(CSPOT34) Bruton's Tyrosine Kinase-Induced Musculoskeletal Disorders: A Real-World Safety Data Analysis of FAERS Database and Meta-Analysis of Randomized Controlled Trials

Background: Bruton’s tyrosine kinase inhibitors (BTKis), are approved for the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) and some B-cell lymphoma subtypes. Certain randomized control trials (RCTs) have reported an increased risk of musculoskeletal disorders in patients treated with BTKis.

Objectives: To evaluate musculoskeletal adverse events related to BTKis using disproportionality analysis of individual case safety reports (ICSRs) and meta-analysis of RCTs.

Methods: We conducted a retrospective case/non-case study for all BTKis using spontaneous reports in the FDA Adverse Event Reporting System (FAERS) until January 2024. Disproportionality analysis was performed by calculating the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), and the Information Component (IC) to identify signals of musculoskeletal disorders (defined as PRR ≥ 2, Lower Bound (LB) of ROR > 1, and IC025 > 0) for BTKis. A comprehensive literature search was conducted in MEDLINE/PubMed, Embase, and Web of Science from inception to November 2023. The data were analyzed using R Statistical Software, version 4.3.2. and results were presented using risk ratios (RR) with 95% confidence intervals (CI).

Results: Acalabrutinib, ibrutinib, and zanubrutinib showed a stronger signal for musculoskeletal disorders among BTKis. Specifically, a signal for muscle spasm was observed for ibrutinib [PRR: 2.2, chi-square: 473.9, LB ROR: 2.0, IC025: 1.0], while no other drugs in the class produced a signal for muscle spasm. Acalabrutinib showed signals for myalgia [PRR: 2.4, chi-square: 60.9, LB ROR: 1.9, IC025: 0.9] and bone pain [PRR: 2.6, chi-square: 27.5, LB ROR: 1.8, IC025: 0.8]. Back pain was identified as a signal for zanubrutinib [PRR: 2.3, chi-square: 16, LB ROR: 1.5, IC025: 0.5]. Out of 3,289 publications retrieved, nine studies were included in the meta-analysis. Ibrutinib was associated with an increased risk of any-grade muscle spasms [RR: 2.32, 95% CI 1.72, 3.12], and any-grade arthralgia [RR: 1.46, 95% CI 1.21, 1.76]. The risk of any-grade back pain after ibrutinib treatment was not statistically significant [RR: 1.22, 95% CI 0.75, 1.96].

Conclusions: Based on the evidence from the FAERS database, we identified a strong association between BTKis and musculoskeletal disorders. The meta-analysis results suggest ibrutinib is associated with an increased risk of muscle spasms and arthralgia.