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Cited by 14Chronic Lymphocytic Leukemia ResearchLymphoma Diagnosis and TreatmentAcute Lymphoblastic Leukemia research

Acquired Mutations in Patients with Relapsed/Refractory Cll Who Progressed in the Alpine Study

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Brown, Jennifer R., Li, Jessica, Eichhorst, Barbara F., Lamanna, Nicole, O’Brien, Susan M., Tam, Constantine S., Qiu, Lugui, Huang, Ruiqi +5 more·2025·Blood Advances
DOI 10.1182/bloodadvances.2024014206PMC PMC12008693
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Abstract

Some patients with chronic lymphocytic leukemia who develop progressive disease (PD) during covalent Bruton tyrosine kinase (BTK) inhibitor treatment acquire resistance mutations in BTK or PLCG2. Here, we report gene mutation data from paired baseline and PD peripheral blood samples from 52 patients (zanubrutinib, n = 24; ibrutinib, n = 28) who, at an early median follow-up of 25.7 months, progressed on zanubrutinib or ibrutinib treatment in ALPINE. No BTK mutations were observed at baseline; at PD, 8 patients (zanubrutinib, n = 5; ibrutinib, n = 3) acquired 17 BTK mutations, 82.4% (zanubrutinib, n = 11/14; ibrutinib, n = 3/3) at C481. Non-C481 mutations occurred in 12.5% (3/24) of zanubrutinib-treated patients (L528W: n = 2; cancer cell fraction [CCF] = 9.58% and 17.6%; A428D: n = 1; CCF = 37.03%). At baseline, 48 of 52 patients had ≥1 driver gene mutation(s), most frequently in NOTCH1 (n = 21), TP53 (n = 19), BRAF (n = 10), SF3B1 (n = 8), and ATM (n = 8). At PD, acquired mutations occurred in 1 zanubrutinib-treated patient (TP53, XPO1) and 5 ibrutinib-treated patients (TP53, n = 1 patient; SETD2, n = 1; SF3B1, n = 1; ASXL1, n = 2). Baseline driver gene mutations were not associated with development of BTK mutations, but patients with ≥2 baseline driver gene mutations were more likely to acquire BTK mutations at PD. The short treatment duration and a low BTK mutations incidence suggests that mechanisms other than BTK/PLCG2 mutations drive most early PD. This trial was registered at www.ClinicalTrials.gov as #NCT03734016.

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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 [20]

    The Results (BTK/PLCG2 mutations in patients without RT; page unavailable) report L528W in 2 of 24 patients who progressed on zanubrutinib. The Introduction and Discussion associate acalabrutinib with T474 mutations, not the claimed T747I; the study itself included no acalabrutinib-treated patients. (LLM, conf=0.88)

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  • Ibrutinib, acalabrutinib, and zanubrutinib bind covalently to residue C481 of BTK, and thus are susceptible to mutations changing C481 to another amino acid, most commonly C481S.

    “Ibrutinib, acalabrutinib, and zanubrutinib bind covalently to residue C481 of BTK, and thus are susceptible to mutations changing C481 to another amino acid, most commonly C481S(19–21).”

    From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [20]

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Cites

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Research works printed but not linked: 23

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Authors
Brown, J. R., Li, J., Eichhorst, B. F., Lamanna, N., O’Brien, S. M., Tam, C. S., Qiu, L., Huang, R., Shi, Y., Idoine, A., Salmi, T., Cohen, A. C., & Shadman, M.
Affiliations
  • Dana-Farber Cancer Institute (US)
  • 2BeiGene Inc, San Mateo, CA
  • University of Cologne (DE)
  • Columbia University Irving Medical Center (US)
  • 5Division of Hematology/Oncology, University of California, Irvine, Irvine, CA
  • The Alfred Hospital (AU)
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
  • BeiGene (China) (CN)
  • 11BeiGene International GmbH, Basel, Switzerland
  • Fred Hutch Cancer Center (US)
Corresponding author
Brown, Jennifer R.
ORCID
Venue
Blood Advances
Publisher
American Society of Hematology
Published
2025-04-11
Volume
9
Issue
8
Pages
1918-1926
ISSN
  • 2473-9529 (ISSN-L)
  • 2473-9537
DOI
10.1182/bloodadvances.2024014206
PMC
PMC12008693
OpenAlex
W4406798108
Cited by
14
References
9
Citations by year
2026: 6 · 2025: 8
FWCI
9.05
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)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • AstraZeneca
  • BeiGene
  • Incyte
  • MorphoSys
  • Genentech
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, relapsed/refractory disease, acquired mutations, BTK mutations, zanubrutinib, ibrutinib, BTK inhibitor resistance, PLCγ2, Notch1, TP53, driver mutations, disease progression
MeSH terms
Agammaglobulinaemia Tyrosine Kinase, Adenine, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Mutation, Piperidines, Pyrazoles, Pyrimidines, Leukemia, Lymphocytic, Chronic, B-Cell, Disease Progression, Drug Resistance, Neoplasm, Protein Kinase Inhibitors

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