Report of Consensus Panel 5 from the 12th International Workshop on Waldenstrom's Macroglobulinemia on the management of patients with intolerance or resistance to covalent BTK inhibitors

Jorge J Castillo¹, Francesco Autore², Neil L Berinstein³, Andrew R Branagan⁴, Meletios A Dimopoulos⁵, Carlos Fernandez de Larrea⁶, Simone Ferrero⁷, Prashant Kapoor⁸, Efstathios Kastritis⁵, Jahanzaib Khwaja⁹, Monique C Minnema¹⁰, Lugui Qiu¹¹, John F Seymour¹², Josephine M I Vos¹³, Christopher J Patterson¹⁴, Christian Buske¹⁵, Jeffrey V Matous¹⁶, Steven P Treon¹⁴, M Lia Palomba¹⁷

Affiliations

¹ Bing Center for Waldenström Macroglobulinemia, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA. Electronic address: jorgej_castillo@dfci.harvard.edu.
² Institute of Hematology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
³ Odette Cancer Centre, Sunnybrook Research Institute, Toronto, Canada.
⁴ Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA.
⁵ Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece.
⁶ Department of Hematology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
⁷ Department of Molecular Biotechnologies and Health Sciences, Division of Hematology, University of Torino, Torino, Italy.
⁸ Division of Hematology, Mayo Clinic, Rochester, MN.
⁹ Department of Haematology, University College London Hospital, London, United Kingdom.
¹⁰ Department of Hematology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
¹¹ National Clinical Research Center for Hematological Diseases, State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
¹² Peter MacCallum Cancer Centre, Royal Melbourne Hospital and University of Melbourne, Melbourne, Victoria, Australia.
¹³ Department of Hematology, Amsterdam University Medical Center (A-UMC), University of Amsterdam, Amsterdam, The Netherlands.
¹⁴ Bing Center for Waldenström Macroglobulinemia, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA.
¹⁵ Comprehensive Cancer Center Ulm, Institute of Experimental Cancer Research, University Hospital Ulm, Ulm, Germany.
¹⁶ Plasma Cell Diseases Group Colorado Blood Cancer Institute, Sarah Cannon Research Institute, Denver, CO.
¹⁷ Lymphoma Service, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY.

PMID: 40379542
DOI: 10.1053/j.seminhematol.2025.04.004

Free article

Report of Consensus Panel 5 from the 12th International Workshop on Waldenstrom's Macroglobulinemia on the management of patients with intolerance or resistance to covalent BTK inhibitors

Jorge J Castillo et al. Semin Hematol. 2025 Apr.

Free article

. 2025 Apr;62(2):113-119.

doi: 10.1053/j.seminhematol.2025.04.004. Epub 2025 Apr 8.

Authors

Affiliations

¹ Bing Center for Waldenström Macroglobulinemia, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA. Electronic address: jorgej_castillo@dfci.harvard.edu.
² Institute of Hematology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
³ Odette Cancer Centre, Sunnybrook Research Institute, Toronto, Canada.
⁴ Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA.
⁵ Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece.
⁶ Department of Hematology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
⁷ Department of Molecular Biotechnologies and Health Sciences, Division of Hematology, University of Torino, Torino, Italy.
⁸ Division of Hematology, Mayo Clinic, Rochester, MN.
⁹ Department of Haematology, University College London Hospital, London, United Kingdom.
¹⁰ Department of Hematology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
¹¹ National Clinical Research Center for Hematological Diseases, State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
¹² Peter MacCallum Cancer Centre, Royal Melbourne Hospital and University of Melbourne, Melbourne, Victoria, Australia.
¹³ Department of Hematology, Amsterdam University Medical Center (A-UMC), University of Amsterdam, Amsterdam, The Netherlands.
¹⁴ Bing Center for Waldenström Macroglobulinemia, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA.
¹⁵ Comprehensive Cancer Center Ulm, Institute of Experimental Cancer Research, University Hospital Ulm, Ulm, Germany.
¹⁶ Plasma Cell Diseases Group Colorado Blood Cancer Institute, Sarah Cannon Research Institute, Denver, CO.
¹⁷ Lymphoma Service, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY.

