Enrichment of BTK Leu528Trp mutations in patients with CLL on zanubrutinib: Potential for pirtobrutinib cross resistance
- Author(s)
- Blombery, P; Thompson, ER; Lew, TE; Tiong, IS; Bennett, R; Cheah, CY; Lewis, KL; Handunnetti, SM; Tang, CPS; Roberts, A; Seymour, JF; Tam, CS;
- Journal Title
- Blood Advances
- Publication Type
- epub ahead of print
- Abstract
- The covalent Bruton's tyrosine kinase inhibitors (BTKi) 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. From 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 to ibrutinib (54% [7/13] vs 4% [1/24], p=0.001). 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 non-covalent BTK inhibitor 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 which may impart cross-resistance to the non-covalent inhibitor pirtobrutinib and therefore implications for sequencing of these treatments in CLL.
- Publisher
- ASH
- Research Division(s)
- Blood Cells And Blood Cancer
- PubMed ID
- 35901282
- Publisher's Version
- https://doi.org/10.1182/bloodadvances.2022008325
- Open Access at Publisher's Site
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Creation Date: 2022-08-08 09:15:44
Last Modified: 2022-08-08 09:35:55