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Review
. 2024 Dec;21(12):867-887.
doi: 10.1038/s41571-024-00956-1. Epub 2024 Nov 1.

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

Michele D Stanchina  1 , Skye Montoya  1 , Alexey V Danilov  2 , Jorge J Castillo  3 , Alvaro J Alencar  1 , Julio C Chavez  4 , Chan Y Cheah  5   6 , Carlos Chiattone  7 , Yucai Wang  8 , Meghan Thompson  9 , Paolo Ghia  10   11 , Justin Taylor  1 , Juan Pablo Alderuccio  12
Affiliations
Review

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

Michele D Stanchina et al. Nat Rev Clin Oncol. 2024 Dec.

Abstract

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.

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Conflict of interest statement

Competing interests A.V.D. has received research funding and consultancy fees from Abbvie, AstraZeneca, Beigene, Bristol Myers Squibb, GenMab, Lilly Oncology, MEI Pharma, Nurix Therapeutics and Presage; research funding from Bayer, Cyclacel and Incyte; and consultancy fees from Genentech, Janssen, Merck and Regeneron. J.J.C. reports consulting or advisory roles for AbbVie/Pharmacyclics, BeiGene, Cellectar, Janssen, Kite Pharma/Gilead, Loxo Oncology/Lilly, Mustang Bio and Roche/Genentech, and institutional research funding from AbbVie, AstraZeneca, BeiGene, Cellectar, Loxo/Lilly, Pharmacyclics and TG Therapeutics. A.J.A. has received consultancy fees from Amgen, BeiGene, Epizyme, Genentech, Incyte, Janssen, Kite, Lilly, Seagen, and TG Therapeutics and research funding from BeiGene, Incyte and Loxo Oncology. J.C.C. has received consultancy fees from AbbVie, ADC Therapeutics, Adicet, AstraZeneca, BeiGene, Bristol Myers Squibb, Cellectar, Genentech, Genmab, Janssen, Kite Pharma/Gilead and Novartis; honoraria from AstraZeneca, BeiGene and Lilly; research funding from AstraZeneca, Janssen and Merck; and has served as a Data and Safety Monitoring Board member for Atara and the National Cancer Institute. C.Y.C. has received consultancy fees or honoraria from AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Dizal, Genmab, Gilead, Janssen, Lilly, Menarini, Novartis, Roche, and TG Therapeutics and research funding from AbbVie, Bristol Myers Squibb, Lilly, MSD and Roche. Y.W. has received institutional research funding from Genentech, Genmab, Incyte, InnoCare, Lilly, Loxo Oncology, MorphoSys, and Novartis and institutional honoraria from Kite Pharma; has served on advisory boards (compensation to institution) for AstraZeneca, BeiGene, Incyte, InnoCare, Jansen, Kite Pharma/Gilead, Lilly, Loxo Oncology and TG Therapeutics; has consulted for (compensation to institution) AbbVie and Innocare; and has an immediate family member who is employed by and has stock ownership in Merck. M.T. has received consultancy fees from AstraZeneca, Loxo Oncology/Lilly and Pharmacyclics/Janssen; honoraria from the Brazilian Association of Hematology, Hemotherapy and Cellular Therapy, Curio Science, Dava Oncology, Intellisphere, the Massachusetts Medical Society, MJH Life Sciences, and VJHemOnc and institutional research funding from Abbvie, AstraZeneca, Beigene, Genentech, Genmab and Nurix Therapeutics. P.G. has received honoraria from AbbVie, ArQule/MSD, AstraZeneca, BeiGene, Celgene/Juno/Bristol Myers Squibb, Janssen, Loxo Oncology/Lilly, MEI Pharma, Roche, and Sanofi and research funding from AbbVie, AstraZeneca, Bristol Myers Squibb, Janssen and Sunesis. J.P.A. has received consultancy fees from AbbVie, ADC Therapeutics, Genentech, and Regeneron and research funding from AbbVie, ADC Therapeutics, BeiGene and Genmab. M.D.S., S.M., C.C. and J.T. declare no competing interests.

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