Evaluating Clinical Safety of BTK Inhibitors: Cardiovascular Events and Drug-Drug Interactions

BACKGROUND

Bruton tyrosine kinase inhibitors (BTKis) are standard therapies for B-cell malignancies, including relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). This study focuses on CLL/SLL. Although second-generation BTKis off er increased selectivity, their cardiovascular (CV) safety and potential drug-drug interactions (DDIs) remain incompletely characterized. This study describes CV toxicity and cytochrome P450 3A4 (CYP3A4)–mediated interactions of covalent (cBTKi) and noncovalent BTKi (ncBTKi) to inform safer therapy selection.

OBJECTIVES

• Assess CV adverse events (CVAEs) with first- and second-

generation cBTKi and ncBTKi.

• Compare CVAE reporting between randomized controlled

trials (RCTs) and real-world evidence (RWE).

• Evaluate CYP3A4-mediated DDIs and propose management

strategies.

METHODS

A targeted literature review included phase 3 RCTs and recent RWE studies reporting CVAEs with ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib. Additional review focused on CYP3A4-mediated DDIs and drug-food interactions.

RESULTS

Ibrutinib showed higher rates of atrial fibrillation (AF), hypertension (HTN), and bleeding vs second-generation cBTKi (acalabrutinib, zanubrutinib) and ncBTKi (pirtobrutinib). For acalabrutinib, AF rates were similar between RCTs and RWE, whereas HTN was more frequent in RWE, likely refl ecting older, comorbid populations. Zanubrutinib and pirtobrutinib showed the lowest AF incidence, followed by acalabrutinib and ibrutinib. Bleeding appeared to be a class eff ect. Variability between RCTs and RWE, and limited real-world data for newer agents, highlight the need for long-term studies. CYP3A4 interactions (eg, azoles, macrolides, calcium channel blockers) require dose adjustment, avoidance, or monitoring.

CONCLUSIONS

Second-generation BTKi may offer improved CV safety vs first-generation agents. Proactive monitoring, early CVAE management, and attention to CYP3A4 interactions are essential. BTKi selection should be individualized based on comorbidities, disease characteristics, prior therapies concomitant medications, and CV risk.

FUTURE DIRECTIONS

• Conduct long-term real-world studies of CV and

bleeding outcomes.

• Clarify mechanisms of off -target kinase inhibition

to predict CVAEs.

• Standardize DDI management and CV monitoring.