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 Over the last few years, chemoimmunotherapy has gradually been replaced by new targeted agents, based on further improvement in survival, especially in patients with high-risk CLL, and fewer adverse effects, that is, a lack of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.

Bruton tyrosine kinase (BTK) is a nonreceptor tyrosine kinase that plays a central role in the signal transduction of the B-cell antigen receptor and other cell surface receptors, both in normal and malignant B lymphocytes. B-cell antigen receptor signaling is activated in secondary lymphatic organs and drives the proliferation of malignant B cells, including chronic lymphocytic leukemia (CLL) cells. During the last 10 years, BTK inhibitors (BTKis) are increasingly replacing chemotherapy-based regimen, especially in patients with CLL and mantle cell lymphoma (MCL). Bruton tyrosine kinase inhibitors are particularly active in patients with CLL and MCL, but also received approval for Waldenström macroglobulinemia, small lymphocytic lymphoma, marginal zone lymphoma, and chronic graft-versus-host disease. Current clinical practice is continuous long-term administration of BTKi, which can be complicated by adverse effects or the development of drug resistance. Alternatives to long-term use of BTKi are being developed, such as combination therapies, permitting for limited duration therapy. Second-generation BTKis are under development, which differ from ibrutinib, the first-in-class BTKi, in their specificity for BTK, and therefore may differentiate themselves from ibrutinib in terms of adverse effects or efficacy.