11 (1.45-3.06), 2.66 (2.53-2.80), and 1.18 (1.05-1.33), respectively. Dasatinib plus triazole antifungal agents (reporting odds ratio: 2.98, 95% CI: 1.93-4.60) and ponatinib plus triazole antifungal agents (reporting odds ratio: 1.53, 95% CI: 1.08-2.16) were associated with a higher disproportionality of cardiac arrhythmias than BCR-ABL inhibitor monotherapy. The median time-to-onset was longer with monotherapy than with BCR-ABL inhibitors plus triazole antifungal agents (2.63 vs. 0.34 months,  < 0.001), both indicating an early failure type.

CONCLUSIONS

BCR-ABL inhibitors plus triazole antifungal agents increase the risk of cardiac arrhythmia, particularly in the early stages of treatment, with the risk decreasing over time.