The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions

SIMPLE SUMMARY: The availability of Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has undoubtedly reshaped the initial management of chronic lymphocytic leukemia (CLL). Acalabrutinib and zanubrutinib are selective second-generation BTK inhibitors designed to have high specificity for BTK and minimize off-target effects. However, despite the positive impact of these drugs on patient outcomes, their introduction has created new practical challenges for clinicians, mainly due to their adverse events and the development of drug resistance. Therefore, new combinations of BTK inhibitors and their combinations are currently being tested. This review summarizes new data about the approved drugs and the agents in clinical development for therapeutic use in CLL. ABSTRACT: The use of Bruton’s tyrosine kinase (BTK) inhibitors has changed the management and clinical history of patients with chronic lymphocytic leukemia (CLL). BTK is a critical molecule that interconnects B-cell antigen receptor (BCR) signaling. BTKis are classified into two categories: irreversible (covalent) inhibitors and reversible (non-covalent) inhibitors. Ibrutinib was the first irreversible BTK inhibitor approved by the U.S. Food and Drug Administration in 2013 as a breakthrough therapy in CLL patients. Subsequently, several studies have evaluated the efficacy and safety of new agents with reduced toxicity when compared with ibrutinib. Two other irreversible, second-generation BTK inhibitors, acalabrutinib and zanubrutinib, were developed to reduce ibrutinib-mediated adverse effects. Additionally, new reversible BTK inhibitors are currently under development in early-phase studies to improve their activity and to diminish adverse effects. This review summarizes the pharmacology, clinical efficacy, safety, dosing, and drug–drug interactions associated with the treatment of CLL with BTK inhibitors and examines their further implications.