title: Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia.
abstract: BACKGROUND
  In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, in patients at risk for a poor outcome.
  
  
  METHODS
  In this multicenter, open-label, phase 3 study, we randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti-CD20 antibody ofatumumab. The primary end point was the duration of progression-free survival, with the duration of overall survival and the overall response rate as secondary end points.
  
  
  RESULTS
  At a median follow-up of 9.4 months, ibrutinib significantly improved progression-free survival; the median duration was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group (hazard ratio for progression or death in the ibrutinib group, 0.22; P<0.001). Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; P=0.005). At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group. The overall response rate was significantly higher in the ibrutinib group than in the ofatumumab group (42.6% vs. 4.1%, P<0.001). An additional 20% of ibrutinib-treated patients had a partial response with lymphocytosis. Similar effects were observed regardless of whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues. The most frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the ofatumumab group.
  
  
  CONCLUSIONS
  Ibrutinib, as compared with ofatumumab, significantly improved progression-free survival, overall survival, and response rate among patients with previously treated CLL or SLL. (Funded by Pharmacyclics and Janssen; RESONATE ClinicalTrials.gov number, NCT01578707.).
authors.affiliation: The authors' affiliations are listed in the Appendix.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Barrientos
authors.forename: Neil E
authors.initials: NE
authors.lastname: Kay
authors.forename: Nishitha M
authors.initials: NM
authors.lastname: Reddy
authors.forename: Steven
authors.initials: S
authors.lastname: Coutre
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Tam
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Mulligan
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jaeger
authors.forename: Steve
authors.initials: S
authors.lastname: Devereux
authors.forename: Paul M
authors.initials: PM
authors.lastname: Barr
authors.forename: Richard R
authors.initials: RR
authors.lastname: Furman
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.forename: Florence
authors.initials: F
authors.lastname: Cymbalista
authors.forename: Christopher
authors.initials: C
authors.lastname: Pocock
authors.forename: Patrick
authors.initials: P
authors.lastname: Thornton
authors.forename: Federico
authors.initials: F
authors.lastname: Caligaris-Cappio
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Robak
authors.forename: Julio
authors.initials: J
authors.lastname: Delgado
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Schuster
authors.forename: Marco
authors.initials: M
authors.lastname: Montillo
authors.forename: Anna
authors.initials: A
authors.lastname: Schuh
authors.forename: Sven
authors.initials: S
authors.lastname: de Vos
authors.forename: Devinder
authors.initials: D
authors.lastname: Gill
authors.forename: Adrian
authors.initials: A
authors.lastname: Bloor
authors.forename: Claire
authors.initials: C
authors.lastname: Dearden
authors.forename: Carol
authors.initials: C
authors.lastname: Moreno
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Jones
authors.forename: Alvina D
authors.initials: AD
authors.lastname: Chu
authors.forename: Maria
authors.initials: M
authors.lastname: Fardis
authors.forename: Jesse
authors.initials: J
authors.lastname: McGreivy
authors.forename: Fong
authors.initials: F
authors.lastname: Clow
authors.forename: Danelle F
authors.initials: DF
authors.lastname: James
authors.forename: Peter
authors.initials: P
authors.lastname: Hillmen
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D003371:Cough / Q000139:chemically induced; D003967:Diarrhea / Q000139:chemically induced; D018572:Disease-Free Survival; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D010880:Piperidines; 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; D015996:Survival Rate
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000225:Adenine; C527517:ofatumumab