Beyond BCL2 (B cell lymphoma) and BTK (Bruton tyrosine kinase) inhibitors: novel agents and resistance mechanisms for chronic lymphocytic leukemia

Abstract Background Chronic lymphocytic leukemia (CLL) is considered the one of most prevalent hematological diseases in the Western world, with an incidence of 4.2/100 000/year that increases to more than 30/100 000/year at an age of greater than 80 years. The Bruton tyrosine kinase inhibitor ibrutinib has been considered the treatment of choice in treatment naïve and relapsed/refractory settings (R/R). Venetoclax, along with navitoclax, are the selected BCL2 inhibitors in first and second-line settings for chronic lymphocytic leukemia. A degree of acquired resistance for this agents has been observed in clinical settings, and is also determined by scientific rationale. Methods A PubMed literature search and Google Scholar search were conducted using the terms “chronic lymphocytic leukemia” AND “novel therapies”, “BTK degraders”, and “acquired resistance”, and “bispecific antibodies”, and “chimeric antigen T cell therapy.” “ recent phase III trials” and “CLL” AND “MURANO trial” AND “BRUIN trial” AND “CLL14 trial” AND “TRANSCEND trial” AND “updates.” Results Acquired resistance has been extensively documented in treatment of CLL, mainly due to the mutation Gly101Val that leads to displacement of pro-apoptotic proteins. Newer agents identified include pirtobrutinib and nemtabrutinib, non-covalent, reversible BTK inhibitors, the anti-CD20 monoclonal antibodies employing CD20 target antigen mechanisms ofatumumab, obinutuzumab, lisocabtagene maraleucel, a CD19 chimeric antigen T cell receptor therapy, teclistamab, a BsAb that targets the B cell maturation antigen or BCMA and Siglec-6 monoclonal antibodies. Conclusion CLL has demonstrated acquired resistance to BTK inhibitors and BCL2 inhibitors, necessitating the development and evaluating of treatment options beyond their use. Cancer immunotherapies such as bispecific antibodies and chimeric T cell therapies present with viable therapies for CLL. Novel agents have also been developed that enhance the cytotoxic effect of T cells. Future studies may focus on the developing treatments that overcome the acquired resistance that results when treatment with standard of care targeted therapies ibrutinib and venetoclax. Graphical Abstract