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Cited by 91Chronic Lymphocytic Leukemia ResearchLymphoma Diagnosis and TreatmentAcute Lymphoblastic Leukemia research

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

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Blombery, Piers, Thompson, Ella R., Lew, Thomas E., Tiong, Ing Soo, Bennett, Rory, Cheah, Chan Y., Lewis, Katharine Louise, Handunnetti, Sasanka M. +4 more·2022·Blood Advances
DOI 10.1182/bloodadvances.2022008325PMC PMC9647719
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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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  • There is a tendency for T747I mutations with acalabrutinib and L528W mutations with zanubrutinib among others.

    “There is a tendency for T747I mutations with acalabrutinib and L528W mutations with zanubrutinib among others (Figure 3)(20–22).”

    From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [22]

    The Results and discussion report enrichment of BTK Leu528Trp (L528W) mutations in patients with CLL treated with zanubrutinib versus ibrutinib. The paper does not support the sentence’s T747I–acalabrutinib association; it states that no patients in its cohort had received acalabrutinib. (LLM, conf=0.87)

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  • In published studies of disease progression during BTKi therapy, approximately 35% of patients were found to have a BTK mutation alone, an additional 10% had coexisting mutations in PLCG2, 5% had a PLCG2 mutation alone, and the remaining 50% were wild-type for BTK and PLCG2.

    “In published studies of disease progression during BTKi therapy,approximately 35% of patients were found to have aBTK mutation alone, an additional 10% had a coexisting mutations in PLCG2, 5% of cases had a PLCG2mutation alone, and the remaining 50% were wild-type (WT) for BTK and PLCG2 (Figure 2)(12, 19, 21–31).”

    From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [22]

    The Results and discussion report BTK variants in 37 selected patients and compare a specific BTK mutation between treatment groups. Our copy does not report the claimed 35%/10%/5%/50% breakdown across BTK mutations alone, coexisting BTK and PLCG2 mutations, PLCG2 mutations alone, and wild-type cases (searched for those percentages and mutation categories). (LLM, conf=0.75)

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1 of the 23 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. [16]Woyach JA Ruppert AS Guinn D BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia J Clin Oncol 35 13 2017 1437 1443 28418267 PMC5455463

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Authors
Blombery, P., Thompson, E. R., Lew, T. E., Tiong, I. S., Bennett, R., Cheah, C. Y., Lewis, K. L., Handunnetti, S. M., Tang, C. P. S., Roberts, A., Seymour, J. F., & Tam, C. S.
Affiliations
  • The Royal Melbourne Hospital (AU)
  • Sir Charles Gairdner Hospital (AU)
Corresponding author
Blombery, Piers
ORCID
Venue
Blood Advances
Publisher
American Society of Hematology
Published
2022-10-13
Volume
6
Issue
20
Pages
5589-5592
ISSN
  • 2473-9529 (ISSN-L)
  • 2473-9537
DOI
10.1182/bloodadvances.2022008325
PMC
PMC9647719
OpenAlex
W4288385981
Cited by
91
References
23
Citations by year
2026: 8 · 2025: 21 · 2024: 38 · 2023: 22 · 2022: 2
FWCI
12.89
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Blood Advances (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc-nd)
Topics
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
Keywords
chronic lymphocytic leukemia, BTK inhibitors, zanubrutinib, pirtobrutinib, ibrutinib, drug resistance, cross-resistance, venetoclax, treatment sequencing
MeSH terms
Agammaglobulinaemia Tyrosine Kinase, Humans, Mutation, Piperidines, Pyrazoles, Pyrimidines, Leukemia, Lymphocytic, Chronic, B-Cell, Protein Kinase Inhibitors

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