ArticleProceedings of the National Academy of Sciences of the United States of America2014
Evolution of ibrutinib resistance in chronic lymphocytic leukemia (CLL).
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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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.
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Who cites it
50 citing papers in PubMed.
- Ofatumumab maintenance prolongs progression-free survival in relapsed chronic lymphocytic leukemia: final analysis of the PROLONG study.Blood cancer journal · 2019Trial
- Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study.Blood · 2018Trial
- Trial
- Resistance mechanisms and approach to chronic lymphocytic leukemia after BTK inhibitor therapy.Leukemia & lymphoma · 2025Review
- Long-read single-cell RNA sequencing enables the study of cancer subclone-specific genotypes and phenotypes in chronic lymphocytic leukemia.Genome research · 2025Article
- Advancements in leukemia management: Bridging diagnosis, prognosis and nanotechnology (Review).International journal of oncology · 2024Review
- New pharmacodynamic parameters linked with ibrutinib responses in chronic lymphocytic leukemia: Prospective study in real-world patients and mathematical modeling.PLoS medicine · 2024Observational
- Long-read single-cell RNA sequencing enables the study of cancer subclone-specific genotype and phenotype in chronic lymphocytic leukemia.bioRxiv : the preprint server for biology · 2024Article
- Assessment of ibrutinib scheduling on leukocyte, lymph node size and blood pressure dynamics in chronic lymphocytic leukemia through pharmacokinetic-pharmacodynamic models.CPT: pharmacometrics & systems pharmacology · 2023Article
- The role of migration in mutant dynamics in fragmented populations.Journal of evolutionary biology · 2023Article
- Article
- Review
- DEVOLUTION-A method for phylogenetic reconstruction of aneuploid cancers based on multiregional genotyping data.Communications biology · 2021Article
- Three-dimensional co-culture model of chronic lymphocytic leukemia bone marrow microenvironment predicts patient-specific response to mobilizing agents.Haematologica · 2021Article
- The contribution of single-cell analysis of acute leukemia in the therapeutic strategy.Biomarker research · 2021Review
- Chronic Lymphocytic Leukemia.Cold Spring Harbor perspectives in medicine · 2021Review
- Clonal Evolution of High-Risk Chronic Lymphocytic Leukemia: A Contemporary Perspective.Frontiers in oncology · 2021Review
- Resistance Mutations to BTK Inhibitors Originate From the NF-κB but Not From the PI3K-RAS-MAPK Arm of the B Cell Receptor Signaling Pathway.Frontiers in immunology · 2021Review
- Translational approach from preclinical to clinical: comparison of dose finding methods of a new Bcl2 inhibitor using PK-PD modeling and interspecies extrapolation.Investigational new drugs · 2020Article
- Aspirin and the chemoprevention of cancers: A mathematical and evolutionary dynamics perspective.Wiley interdisciplinary reviews. Systems biology and medicine · 2020Review
Corrections and comments
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Authors and funding
3 authors.
Funding
Abstract
The Bruton tyrosine kinase inhibitor (BTKi) ibrutinib is a new targeted therapy for patients with chronic lymphocytic leukemia (CLL). Ibrutinib is given orally on a continuous schedule and induces durable remissions in the majority of CLL patients. However, a small proportion of patients initially responds to the BTKi and then develops resistance. Estimating the frequency, timing, and individual risk of developing resistance to ibrutinib, therefore, would be valuable for long-term management of patients. Computational evolutionary models, based on measured kinetic parameters of patients, allow us to approach these questions and to develop a roadmap for personalized prognosis and treatment management. Our kinetic models predict that BTKi-resistant mutants exist before initiation of ibrutinib therapy, although they only comprise a minority of the overall tumor burden. Furthermore, we can estimate the time required for resistant cells to grow to detectable levels. We predict that this can be highly variable, depending mostly on growth and death rates of the individual CLL cell clone. For a specific patient, this time can be predicted with a high degree of certainty. Our model can thus be used to predict for how long ibrutinib can suppress the disease in individual patients. Furthermore, the model can suggest whether prior debulking of the tumor with chemo-immunotherapy can prolong progression-free survival under ibrutinib. Finally, by applying the models to data that document progression during ibrutinib therapy, we estimated that resistant mutants might have a small (<2%) mean fitness advantage in the absence of treatment, compared with sensitive cells.
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