title: 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.affiliation: Department of Lymphoma and Myeloma, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. miwang@mdanderson.org
authors.forename: Michael L
authors.initials: ML
authors.lastname: Wang
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authors.lastname: Rule
authors.forename: Peter
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authors.lastname: Chmielowska
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authors.lastname: Stilgenbauer
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authors.forename: Wieslaw Wiktor
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authors.lastname: Jedrzejczak
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authors.initials: SE
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authors.forename: Liang
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authors.lastname: Zhang
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authors.lastname: Newberry
authors.forename: Zhishuo
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authors.lastname: Ou
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authors.forename: Bingliang
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authors.lastname: Fang
authors.forename: Jesse
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authors.lastname: McGreivy
authors.forename: Fong
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authors.lastname: Clow
authors.forename: Joseph J
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authors.lastname: Buggy
authors.forename: Betty Y
authors.initials: BY
authors.lastname: Chang
authors.forename: Darrin M
authors.initials: DM
authors.lastname: Beaupre
authors.forename: Lori A
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authors.lastname: Kunkel
authors.forename: Kristie A
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authors.lastname: Blum
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000284:Administration, Oral; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000369:Aged, 80 and over; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D018655:Lymphocyte Count; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D012008:Recurrence; D016019:Survival Analysis
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000225:Adenine