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Cited by 37Chronic Lymphocytic Leukemia ResearchLymphoma Diagnosis and TreatmentAcute Lymphoblastic Leukemia research

Resistance to Bruton tyrosine kinase inhibitors: the Achilles heel of their success story in lymphoid malignancies

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Stephens, Deborah M., Byrd, John C.·2021·Blood
DOI 10.1182/blood.2020006783PMC PMC8570054
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Abstract

Bruton tyrosine kinase inhibitors (BTKi) have significantly changed the treatment landscape for patients with B-cell malignancies, including chronic lymphocytic leukemia, Waldenstrom macroglobulinemia, mantle cell lymphoma, and marginal zone lymphoma. Unfortunately, patients with BTKi-resistant disease have shortened survival. Clinical and molecular risk factors, such as number of prior therapies and presence of TP53 mutations, can be used to predict patients at the highest risk of developing BTKi resistance. Many mechanisms of BTKi resistance have been reported with mutations in BTK and phospholipase C γ2 supported with the most data. The introduction of venetoclax has lengthened the survival of patients with BTKi-resistant disease. Ongoing clinical trials with promising treatment modalities, such as next-generation BTKi and chimeric antigen receptor T-cell therapy, have reported promising efficacy in patients with BTKi-resistant disease. Continued research focusing on resistance mechanisms and methods of how to circumvent resistance is needed to further prolong the survival of patients with BTKi-resistant B-cell malignancies.

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  • BTK T474I/S have been termed "gatekeeper mutations" as they cause steric interference with binding for ibrutinib or acalabrutinib.

    “BTKT474I/S have been termed “gatekeeper mutations” as they cause steric interference with binding for ibrutinib or acalabrutinib (39, 40).”

    From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [39]

    The Introduction states that BTK T474 mutations are called “gatekeeper mutations” because they interfere with ibrutinib or acalabrutinib binding. It does not specify the T474I/S substitutions or describe the interference as steric. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Stephens, D. M., & Byrd, J. C.
Affiliations
  • University of Utah (US)
  • University of Cincinnati (US)
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2021-09-30
Volume
138
Issue
13
Pages
1099-1109
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood.2020006783
PMC
PMC8570054
OpenAlex
W3184205536
Cited by
37
References
9
Citations by year
2026: 9 · 2025: 9 · 2024: 7 · 2023: 7 · 2022: 5
FWCI
2.67
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Cancer Institute (R35CA197734, K23CA212271)
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
BTK inhibitors, BTK inhibitor resistance, B-cell malignancies, chronic lymphocytic leukemia, Waldenström macroglobulinemia, mantle cell lymphoma, marginal zone lymphoma, TP53 mutation, BTK mutations, PLCG2 mutations, venetoclax, CAR T-cell therapy, resistance mechanisms
MeSH terms
Agammaglobulinaemia Tyrosine Kinase, Aged, Animals, Antineoplastic Agents, Humans, Waldenstrom Macroglobulinemia, Male, Mutation, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, Large B-Cell, Diffuse, Drug Resistance, Neoplasm, Lymphoma, Mantle-Cell, Protein Kinase Inhibitors

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