title: Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia.
abstract: BACKGROUND
  The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton's tyrosine kinase (BTK), an essential component of B-cell-receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells.
  
  
  METHODS
  We conducted a phase 1b-2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg.
  
  
  RESULTS
  Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The overall response rate was the same in the group that received 420 mg and the group that received 840 mg (71%), and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%.
  
  
  CONCLUSIONS
  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. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01105247.).
authors.affiliation: Division of Hematology, Department of Internal Medicine, Ohio State University, Columbus, OH 43210, USA. john.byrd@osumc.edu
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Richard R
authors.initials: RR
authors.lastname: Furman
authors.forename: Steven E
authors.initials: SE
authors.lastname: Coutre
authors.forename: Ian W
authors.initials: IW
authors.lastname: Flinn
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
authors.forename: Kristie A
authors.initials: KA
authors.lastname: Blum
authors.forename: Barbara
authors.initials: B
authors.lastname: Grant
authors.forename: Jeff P
authors.initials: JP
authors.lastname: Sharman
authors.forename: Morton
authors.initials: M
authors.lastname: Coleman
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Jones
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Zhao
authors.forename: Nyla A
authors.initials: NA
authors.lastname: Heerema
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: Juthamas
authors.initials: J
authors.lastname: Sukbuntherng
authors.forename: Betty Y
authors.initials: BY
authors.lastname: Chang
authors.forename: Fong
authors.initials: F
authors.lastname: Clow
authors.forename: Eric
authors.initials: E
authors.lastname: Hedrick
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Buggy
authors.forename: Danelle F
authors.initials: DF
authors.lastname: James
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D012008:Recurrence; D012074:Remission Induction; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000225:Adenine