Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Has Significant Activity in Patients With Relapsed/Refractory B-Cell Malignancies
Ranjana H. Advani,Joseph J. Buggy,Jeff P. Sharman,Sonali M. Smith,Thomas E. Boyd,Barbara Grant,Kathryn S. Kolibaba,Richard R. Furman,Sara Rodriguez,Betty Y. Chang,Juthamas Sukbuntherng,Raquel Izumi,Ahmed Hamdy,Eric Hedrick,Nathan Fowler +14 more
TLDR
Ibrutinib, a novel BTK-targeting inhibitor, is well tolerated, with substantial activity across B-cell histologies, consistent with the irreversible mechanism.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 maximumtolerated 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. J Clin Oncol 31:88-94. © 2012 by American Society of Clinical Oncologyread more
Citations
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Journal ArticleDOI
Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia
John C. Byrd,Richard R. Furman,Steven Coutre,Ian W. Flinn,Jan A. Burger,Kristie A. Blum,Barbara Grant,Jeff P. Sharman,Morton Coleman,William G. Wierda,Jeffrey A. Jones,Weiqiang Zhao,Nyla A. Heerema,Amy J. Johnson,Juthamas Sukbuntherng,Betty Y. Chang,Fong Clow,Eric Hedrick,Joseph J. Buggy,Danelle F. James,Susan O'Brien +20 more
TL;DR: Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions.
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Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia
Andrew W. Roberts,Matthew S. Davids,John M. Pagel,Brad S. Kahl,Soham D. Puvvada,John F. Gerecitano,Thomas J. Kipps,Mary Ann Anderson,Mary Ann Anderson,Jennifer R. Brown,Lori A. Gressick,Shekman Wong,Martin Dunbar,Ming Zhu,Monali Desai,Elisa Cerri,Sari H. Enschede,Rod A. Humerickhouse,William G. Wierda,John F. Seymour,John F. Seymour +20 more
TL;DR: Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features.
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David A. Fruman,Christian Rommel +1 more
TL;DR: Through a greater focus on patient selection, increased understanding of immune modulation and strategic application of rational combinations, it should be possible to realize the potential of this promising class of targeted anticancer agents.
Journal ArticleDOI
Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma
Michael L. Wang,Simon Rule,Peter Martin,Andre Goy,Rebecca Auer,Brad S. Kahl,Brad S. Kahl,Wojciech Jurczak,Ranjana H. Advani,Jorge E. Romaguera,Michael E. Williams,Jacqueline C. Barrientos,Ewa Chmielowska,John Radford,Stephan Stilgenbauer,Martin Dreyling,Wiesław Wiktor Jędrzejczak,Peter Johnson,Stephen E. Spurgeon,Lei Li,Liang Zhang,Kate J. Newberry,Zhishuo Ou,Nancy Cheng,Bingliang Fang,Jesse McGreivy,Fong Clow,Joseph J. Buggy,Betty Y. Chang,Darrin M. Beaupre,Lori Kunkel,Kristie A. Blum +31 more
TL;DR: Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma and is enrolled into two groups: patients who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles.
Journal ArticleDOI
Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia.
John C. Byrd,Jennifer R. Brown,Susan O'Brien,Jacqueline C. Barrientos,Neil E. Kay,Nishitha Reddy,Steven Coutre,Constantine S. Tam,Stephen P. Mulligan,Ulrich Jaeger,S Devereux,Paul M. Barr,Richard R. Furman,Thomas J. Kipps,Florence Cymbalista,Christopher Pocock,Patrick Thornton,Federico Caligaris-Cappio,Tadeusz Robak,Julio Delgado,Stephen J. Schuster,Marco Montillo,Anna Schuh,S. de Vos,Devinder Gill,Adrian Bloor,Claire Dearden,Carol Moreno,Jeffrey Jones,Alvina D. Chu,Maria Fardis,Jesse McGreivy,Fong Clow,Danelle F. James,Peter Hillmen +34 more
TL;DR: Ibrutinib, as compared with ofatumumab, significantly improved progression-free survival, overall survival, and response rate among patients with previously treated CLL or SLL.
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The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy
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