Experts discuss mutation testing and patient factors to guide second-line CLL therapy after BTK inhibitor resistance

A 66-year-old man who was diagnosed with chronic lymphocytic leukemia five years ago and initially had an unmutated IGHV profile without TP53 alteration has been on continuous covalent BTK inhibitor therapy for four years, achieving a partial response.

He now shows disease progression with enlarging cervical and abdominal lymph nodes, a rising absolute lymphocyte count from 35,000 to 72,000, hemoglobin of 11.4 g/dL and platelets of 145,000. Molecular testing identified a BTK C481S mutation and an acquired TP53 mutation.

The presenting physicians stress that mutation profiling, existing comorbidities and the patient’s treatment preferences are critical when selecting a second‑line regimen after BTK inhibitor resistance. They note that the patient has tolerated his current therapy well and has no major cardiovascular issues, which may influence the choice of alternative agents.

Overall, the discussion highlights the need for personalized treatment strategies in relapsed CLL, balancing efficacy, safety and patient‑centered considerations.