BTK and B-cell chronic lymphocytic leukemia: With these unprecedented successes have come new challenges: the costs and unique adverse events (AEs) associated with indefinite BTK blockade, the problem of relapse after “time-limited” (1–2 year) venetoclax/anti-CD20 monoclonal antibody regimens, the immune-mediated AEs observed with the phosphatidylinositol-3-kinase (PI3K) inhibitors, and the risk of tumor lysis syndrome (TLS) with venetoclax-based regimens, etc. The best frontline regimen for patients with CLL continues to evolve, and the optimal sequencing of therapies in later lines remains unclear.