This activity focuses on optimizing first-line treatment strategies for patients with chronic lymphocytic leukemia (CLL). Drs. William Wierda and Matthew Davids discuss key distinctions between continuous BTK inhibitor therapy and time-limited venetoclax-based regimens, while highlighting considerations such as comorbidities, toxicities, IGHV status, and TP53 aberrations. They examine recent and emerging data from trials including CLL17, AMPLIFY, and BRUIN CLL-313, as well as novel agents. The conversation underscores the importance of personalized therapy selection in frontline CLL care.