Objective:

To assess incident pericardial effusion or cardiac tamponade after starting a BTK inhibitor (BTKi), comparing individual agents and newer- versus earlier-generation therapy.

Approach:

• Design and setting: Retrospective cross-sectional study of Mayo Clinic enterprise electronic health records. Adults initiating ibrutinib, acalabrutinib, zanubrutinib, or pirtobrutinib from 2012 through 2025 were followed through April 11, 2026.
• Participants: Of 680 BTKi recipients, 105 with documented pericardial disease or effusion before treatment were excluded; 575 patients were analyzed.
• Outcome and analysis: The primary outcome was time to first incident pericardial effusion or cardiac tamponade. Adjusted Cox models compared agents and generations; a sensitivity analysis censored follow-up at treatment discontinuation.

Key Findings:

• Thirty-four of 575 patients (5.9%; 95% CI, 4.1%-8.2%) experienced the primary outcome, equivalent to 1.9 events per 100 person-years. Median time to an event was 683.5 days.
• Cardiac tamponade occurred in 3 patients (0.5%), all receiving ibrutinib; pericarditis occurred in 7 patients (1.2%).
• Event counts were 24/331 (7.3%) with ibrutinib, 4/122 (3.3%) with acalabrutinib, 5/85 (5.9%) with zanubrutinib, and 1/37 (2.7%) with pirtobrutinib.
• No association with the primary outcome was identified for newer-generation BTKis compared with ibrutinib (adjusted HR, 0.82; 95% CI, 0.38-1.78). Agent-specific adjusted HRs versus ibrutinib were 0.62 (95% CI, 0.21-1.87) for acalabrutinib, 1.44 (95% CI, 0.52-3.94) for zanubrutinib, and 0.41 (95% CI, 0.05-3.20) for pirtobrutinib.
• Patients with events were older and more often had coronary artery disease than those without events; these comparisons were descriptive and unadjusted.

Interpretation:

Pericardial effusion or tamponade was documented in 5.9% of this cohort after BTKi initiation. The study identified no association between the primary outcome and newer-generation therapy versus ibrutinib, but the estimates were imprecise.

Limitations:

• Treatment selection may have been influenced by clinical and treatment-related factors, including cancer type, comorbidities, prior therapy, and clinician preference.
• Newer-generation BTKis had shorter follow-up, while events often occurred after prolonged exposure.
• Clinically indicated echocardiography may have missed asymptomatic effusions, and events managed outside Mayo Clinic may not have been captured.
• The small number of events limited agent-specific inference and increased the risk of model overfitting.

Conclusion:

Pericardial effusion and cardiac tamponade are clinically relevant events to monitor for after BTKi initiation. This study found no statistically significant difference in risk between newer-generation BTKis and ibrutinib, but limited event numbers and imprecise estimates mean that differences between agents cannot be ruled out.

Sources:

• Bruton Tyrosine Kinase Inhibitor–Associated Pericardial Events by Agent and Generation