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.)

• Authors: Michael L Wang, Simon Rule, Peter Martin, Andre Goy, Rebecca Auer, 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, Wieslaw Wiktor Jedrzejczak, Peter Johnson, Stephen E Spurgeon, Lei Li, Liang Zhang, Kate Newberry, Zhishuo Ou, Nancy Cheng, Bingliang Fang, Jesse McGreivy, Fong Clow, Joseph J Buggy, Betty Y Chang, Darrin M Beaupre, Lori A Kunkel, Kristie A Blum
• Journal: The New England journal of medicine (N Engl J Med) Vol. 369 Issue 6 Pg. 507-16 (Aug 08 2013) ISSN: 1533-4406 [Electronic] United States
• PMID: 23782157 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Piperidines
• Protein Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• ibrutinib
• Protein-Tyrosine Kinases
• Agammaglobulinaemia Tyrosine Kinase
• BTK protein, human
• Adenine

Topics

• Adenine (analogs & derivatives)
• Administration, Oral
• Adult
• Agammaglobulinaemia Tyrosine Kinase
• Aged
• Aged, 80 and over
• Drug Resistance, Neoplasm
• Female
• Humans
• Lymphocyte Count
• Lymphoma, Mantle-Cell (drug therapy, mortality)
• Male
• Middle Aged
• Piperidines
• Protein Kinase Inhibitors (adverse effects, therapeutic use)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyrazoles (adverse effects, therapeutic use)
• Pyrimidines (adverse effects, therapeutic use)
• Recurrence
• Survival Analysis