Abstract Inhibitors of Bruton Tyrosine Kinase (BTKi) are one of the most important classes of drug used to treat chronic lymphocytic leukemia (CLL) and have substantial uses in other B-cell malignancies. In CLL, BTKi replaced chemoimmunotherapy by improving PFS, mitigate the impact of high-risk disease features, and normalize survival to that of age matched controls. Building upon this success, newer drugs that target BTK improve toxicity through increased selectivity or overcome resistance through novel binding or protein degradation mechanisms. Advances were also seen with the development of combination regimens that included a BTKi and can shorten treatment duration or improve outcomes. Toxicity can be a major limitation of continuous BTKi treatment. BTKi increase risk of cardiovascular adverse events (AEs) and bleeding as well as other AEs that can be treatment-limiting for some patients. Toxicity has been greatly reduced with newer cBTKi, such as acalabrutinib and zanubrutinib, that are more selective and have a reduced incidence of cardiovascular AEs. Additionally, the highly selective, reversible, non-covalent BTKi (ncBKTi), pirtobrutinib, has an even more favorable AE profile. While toxicity still exists, these more selective agents have allowed more patients to benefit from this class of drug. The continuous dosing strategy with BTKi increase exposure and therefore resistance. A major mechanism of resistance in CLL is acquired mutations in BTK or its immediate downstream target, PLCG2. This can be overcome by agents that bind BTK in a different manner, such as the ncBTKis pirtobrutinib and nemtabrutinib, and drugs like rocbrutinib that have both covalent and non-covalent binding mechanisms. However, use of pharmacologic inhibitors of BTK will eventually be limited by development of new or multiple mutations. Drugs that degrade BTK such as bexobrutideg and BGB-16673, can be effective. By removing BTK entirely, BTK degraders limit both BTK’s kinase and scaffolding function and may limit BCR signaling when activating PLCG2 mutations are present. BTK degraders are being developed in CLL and other B-cell malignancies and are likely to become a standard in the future, especially in a resistance setting. One approach to address both toxicity and resistance is fixed-duration combination regimens and include a BTKi. In CLL fixed-duration regimens that include a BTKi and BCL2 inhibitor given for around a year have been established with phase 3 studies showing improved PFS compared to chemoimmunotherapy. This limits toxicity and resistance, as patients discontinue therapy in response. CLL is not the only disease where novel BTKi combinations have had an impact. In mantle cell lymphoma, using a BTKi with an aggressive induction regimen replaces the need for autologous stem cell transplant in many cases. BTK remains an important target in CLL and other B-cell cancers. Based on past progress, it is anticipated that targeting BTK will continue to be an important therapeutic strategy for the foreseeable future. Citation Format: Kerry A. Rogers. Targeting BTK in CLL and other B-cell Malignancies: Continuous Progress with a Continuous Therapy abstract. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7 (3Suppl): Abstract nr IA004.
Kerry A. Rogers (Wed,) studied this question.