Resistance to Bruton tyrosine kinase inhibition in chronic lymphocytic leukaemia and non‐Hodgkin lymphoma

Nakhoda, Shazia; Vistarop, Aldana; Wang, Y. Lynn

doi:10.1111/bjh.18418

Cited by 104Chronic Lymphocytic Leukemia ResearchLymphoma Diagnosis and TreatmentAcute Lymphoblastic Leukemia research

Resistance to Bruton tyrosine kinase inhibition in chronic lymphocytic leukaemia and non‐Hodgkin lymphoma

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Nakhoda, Shazia, Vistarop, Aldana, Wang, Y. Lynn·2023·British Journal of Haematology

DOI 10.1111/bjh.18418PMC PMC9839590

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Abstract

Summary: Bruton tyrosine kinase inhibitors (BTKi) have transformed the therapeutic landscape of chronic lymphocytic leukaemia (CLL) and non‐Hodgkin lymphoma. However, primary and acquired resistance to BTKi can be seen due to a variety of mechanisms including tumour intrinsic and extrinsic mechanisms such as gene mutations, activation of bypass signalling pathways and tumour microenvironment. Herein, we provide an updated review of the key clinical data of BTKi treatment in CLL, mantle cell lymphoma, and diffuse large B‐cell lymphoma (DLBCL). We incorporate the most recent findings regarding mechanisms of resistance to covalent and non‐covalent inhibitors, including ibrutinib, acalabrutinib, zanubrutinib and pirtobrutinib. We also cover the clinical sensitivity of certain molecular subtypes of DLBCL to an ibrutinib‐containing regimen. Lastly, we summarise ongoing clinical investigations aimed at overcoming resistance via use of BTKi‐containing combined therapies or the novel non‐covalent BTKi. The review article targets an audience of clinical practitioners, clinical investigators and translational researchers.

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Inhibition of BTK abrogates BCR-driven survival and proliferation, and is an effective therapeutic strategy against several B-cell malignancies, particularly CLL/SLL.
“As a result, inhibition of BTK abrogatesBCR-driven survival and proliferation, and is an effective therapeutic strategyagainst several B-cell malignancies, particularly chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)(3).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [3]
The Introduction says BTK inhibition disrupts BCR signaling, and the Conclusion describes it as pivotal in treating B-cell malignancies; the Chronic Lymphocytic Leukemia section says ibrutinib has drastically changed CLL management. But the Introduction specifies that BCR inhibition primarily slows proliferation rather than directly kills cells, so saying it 'abrogates' survival and proliferation overstates the source. Page numbers are not provided in our copy. (LLM, conf=0.88)
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A PHASE IIA STUDY EVALUATING THE SAFETY AND TOLERABILITY OF UMBRALISIB AND IBRUTINIB IN PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE LARGE B‐CELL LYMPHOMA
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[43]Quinquenel A,, Prevalence of BTK and PLCG2 mutations in a real-life CLL cohort still on ibrutinib after 3 years: a FILO group study. Blood, 2019. 134(7): p. 641– 644. 31243043
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Authors: Nakhoda, S., Vistarop, A., & Wang, Y. L.
Affiliations: Fox Chase Cancer Center (US)
Corresponding author: Wang, Y. Lynn
ORCID: Nakhoda, Shazia
Vistarop, Aldana
Wang, Y. Lynn
Venue: British Journal of Haematology
Publisher: Wiley
Published: 2022-08-27
Volume: 200
Issue: 2
Pages: 137-149
ISSN: 0007-1048 (ISSN-L)
1365-2141
DOI: 10.1111/bjh.18418
PMC: PMC9839590
OpenAlex: W4293368300
Cited by: 104
References: 126
Citations by year: 2026: 21 · 2025: 30 · 2024: 34 · 2023: 19
FWCI: 3.44
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: British Journal of Haematology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute (R21CA263415)
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, chronic lymphocytic leukemia, non-Hodgkin lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib, drug resistance mechanisms, tumor microenvironment, non-covalent BTK inhibitors, combination therapy
MeSH terms: Agammaglobulinaemia Tyrosine Kinase, Adult, Humans, Lymphoma, Non-Hodgkin, Pyrazoles, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Mantle-Cell, Protein Kinase Inhibitors, Tumor Microenvironment

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Resistance to Bruton tyrosine kinase inhibition in chronic lymphocytic leukaemia and non‐Hodgkin lymphoma

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