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. 2022 Oct 25;6(20):5589-5592.
doi: 10.1182/bloodadvances.2022008325.

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

Piers Blombery  1   2 , Ella R Thompson  1   2 , Thomas E Lew  1   2   3 , Ing Soo Tiong  1 , Rory Bennett  1 , Chan Y Cheah  4 , Katharine Louise Lewis  4 , Sasanka M Handunnetti  1 , Chloe Pek Sang Tang  1 , Andrew Roberts  1   2   3 , John F Seymour  1   2 , Constantine S Tam  1   2
Affiliations

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

Piers Blombery et al. Blood Adv. .

Abstract

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.

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Conflict of interest statement

Conflict-of-interest disclosure: T.E.L. is a past employee and A.R. is an employee of the Walter and Eliza Hall Institute of Medical Research, which receives milestone and royalty payments related to venetoclax. Both are recipients of a share in royalty payments paid to the Walter and Eliza Hall Institute of Medical Research. T.E.L. has received honoraria from AbbVie. A.R. has received research funding from Janssen and AbbVie. P.B. reports receiving consulting and advisory fees and honoraria from Adaptive Biotechnologies, AstraZeneca, and Servier. I.S.T. reports receiving consulting fees and honoraria from Pfizer, Servicer, and Amgen. C.S.T. reports receiving honoraria from AbbVie, BeiGene, Janssen, Novartis, and Roche and research support from AbbVie and Janssen. J.F.S. has been a consultant to Celgene and F. Hoffmann-La Roche Ltd; has received research funding from AbbVie, Celgene, Janssen, and F. Hoffmann-La Roche Ltd; serves on speakers bureaus for AbbVie, Celgene, and F. Hoffmann-La Roche Ltd; has membership on the board of directors or advisory committees for and has received honoraria from AbbVie, AstraZeneca, BMS, Gilead, Janssen, Mei Pharma, Morphosys, F. Hoffmann-La Roche Ltd, Sunesis, and Takeda. C.Y.C. reports receiving consulting and advisory fees and honoraria from Roche, Janssen, MSD, Gilead, AstraZeneca, Eli Lilly, TG Therapeutics, Beigene, Novartis, and BMS and research funding from BMS, Roche, AbbVie, and MSD. S.M.H. has received travel grants from AbbVie and Novartis and honoraria from Roche and Gilead. K.L.L. reports membership on a board or advisory committee/honoraria/patents and royalties and consultancy for AstraZeneca, IQVIA, Janssen, Loxo/Lilly, Novartis, and Roche. The remaining authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.
Longitudinal disease and mutation assessment in a patient with disease progressing on zanubrutinib and pirtobrutinib. Peripheral blood lymphocyte count over time during transition from zanubrutinib to pirtobrutinib therapy (top). CCF of detectable BTK mutations over the same period. Blue symbols indicate mutations corresponding to the Cys481Ser amino acid change; red symbols indicate the mutation corresponding to the kinase-dead Leu528Trp mutation (bottom). Changes in CCF during pirtobrutinib therapy are annotated with a connecting line.
See this image and copyright information in PMC

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