Peripheral and central nervous system toxicities of Bruton tyrosine kinase Inhibitors: a real-world pharmacovigilance study.

Background: Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the management of B-cell malignancies, yet emerging evidence indicates that they may be associated with nervous system disorders adverse events (AEs). Given their expanding therapeutic applications, especially in nervous system disorders, understanding their neurotoxicity profiles is of critical clinical importance. Methods: We conducted a retrospective pharmacovigilance analysis using data from the United States. FDA Adverse Event Reporting System (FAERS) covering Q1 2013 to Q4 2024. Reports listing acalabrutinib, ibrutinib, or zanubrutinib as the primary suspect drug were extracted. Nervous system disorder AEs were identified based on MedDRA System Organ Class classification. Disproportionality analyses were performed using reporting odds ratio (ROR) and proportional reporting ratio (PRR), and multivariate logistic regression was applied to adjust for confounders, including age, sex, and weight. Time-to-onset distributions, severity patterns, and mortality rates were also evaluated. Results: Out of 75,240 BTK inhibitor-associated AE reports, 10,435 (13.87%) were coded to the MedDRA System Organ Class (SOC) "Nervous system disorders." Ibrutinib contributed the largest absolute number of neurological AE reports ( Conclusion: In this FAERS-based pharmacovigilance study, BTK inhibitors showed distinct reporting patterns of nervous system disorders AEs, particularly at the preferred-term and HLGT levels, rather than an overall SOC-level disproportionality signal. Ibrutinib contributed the largest number of neurological AE reports, whereas comparisons involving zanubrutinib require caution because of sparse reporting and shorter market exposure. These findings support careful neurological monitoring and individualized risk assessment, but they should not be interpreted as evidence of causality.