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Medical expert outlines that resistance to BTK inhibitors in patients with chronic lymphocytic leukemia is commonly mediated by mutations in BTK or phospholipase Cγ2 proteins, and highlights new, unique mutation patterns in zanubrutinib; he also mentions emerging therapies including noncovalent BTK inhibitors and clinical trials focusing on BTK degradation for additional lines of therapy.

Key opinion leaders detail strategies for patients with chronic lymphocytic leukemia relapsing after fixed-duration BTK and BCL2 inhibitor treatment, emphasizing the importance of genetic testing for mutations that could render them resistant to a re-challenge and considering third-generation BTK inhibitors if mutations are found.

Ricardo Parrondo, MD, discusses the potential of combining BTK and BCL2 inhibitors in chronic lymphocytic leukemia treatment, emphasizing their synergistic effect and cautioning against use in frail patients or those with cardiovascular comorbidities, while Pooja Advani, MBBS, MD, stresses the importance of medical history and risk stratification, especially regarding cardiovascular adverse effects.