Enrichment of BTK Leu528Trp mutations in patients with CLL on zanubrutinib: potential for pirtobrutinib cross-resistance.

Autor:	Blombery P; Clinical Haematology, Peter MacCallum Cancer Center and Royal Melbourne Hospital, Melbourne, VIC, Australia.; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia., Thompson ER; Clinical Haematology, Peter MacCallum Cancer Center and Royal Melbourne Hospital, Melbourne, VIC, Australia.; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia., Lew TE; Clinical Haematology, Peter MacCallum Cancer Center and Royal Melbourne Hospital, Melbourne, VIC, Australia.; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia.; Blood Cells and Blood Cancer Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia., Tiong IS; Clinical Haematology, Peter MacCallum Cancer Center and Royal Melbourne Hospital, Melbourne, VIC, Australia., Bennett R; Clinical Haematology, Peter MacCallum Cancer Center and Royal Melbourne Hospital, Melbourne, VIC, Australia., Cheah CY; Department of Haematology, Sir Charles Gairdner Hospital, Perth, WA, Australia., Lewis KL; Department of Haematology, Sir Charles Gairdner Hospital, Perth, WA, Australia., Handunnetti SM; Clinical Haematology, Peter MacCallum Cancer Center and Royal Melbourne Hospital, Melbourne, VIC, Australia., Tang CPS; Clinical Haematology, Peter MacCallum Cancer Center and Royal Melbourne Hospital, Melbourne, VIC, Australia., Roberts A; Clinical Haematology, Peter MacCallum Cancer Center and Royal Melbourne Hospital, Melbourne, VIC, Australia.; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia.; Blood Cells and Blood Cancer Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia., Seymour JF; Clinical Haematology, Peter MacCallum Cancer Center and Royal Melbourne Hospital, Melbourne, VIC, Australia.; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia., Tam CS; Clinical Haematology, Peter MacCallum Cancer Center and Royal Melbourne Hospital, Melbourne, VIC, Australia.; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2022 Oct 25; Vol. 6 (20), pp. 5589-5592.
DOI:	10.1182/bloodadvances.2022008325
Abstrakt:	The covalent Bruton's tyrosine kinase inhibitors (BTKis) are highly effective for the treatment of chronic lymphocytic leukemia (CLL). The dominant resistance mechanism observed with the BTKi ibrutinib is the development of BTK Cys481 codon mutations. Whether a similar resistance mutation profile exists for the newer-generation, more selective BTKi zanubrutinib is unknown. In samples referred for diagnostic next-generation sequencing in patients with progressive CLL, we observed an enrichment in the kinase-dead BTK Leu528Trp mutation in patients treated with zanubrutinib compared with ibrutinib (54%; 7 of 13 vs 4%; 1 of 24, P = .001). We describe 2 patients with BTK Leu528Trp mutations who showed clinical cross-resistance and progressive enrichment of the BTK Leu528Trp mutation over time when treated with the noncovalent BTKi pirtobrutinib. Both patients subsequently responded to venetoclax-based treatment. In summary, we have identified an enrichment of the BTK Leu528Trp mutation arising in patients treated with zanubrutinib that may impart cross-resistance to the noncovalent inhibitor pirtobrutinib and therefore may have implications for sequencing of these treatments in CLL. (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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