Next Generation BTK Inhibitors in CLL: Evolving Challenges and New Opportunities

Simple Summary Chronic lymphocytic leukemia (CLL) treatment scenario is rapidly evolving. As a consequence of longer observation, despite remarkable clinical results, treatment with ibrutinib is associated with long-term toxicities and resistance. New strategies based on BTK inhibition are under development, offering effective salvage treatment both to intolerant and refractory patients. This review is aimed at summarizing and discussing the role of next-generation BTK inhibitors in CLL. Ibrutinib revolutionized the CLL treatment approach and prognosis demonstrating its efficacy and safety even at extended follow-up. During the last few years, several next-generation inhibitors have been developed to overcome the occurrence of toxicity or resistance in patients on continuous treatment. In a head-to-head comparison of two phase III trials, both acalabrutinib and zanubrutinib demonstrated a lower incidence of adverse events in respect to ibrutinib. Nevertheless, resistance mutations remain a concern with continuous therapy and were demonstrated with both first- and next-generation covalent inhibitors. Reversible inhibitors showed efficacy independently of previous treatment and the presence of BTK mutations. Other strategies are currently under development in CLL, especially for high-risk patients, and include BTK inhibitor combinations with BCl2 inhibitors with or without anti-CD20 monoclonal antibodies. Finally, new mechanisms for BTK inhibition are under investigations in patients progressing with both covalent and non-covalent BTK and BCl2 inhibitors. Here we summarize and discuss results from main experiences on irreversible and reversable BTK inhibitors in CLL.