Cited by 1,128Chronic Lymphocytic Leukemia ResearchLymphoma Diagnosis and TreatmentCutaneous lymphoproliferative disorders research

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Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Has Significant Activity in Patients With Relapsed/Refractory B-Cell Malignancies

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Advani, Ranjana H., Buggy, Joseph J., Sharman, Jeff P., Smith, Sonali M., Boyd, Thomas E., Grant, Barbara, Kolibaba, Kathryn S., Furman, Richard R., Rodriguez, Sara, Chang, Betty Y., Sukbuntherng, Juthamas, Izumi, Raquel, Hamdy, Ahmed, Hedrick, Eric, Fowler, Nathan H.·2013·Journal of Clinical Oncology

DOI 10.1200/jco.2012.42.7906PMC PMC5505166

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Abstract

Purpose: Survival and progression of mature B-cell malignancies depend on signals from the B-cell antigen receptor, and Bruton tyrosine kinase (BTK) is a critical signaling kinase in this pathway. We evaluated ibrutinib (PCI-32765), a small-molecule irreversible inhibitor of BTK, in patients with B-cell malignancies. Patients and Methods: Patients with relapsed or refractory B-cell lymphoma and chronic lymphocytic leukemia received escalating oral doses of ibrutinib. Two schedules were evaluated: one, 28 days on, 7 days off; and two, once-daily continuous dosing. Occupancy of BTK by ibrutinib in peripheral blood was monitored using a fluorescent affinity probe. Dose escalation proceeded until either the maximum-tolerated dose (MTD) was achieved or, in the absence of MTD, until three dose levels above full BTK occupancy by ibrutinib. Response was evaluated every two cycles. Results: Fifty-six patients with a variety of B-cell malignancies were treated over seven cohorts. Most adverse events were grade 1 and 2 in severity and self-limited. Dose-limiting events were not observed, even with prolonged dosing. Full occupancy of the BTK active site occurred at 2.5 mg/kg per day, and dose escalation continued to 12.5 mg/kg per day without reaching MTD. Pharmacokinetic data indicated rapid absorption and elimination, yet BTK occupancy was maintained for at least 24 hours, consistent with the irreversible mechanism. Objective response rate in 50 evaluable patients was 60%, including complete response of 16%. Median progression-free survival in all patients was 13.6 months. Conclusion: Ibrutinib, a novel BTK-targeting inhibitor, is well tolerated, with substantial activity across B-cell histologies.

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Authors: Advani, R. H., Buggy, J. J., Sharman, J. P., Smith, S. M., Boyd, T. E., Grant, B., Kolibaba, K. S., Furman, R. R., Rodriguez, S., Chang, B. Y., Sukbuntherng, J., Izumi, R., Hamdy, A., Hedrick, E., & Fowler, N. H.
Affiliations: University of Vermont (US)
Corresponding author: Advani, Ranjana H.
ORCID: Advani, Ranjana H.
Sharman, Jeff P.
Smith, Sonali M.
Kolibaba, Kathryn S.
Furman, Richard R.
Chang, Betty Y.
Izumi, Raquel
Hamdy, Ahmed
Fowler, Nathan H.
Venue: Journal of Clinical Oncology
Publisher: American Society of Clinical Oncology (ASCO)
Published: 2013-01-01
Volume: 31
Issue: 1
Pages: 88-94
ISSN: 0732-183X (ISSN-L)
1527-7755
DOI: 10.1200/jco.2012.42.7906
PMC: PMC5505166
OpenAlex: W2171771895
Cited by: 1,128
References: 32
Citations by year: 2026: 17 · 2025: 38 · 2024: 47 · 2023: 44 · 2022: 46 · 2021: 90 · 2020: 79 · 2019: 92 · 2018: 73 · 2017: 117 · 2016: 94 · 2015: 135 · 2014: 134 · 2013: 110
FWCI: 58.95
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Oncology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Abbott Laboratories
GlaxoSmithKline
Gilead Sciences
Celgene
Genentech
Takeda Oncology
Pharmacyclics
National Cancer Institute (P30CA016672)
Topics: Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
Health Sciences › Medicine › Dermatology › Cutaneous lymphoproliferative disorders research
Keywords: ibrutinib, BTK inhibitors, relapsed/refractory B-cell malignancies, B-cell lymphoma, chronic lymphocytic leukemia, B cell receptor signaling, irreversible kinase inhibitors, BTK occupancy, dose-limiting toxicity, pharmacokinetics, progression-free survival
MeSH terms: Agammaglobulinaemia Tyrosine Kinase, Adenine, Administration, Oral, Adult, Aged, Aged, 80 and over, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasm Recurrence, Local, Neoplasm Staging, Piperidines, Prognosis, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, B-Cell, Salvage Therapy, Drug Resistance, Neoplasm, Maximum Tolerated Dose, Protein Kinase Inhibitors

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Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Has Significant Activity in Patients With Relapsed/Refractory B-Cell Malignancies

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