Preetam Jain, Consultant Medical Oncologist and Hemato-Oncologist at Bombay Hospital and Medical Research Centre, shared a post on X:
“Treatment sequencing in relapsed/refractory CLL continues to evolve rapidly.
- Double-refractory CLL (after both covalent BTKi and venetoclax) remains a major unmet clinical need, where clinical trials should be strongly considered.
- Resistance matters. BTK C481 mutations impair binding of covalent BTK inhibitors, making a mechanism switch preferable over another covalent BTKi. Resistance testing for BTK, BCL2, and TP53 is increasingly valuable at relapse to guide sequencing.
- Noncovalent BTK inhibitors (e.g., pirtobrutinib) overcome C481-mediated resistance and have expanded salvage options after covalent BTKi failure.
- The BRUIN CLL-321 trial established pirtobrutinib as an effective option after prior covalent BTKi, allowing continued BTK pathway inhibition while preserving other therapeutic classes.
- Biomarker-driven sequencing is likely to become increasingly important, although routine resistance testing is still evolving across regions.
- The future may lie in triplet regimens, including pirtobrutinib + venetoclax + rituximab, aiming for deeper, more durable remissions.
Precision sequencing – not simply adding another drug – is becoming the cornerstone of modern CLL management.”