PMID: 40379542
DOI: 10.1053/j.seminhematol.2025.04.004

Abstract

Over the last decade, covalent Bruton tyrosine kinase (BTK) inhibitors have become a standard option for treating patients with symptomatic Waldenström Macroglobulinemia (WM) in the frontline or relapsed settings. However, the definition of intolerance and resistance to covalent BTK inhibitors has not been established. Understanding the best approaches to managing such patients is crucial to avoiding premature abandonment of effective therapy or pursuing futile therapies unlikely to be effective in controlling symptomatic disease progression. With the advent of noncovalent BTK inhibitors and BCL2 antagonists, in addition to clinical trials evaluating phospholipid-drug conjugates, antibody-drug conjugates, and bispecific antibodies, the present Consensus Panel 5 aims to establish working definitions for intolerance and resistance to covalent BTK inhibitors, as well as provide strategies to identify and manage these issues not infrequently encountered in clinical practice.

Keywords: Covalent BTK inhibitors; Intolerance; Pirtobrutinib; Resistance; Venetoclax; Waldenstrom Macroglobulinemia.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JJC received honoraria from Abbvie, AstraZeneca, Beigene, Cellectar, J&J, Kite, Loxo, and Pharmacyclics, and research funds from Abbvie, AstraZeneca, Beigene, Cellectar, Loxo, and Pharmacyclics. FA received honoraria from Abbvie, AstraZeneca, Beigene, and J&J. NLB received research funds from AstraZeneca and honoraria from Abbvie, AstraZeneca, and Beigene. ARB received honoraria or research funds from Adaptive, BeiGene, CSL Behring, Genzyme, Karyopharm, Pharmacyclics, and Sanofi. MAD received honoraria from Amgen, AstraZeneca, Beigene, BMS, GSK, Janssen, Menarini, Regeneron, Sanofi, Swixx, And Takeda. CFL received honoraria from Amgen, Beigene, BMS, GSK, J&J, Sanofi, Menarini, Oncopeptides, Pfizer, and Roche, and research funds from Amgen, BMS, GSK, and J&J. SF received honoraria from Abbvie, AstraZeneca, Beigene, EUSA Pharma, Gentili, Gilead, Incyte, Italfarmaco, Janssen, Lilly, Janssen, Recordati, Roche, and Sandoz, and research funds from Beigene, Gilead, and Morphosys. PK received research funding or honoraria from AbbVie, Amgen, Angitia Bio, Ascentage, BeiGene, Bristol Myers Squibb, CVS Caremark, GlaxoSmithKline, Ichnos, Janssen, Karyopharm, Keosys, Kite, Loxo, Mustang Bio, Oncopeptides, Pharmacyclics, and X4. SK received honoraria from GSK, Janssen, Pfizer, and Prothena, and research funds from GSK, Janssen, and Pfizer. MCM received research funds from Beigene, and honoraria from Beigene, J&J, Sanofi, and Siemens. LQ received honoraria from AstraZeneca, Beigene, GSK, J&J, Pfizer, Roche, and Sanofi. JFS reports consultancy for Genor Bio, TG Therapeutics; Research Funding from Abbvie, BMS, Roche. Speakers bureau for AbbVie, Astra Zeneca, BMS, Roche; speaking honoraria from AbbVie, Astra Zeneca, Beigene, BMS, Gilead, Janssen, Roche. JMIV received honoraria from Amgen, Beigene, BMS, Janssen, and Sanofi, and research funds from AbbVie/Genmab, and BeiGene. CB reports consultancy, honoraria, advisory board, and travel expenses from Roche/Genentech, Janssen, BeiGene, Novartis, Pfizer, Incyte, AbbVie, Gilead, Celltrion, MorphoSys, Regeneron, Sobi, and Lilly. JVM received consulting fees from Beigene. ST received research funding and/or consulting fees from Abbvie/Pharmacyclics, Janssen, Beigene, Lilly, BMS, and Ono Pharmaceuticals. MLP received honoraria from Beigene, BMS, Cellectar, Kite, and Synthekine. JK and CJP have no conflicts of interest to disclose.

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Report of Consensus Panel 5 from the 12th International Workshop on Waldenstrom's Macroglobulinemia on the management of patients with intolerance or resistance to covalent BTK inhibitors

Affiliations

Report of Consensus Panel 5 from the 12th International Workshop on Waldenstrom's Macroglobulinemia on the management of patients with intolerance or resistance to covalent BTK inhibitors

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Affiliations

Abstract

Conflict of interest statement

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