ArticleClinical cancer research : an official journal of the American Association for Cancer Research2015
Pharmacological and Protein Profiling Suggests Venetoclax (ABT-199) as Optimal Partner with Ibrutinib in Chronic Lymphocytic Leukemia.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 130 papers.
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Who cites it
130 citing papers in PubMed, 216 citations in OpenAlex.
- Fixed-duration pirtobrutinib plus venetoclax-rituximab versus venetoclax-rituximab for patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (BRUIN CLL-322): an open-label, multicentre, randomised, controlled, phase 3 trial.Lancet (London, England) · 2026Trial
- Docirbrutinib is a pan-mutant BTK inhibitor and inhibits B-cell receptor signaling in chronic lymphocytic leukemia cells in preclinical and early clinical investigations.Blood cancer journal · 2026Trial
- Phase II Study of Acalabrutinib, Venetoclax, and Obinutuzumab in a Treatment-Naïve Chronic Lymphocytic Leukemia Population Enriched for High-Risk Disease.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2025Trial
- Five-year follow-up of a phase 2 study of ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial therapy in CLL.Blood advances · 2024Trial
- Immune restoration with ibrutinib plus venetoclax in first-line chronic lymphocytic leukemia: the phase 2 CAPTIVATE study.Blood advances · 2023Trial
- A phase 1b study of ibrutinib in combination with obinutuzumab in patients with relapsed or refractory chronic lymphocytic leukemia.Leukemia · 2023Trial
- Dose-finding study of ibrutinib and venetoclax in relapsed or refractory mantle cell lymphoma.Blood advances · 2022Trial
- Ibrutinib Plus Venetoclax for First-Line Treatment of Chronic Lymphocytic Leukemia: Primary Analysis Results From the Minimal Residual Disease Cohort of the Randomized Phase II CAPTIVATE Study.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2021Trial
- Zanubrutinib, obinutuzumab, and venetoclax with minimal residual disease-driven discontinuation in previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: a multicentre, single-arm, phase 2 trial.The Lancet. Haematology · 2021Trial
- Phase II Study of Combination Obinutuzumab, Ibrutinib, and Venetoclax in Treatment-Naïve and Relapsed or Refractory Chronic Lymphocytic Leukemia.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2020Trial
- Ibrutinib and Venetoclax for First-Line Treatment of CLL.The New England journal of medicine · 2019Trial
- A pilot study of lower doses of ibrutinib in patients with chronic lymphocytic leukemia.Blood · 2018Trial
- Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials.British journal of haematology · 2018Trial
- Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial.The Lancet. Oncology · 2018Trial
- Bruton's Tyrosine Kinase Inhibitors: Mechanisms, Efficacy, Toxicities and Applications for the Treatment of Human Diseases.MedComm · 2026Review
- Nintedanib increases BCL-2 in fibrotic fibroblasts, enhancing ABT-199 apoptosis and fibrosis resolution.American journal of respiratory cell and molecular biology · 2026Article
- IbrutinibHaematologica · 2026Article
- Fixed-duration ibrutinib-venetoclax for first-line treatment of patients with chronic lymphocytic leukemia: the REALITY-WW prospective real-world study cohort.Future oncology (London, England) · 2025Observational
- Optimizing Ibrutinib Posology in Chronic Lymphocytic Leukemia Using a Semi-Mechanistic Pharmacometric Framework.CPT: pharmacometrics & systems pharmacology · 2025Article
- Pharmacological profiling in CLL patients during pirtobrutinib therapy and disease progression.Blood cancer journal · 2025Article
70 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
purposeBruton's tyrosine kinase (BTK) is a critical enzyme in the B-cell receptor pathway and is inhibited by ibrutinib due to covalent binding to the kinase domain. Though ibrutinib results in impressive clinical activity in chronic lymphocytic leukemia (CLL), most patients achieve only partial remission due to residual disease. We performed a pharmacologic profiling of residual circulating CLL cells from patients receiving ibrutinib to identify optimal agents that could induce cell death of these lymphocytes. EXPERIMENTAL
designEx vivo serial samples of CLL cells from patients on ibrutinib were obtained prior and after (weeks 2, 4, and 12) the start of treatment. These cells were incubated with PI3K inhibitors (idelalisib or IPI-145), bendamustine, additional ibrutinib, or BCL-2 antagonists (ABT-737 or ABT-199), and cell death was measured. In vitro investigations complemented ex vivo studies. Immunoblots for BTK signaling pathway and antiapoptotic proteins were performed.
resultsThe BCL-2 antagonists, especially ABT-199, induced high cell death during ex vivo incubations. In concert with the ex vivo data, in vitro combinations also resulted in high cytotoxicity. Serial samples of CLL cells obtained before and 2, 4, 12, or 36 weeks after the start of ibrutinib showed inhibition of BTK activity and sensitivity to ABTs. Among the three BCL-2 family antiapoptotic proteins that are overexpressed in CLL, levels of MCL-1 and BCL-XL were decreased after ibrutinib while ABT-199 selectively antagonizes BCL-2.
conclusionsOur biologic and molecular results suggest that ibrutinib and ABT-199 combination should be tested clinically against CLL.
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