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

Blombery, P; Thompson, ER; Lew, TE; Tiong, IS; Bennett, R; Cheah, CY; Lewis, KL; Handunnetti, SM; Tang, CPS; Roberts, A; Seymour, JF; Tam, CS

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;
Details: Publication Year 2022-10-25,Volume 6,Issue #20,Page 5589-5592
Journal Title: Blood Advances
Publication Type: Research article
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.
Keywords: Agammaglobulinaemia Tyrosine Kinase; Humans; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/genetics; Mutation; Piperidines; Protein Kinase Inhibitors/pharmacology/therapeutic use; Pyrazoles; Pyrimidines
Department(s): Clinical Haematology; Pathology
PubMed ID: 35901282
Publisher's Version: https://doi.org/10.1182/bloodadvances.2022008325
Open Access at Publisher's Site: https://doi.org/10.1182/bloodadvances.2022008325
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-10-04 07:33:16

Last Modified: 2024-10-04 07:34:42