Prevalence of BTK and PLCG2 mutations in a real-life CLL cohort still on ibrutinib after 3 years: a FILO group study
Open accessAbstract
Mutational analyses performed following acquired ibrutinib resistance have suggested that chronic lymphocytic leukemia (CLL) progression on ibrutinib is linked to mutations in Bruton tyrosine kinase (BTK) and/or phospholipase Cγ2 (PLCG2) genes. Mutational information for patients still on ibrutinib is limited. We report a study aimed to provide a “snapshot” of the prevalence of mutations in a real-life CLL cohort still on ibrutinib after at least 3 years of treatment. Of 204 patients who initiated ibrutinib via an early-access program at 29 French Innovative Leukemia Organization (FILO) centers, 63 (31%) were still on ibrutinib after 3 years and 57 provided a fresh blood sample. Thirty patients had a CLL clone ≥0.5 × 109/L, enabling next-generation sequencing (NGS); BTK and PLCG2 mutations were detected in 57% and 13% of the NGS samples, respectively. After median follow-up of 8.5 months from sample collection, the presence of a BTK mutation was significantly associated with subsequent CLL progression (P = .0005 vs no BTK mutation). Our findings support that mutational analysis should be considered in patients receiving ibrutinib who have residual clonal lymphocytosis, and that clinical trials are needed to evaluate whether patients with a BTK mutation may benefit from an early switch to another treatment.
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The second most common BTKi resistance mechanism described in patients with CLL is mutation of PLCG2.
“The second most common BTKi resistance mechanism described in patients with CLL is mutation ofPLCG2(26).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [26]
The Introduction links PLCG2 mutations to acquired ibrutinib resistance, and the Results and discussion report PLCG2 mutations in 13% of tested patients, versus BTK mutations in 57%. But this cohort was still receiving ibrutinib, and the paper does not establish that PLCG2 mutation is the second most common resistance mechanism across BTK inhibitors in patients with CLL. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn 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 [26]
The Results and discussion (page not provided) report BTK-only and coexisting BTK/PLCG2 mutations among two patients profiled at relapse, so the paper supports those mutation patterns during progression. It does not report the claimed 35%/10%/5%/50% distribution across published studies; its main prevalence figures concern patients still on ibrutinib after three years, not a pooled group of patients progressing during therapy. (LLM, conf=0.82)
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Cited by
Sorted by citations
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“the second most common BtKi resistance mechanism described in patients with cll is mutation of PLCG2 [25].”
- Authors
- Quinquenel, A., Fornecker, L.-M., Letestu, R., Ysebaert, L., Fleury, C., Lazarian, G., Dilhuydy, M.-S., Nollet, D., Guieze, R., Feugier, P., Roos-Weil, D., Willems, L., Michallet, A.-S., Delmer, A., Hormigos, K., Levy, V., Cymbalista, F., & Baran-Marszak, F.
- Affiliations
- Centre Hospitalier Universitaire de Reims (FR)
- Inserm (FR)
- Institut universitaire du cancer de Toulouse Oncopole (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Centre Hospitalier Universitaire de Bordeaux (FR)
- Centre Hospitalier Universitaire de Tours (FR)
- CHU Clermont-Ferrand, Clermont Ferrand, France;
- Centre Hospitalier Régional et Universitaire de Nancy (FR)
- Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France;
- Hôpital Cochin (FR)
- Centre Léon Bérard (FR)
- Centre National de la Recherche Scientifique (FR)
- Groupe de Hôpitaux Universitaires Paris Seine-Saint-Denis (GHUPSSD), Assistance Publique–Hôpitaux de Paris (AP-HP), Bobigny, France;
- Corresponding author
- Quinquenel, Anne
- Fornecker, Luc-Matthieu
- Cymbalista, Florence
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2019-08-15
- Volume
- 134
- Issue
- 7
- Pages
- 641-644
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2954828829
- Cited by
- 133
- References
- 3
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 25 · 2023: 16 · 2022: 20 · 2021: 26 · 2020: 21 · 2019: 3
- FWCI
- 9.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Sunesis
- 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, ibrutinib, Bruton's tyrosine kinase, BTK mutations, PLCG2 mutations, acquired drug resistance, mutation analysis, real-world cohort, early access program
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, Adenine, Aged, Aged, 80 and over, Female, Follow-Up Studies, Humans, Male, Middle Aged, Mutation, Piperidines, Pyrazoles, Pyrimidines, Leukemia, Lymphocytic, Chronic, B-Cell, Disease Progression, Protein Kinase Inhibitors, Phospholipase C gamma
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