Observational studyBlood advances2023
BTK and PLCG2 remain unmutated in one-third of patients with CLL relapsing on ibrutinib.
Observational study in Blood advances, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
46 citing papers in PubMed, 1 synthesis or guideline pooled it, 63 citations in OpenAlex.
- Real world results of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia: a meta-analysis of clinical studies.BMC pharmacology & toxicology · 2025Pooled it
- Trial
- Acquired mutations in patients with relapsed/refractory CLL who progressed in the ALPINE study.Blood advances · 2025Trial
- Trial
- Novel therapeutic targets at the crossroad between epigenetics and signal transduction pathways in B-cell lymphomas.Clinical and experimental medicine · 2026Review
- BRAF Alterations in Chronic Lymphocytic Leukemia: Genomic Landscape, Co-Mutation Patterns, and Clinical Relevance.Current hematologic malignancy reports · 2026Review
- When Targeted Therapy Falls Short: Unraveling Resistance Mechanisms in Chronic Lymphocytic Leukemia.Current hematologic malignancy reports · 2026Review
- Mechanisms of resistance to bruton's tyrosine kinase inhibitors: synergistic effects of tumor microenvironment regulation and signaling pathways.Annals of hematology · 2026Review
- BTK Inhibition in Hematology: From CLL/SLL to Emerging Applications Across B-Cell and Immune Disorders.Biomolecules · 2026Review
- Article
- Monoclonal gammopathy defines distinct clinical subsets in chronic lymphocytic leukemia across therapeutic eras.Blood advances · 2025Article
- Tumor Extracellular Vesicle Digital Scoring Assays for Cancer Detection and Monitoring.Precision chemistry · 2025Review
- Genes-first and phenotypes-first paths to treatment resistance in hematological malignancies.Cell death & disease · 2025Review
- Review
- Resistance to targeted therapies in chronic lymphocytic leukemia: Current status and perspectives for clinical and diagnostic practice.Leukemia · 2025Review
- A ddPCR method for simultaneous detection and quantification of Salmonella enterica, Staphylococcus aureus, Listeria monocytogenes, and Bacillus cereus in foods.Scientific reports · 2025Article
- Article
- Molecular methods for rapid detection and identification of foodborne pathogenic bacteria.World journal of microbiology & biotechnology · 2025Review
- Co-expression of CD69, CD49d, CD279 and CD20 in chronic lymphocytic leukemia cells is a new biomarker of active disease before or under therapy.Haematologica · 2025Article
- Bruton's Tyrosine Kinase (BTK) Mutations in Chronic Lymphocytic Leukemia (CLL): A Clinical View.Mediterranean journal of hematology and infectious diseases · 2025Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
39 authors at 20 institutions in 8 countries.
Funding
Abstract
Patients with chronic lymphocytic leukemia (CLL) progressing on ibrutinib constitute an unmet need. Though Bruton tyrosine kinase (BTK) and PLCG2 mutations are associated with ibrutinib resistance, their frequency and relevance to progression are not fully understood. In this multicenter retrospective observational study, we analyzed 98 patients with CLL on ibrutinib (49 relapsing after an initial response and 49 still responding after ≥1 year of continuous treatment) using a next-generation sequencing (NGS) panel (1% sensitivity) comprising 13 CLL-relevant genes including BTK and PLCG2. BTK hotspot mutations were validated by droplet digital polymerase chain reaction (ddPCR) (0.1% sensitivity). By integrating NGS and ddPCR results, 32 of 49 relapsing cases (65%) carried at least 1 hotspot BTK and/or PLCG2 mutation(s); in 6 of 32, BTK mutations were only detected by ddPCR (variant allele frequency [VAF] 0.1% to 1.2%). BTK/PLCG2 mutations were also identified in 6 of 49 responding patients (12%; 5/6 VAF <10%), of whom 2 progressed later. Among the relapsing patients, the BTK-mutated (BTKmut) group was enriched for EGR2 mutations, whereas BTK-wildtype (BTKwt) cases more frequently displayed BIRC3 and NFKBIE mutations. Using an extended capture-based panel, only BRAF and IKZF3 mutations showed a predominance in relapsing cases, who were enriched for del(8p) (n = 11; 3 BTKwt). Finally, no difference in TP53 mutation burden was observed between BTKmut and BTKwt relapsing cases, and ibrutinib treatment did not favor selection of TP53-aberrant clones. In conclusion, we show that BTK/PLCG2 mutations were absent in a substantial fraction (35%) of a real-world cohort failing ibrutinib, and propose additional mechanisms contributing to resistance.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.