Navigating the changing landscape of BTK-targeted therapies for B cell lymphomas and chronic lymphocytic leukaemia

• Published in: Nature reviews. Clinical oncology 2024-12, Vol.21 (12), p.867-887
• Main Authors: Stanchina, Michele D., Montoya, Skye, Danilov, Alexey V., Castillo, Jorge J., Alencar, Alvaro J., Chavez, Julio C., Cheah, Chan Y., Chiattone, Carlos, Wang, Yucai, Thompson, Meghan, Ghia, Paolo, Taylor, Justin, Alderuccio, Juan Pablo
• Format: Article
• Language: English
• Subjects: 692/4028/67/1990; 692/4028/67/1990/291/1621/1915; B-cell lymphoma; B-cell receptor; Bruton's tyrosine kinase; Chronic lymphocytic leukemia; Clinical trials; Enzyme inhibitors; Leukemia; Lymphoma; Malignancy; Mantle cell lymphoma; Medicine; Medicine & Public Health; Oncology; Review Article; Signal transduction
• ISSN: 1759-4774; 1759-4782; 1759-4782
• DOI: 10.1038/s41571-024-00956-1

The B cell receptor (BCR) signalling pathway has an integral role in the pathogenesis of many B cell malignancies, including chronic lymphocytic leukaemia, mantle cell lymphoma, diffuse large B cell lymphoma and Waldenström macroglobulinaemia. Bruton tyrosine kinase (BTK) is a key node mediating signal transduction downstream of the BCR. The advent of BTK inhibitors has revolutionized the treatment landscape of B cell malignancies, with these agents often replacing highly intensive and toxic chemoimmunotherapy regimens as the standard of care. In this Review, we discuss the pivotal trials that have led to the approval of various covalent BTK inhibitors, the current treatment indications for these agents and mechanisms of resistance. In addition, we discuss novel BTK-targeted therapies, including covalent, as well as non-covalent, BTK inhibitors, BTK degraders and combination doublet and triplet regimens, to provide insights on the best current treatment paradigms in the frontline setting and at disease relapse. In several B cell malignancies, BTK is a crucial mediator of oncogenic signalling pathways and inhibitors of this kinase have substantially improved patient outcomes. This Review discusses the currently approved indications for covalent and non-covalent BTK inhibitors, as well as mechanisms of resistance, and novel BTK-targeted agents and treatment strategies that have the potential to further improve outcomes. Key points Activation of the B cell receptor induces several signalling pathways that promote B cell survival and proliferation and is therefore a crucial driver of chronic lymphocytic leukaemia and B cell non-Hodgkin lymphoma; ibrutinib, the first-in-class Bruton tyrosine kinase (BTK) inhibitor, suppresses these downstream signalling cascades and has revolutionized therapy for many B cell malignancies. Second-generation covalent BTK inhibitors, such as acalabrutinib and zanubrutinib, have improved safety profiles without compromised efficacy compared with ibrutinib. Resistance to covalent BTK inhibitors can be caused by mutations within the drug-binding site of BTK, most commonly at residue C481, which forms the covalent bond with these agents. Non-covalent BTK inhibitors, such as pirtobrutinib and nemtabrutinib, bind to BTK at a different site and can overcome certain mutations that confer resistance to covalent inhibitors; however, they are associated with their own mechanisms of resistance. BTK degraders were designed to completely elimin