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

Abstract

A B S T R A C T PurposeSurvival 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 MethodsPatients 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. ResultsFifty-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. ConclusionIbrutinib, a novel BTK-targeting inhibitor, is well tolerated, with substantial activity across B-cell histologies. J Clin

PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1

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Allogeneic hematopoietic cell transplantation as curative therapy for non-transformed follicular lymphomas

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Ibrutinib Resistance in Chronic Lymphocytic Leukemia

“…After the failure of multiple treatments, she began receiving ibrutinib at a dose of 560 mg daily in 2010 as part of a phase 1, dose-escalation study of ibrutinib in B-cell cancers. 1 By month 11, a partial response was achieved with an absolute lymphocyte count of 4530 cells per cubic millimeter. Computed tomography at month 18 showed a marked but incomplete reduction of lymphadenopathy.…”

“…[1][2][3][4] However, 5.3% of patients have disease progression, and the mechanism of resistance is largely unknown. Herein we describe the mechanism of resistance in such a case.…”