Treating Through Toxicities in CLL—Decisions Around BTKi Continuity

Treating Through Toxicities in CLL—Decisions Around BTKi Continuity

Managing chronic low-grade toxicities in patients receiving long-term BTKi therapy requires individualized assessment and shared decision-making, particularly given the extended treatment durations now commonly seen in clinical practice. With median progression-free survival approaching 9 years for continuous ibrutinib in frontline trials without 17p deletion, patients may experience prolonged exposure to treatment-related adverse effects that significantly impact quality of life. Common persistent toxicities include myalgias, which many patients find particularly difficult to tolerate, and cardiac symptoms such as intermittent palpitations that may require comprehensive workup to rule out atrial fibrillation or other serious arrhythmia. The challenge lies in balancing continued disease control with maintaining an acceptable quality of life over potentially decade-long treatment periods.

Treatment modification strategies depend on the specific toxicity profile and the patient’s current disease response status. For patients who have achieved good responses, including partial remission or complete remission with newer second-generation BTKi, treatment interruption becomes a viable option worth discussing. Data from the E1912 trial demonstrate that patients who discontinue long-term continuous BTKi therapy due to toxicity concerns can expect a median time to next therapy of approximately 2 years, providing a meaningful treatment-free interval. This information helps frame conversations with patients about whether continuing therapy outweighs the burden of ongoing adverse effects, particularly when patients have achieved durable disease control.

Alternative management approaches include switching between different covalent BTKi when toxicity profiles differ significantly between agents. Prospective data support transitioning patients from ibrutinib to acalabrutinib or zanubrutinib when specific toxicities become problematic, as the improved safety profiles of second-generation agents may resolve particular adverse effects while maintaining disease control. For patients who cannot tolerate any BTKi approach due to persistent toxicities, switching to venetoclax-based treatment represents a viable alternative strategy, particularly for patients who have not previously received BCL2 inhibitor therapy. This approach eliminates BTKi-related toxicities while providing an effective alternative mechanism of action for continued disease management.