Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma

Abstract

BACKGROUND Bruton's tyrosine kinase (BTK) is a mediator of the B-cell–receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin's lymphoma, including mantle-cell lymphoma. METHODS In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety. RESULTS The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progression-free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months. CONCLUSIONS Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01236391.)

Absorption, Metabolism, and Excretion of Oral 14C Radiolabeled Ibrutinib: An Open-Label, Phase I, Single-Dose Study in Healthy Men

“…The U.S. Food and Drug Administration declared ibrutinib as a breakthrough therapy in February 2013 for the treatment of relapsed/ refractory mantle cell lymphoma and gave approval for this indication in November 2013 (Wang et al, 2013). Recently, in February 2014 the Food and Drug Administration provided accelerated approval for ibrutinib for chronic lymphocytic leukemia in patients who had received at least one previous therapy (Byrd et al, 2013;O'Brien et al, 2014).…”

Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions

“…Most events were grade 1 to 2 (spontaneous bruising or petechiae), but in 5% of patients, they were of grade 3 or higher after trauma. [4][5][6] Platelets are the most important blood cells to prevent bleeding after vascular injury. Two Tec family kinases, Btk and Tec, are involved in platelet activation downstream of the collagen receptor glycoprotein VI (GPVI) via phospholipase Cg2 (PLCg2) phosphorylation and activation.…”

Evolution of ibrutinib resistance in chronic lymphocytic leukemia (CLL)

“…Ibrutinib (previously called PCI-32765) is a potent (IC 50 , 0.5 nM) BTK inhibitor that inactivates BTK through irreversible covalent bonding to Cys-481 in the ATP-binding domain of BTK (3)(4)(5). Early-stage clinical trials found ibrutinib to be particularly active in patients with CLL (6, 7) and mantle cell lymphoma (8), and the drug recently has been Food and Drug Administration-approved for patients with relapsed CLL and mantle cell lymphoma.…”