Mechanism-of-Action Switching and Treatment Selection After Progression in CLL

Dr. Shadman addresses when to switch within the BTKi class versus changing mechanism of action. For intolerance to covalent BTKis, every available covalent agent should be tried before declaring class intolerance. Prospective data show that patients can often tolerate second-generation agents after ibrutinib intolerance, and acalabrutinib to zanubrutinib switching is also supported by data. Rare life-threatening events such as subdural hematoma may justify switching to venetoclax-based therapy due to bleeding risk as a class effect.

For progressive disease on a covalent BTKi, within-class switching to another covalent agent is not appropriate due to shared resistance mechanisms, particularly the C481S BTK mutation (the most prevalent resistance mechanism), PLCɣ2 mutations, and a substantial proportion of progressions without identified resistance mechanisms. Switching to either non-covalent BTKi pirtobrutinib or venetoclax (BCL-2 inhibitor) represents the appropriate options.

Dr. Lipsky discusses the clinical decision between pirtobrutinib and venetoclax in second line, noting that venetoclax should always be preserved in mind as a potential rescue option for patients who haven't received it, given its potent activity. Reasons to continue BTK inhibition pathway with pirtobrutinib include patient familiarity, established reasons why BTK inhibition was initially chosen, or older patients for whom continuity of known therapy is practical.

Reasons to switch to venetoclax include rapidly progressive bulky disease (CLL14 data shows bulky disease predicts shorter venetoclax-obinutuzumab PFS, making BTKi potentially preferable, though conversely deep responses with BCL-2 inhibition may be sought for rapidly proliferating disease), and the BRUIN-322 study data comparing when and how to use pirtobrutinib versus venetoclax-based regimens will provide additional guidance.