Integrating New Therapies for Chronic Lymphocytic Leukemia

Over the last 2 decades, treatment of chronic lymphocytic leukemia (CLL) therapy has drastically changed, resulting in greatly improved survival and treatment tolerance with current targeted therapies. First, the transition from chemotherapy (alkylating agents, nucleoside analogs) to chemoimmunotherapy with the addition of anti-CD20 antibodies resulted in deeper and more complete remissions, with an improvement in progression-free and overall survival. Over the last few years, chemoimmunotherapy has gradually been replaced by new targeted agents, based on further improvement in survival, especially in patients with high-risk CLL, and fewer adverse effects, that is, a lack of myelosuppression and lack of DNA damage and associated risk of secondary acute myeloid leukemia/myelodysplastic syndrome. The most active targeted treatments for CLL patients are the kinase inhibitors, which inhibit signaling of surface receptors, especially the B-cell antigen receptor, and the BCL-2 antagonist venetoclax. Among the kinase inhibitors, Bruton tyrosine kinase inhibitors are highly effective and generally well-tolerated and induce durable responses in the vast majority of patients. PI3 kinase inhibitors are alternatives for patients with intolerance to Bruton tyrosine kinase inhibitors. This review discusses the rationale for the transition from chemotherapy-based treatment to the novel agents, the activity, adverse effects, sequencing, and combinations of the novel agents and provides an outlook into future CLL therapy for the next decade.