title: Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study.
abstract: BACKGROUND
  Ibrutinib, an orally administered covalent inhibitor of Bruton's tyrosine kinase (BTK), is an effective treatment for relapsed chronic lymphocytic leukaemia (CLL). We investigated the activity and safety of the combination of ibrutinib with the monoclonal antibody rituximab in patients with high-risk CLL.
  
  
  METHODS
  In this single-arm phase 2 study, we enrolled adult patients with high-risk CLL at the MD Anderson Cancer Center (Houston, TX, USA). All enrolled participants had high-risk cytogenetic abnormalities (deletion 17p, TP53 mutation, or deletion 11q) or a short progression-free survival (PFS <36 months) after previous first-line chemoimmunotherapy. Patients with symptomatic disease requiring therapy received 28-day cycles of once-daily ibrutinib 420 mg together with rituximab (375 mg/m(2), intravenously, every week during cycle 1, then once per cycle until cycle 6), followed by continuous daily single-agent ibrutinib 420 mg until disease progression or until toxicities or complications precluded further treatment. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov number NCT01520519, and is no longer accruing patients.
  
  
  RESULTS
  Between Feb 28, 2012, and Sept 11, 2012, we enrolled 40 patients with CLL with high-risk disease features, 20 of whom had deletion 17p (del[17p]) or TP53 mutations (16 previously treated, four untreated), 13 had relapsed CLL with deletion 11q (del[11q]), and seven a PFS less than 36 months after first-line chemoimmunotherapy. 18-month PFS in all patients was 78·0% (95% CI 60·6-88·5), whereas in those with a del(17p) or TP53 mutation it was 72·4% (45·6-87·6) Toxicity was mainly mild to moderate in severity (grade 1-2). Diarrhoea occurred in ten (25%) patients (grade 1 in nine patients and grade 2 in one), bleeding events in 14 (33%) patients (eight grade 1 and five grade 2), nausea or vomiting in 15 patients (38%) (ten grade 1 and five grade 2), and fatigue in seven (18%) patients (four grade 1 and three grade 2). Five patients (13%) had grade 3 infections (two lung infections, one upper respiratory tract infection, one sepsis, and one mucositis), and no grade 4 or 5 infections occurred. One patient had grade 4 neutropenia.
  
  
  CONCLUSIONS
  The encouraging safety and activity of ibrutinib and rituximab in this population of patients with high-risk CLL merits further investigation of this combination.
  
  
  BACKGROUND
  Pharmacyclics Inc, Cancer Prevention and Research Institute of Texas, Leukemia and Lymphoma Society, National Cancer Institute, MD Anderson Cancer Center.
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA. Electronic address: jaburger@mdanderson.org.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.affiliation: Institute of Pathology, University of Würzburg, Würzburg, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Hartmann
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoellenriegel
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Nathalie Y
authors.initials: NY
authors.lastname: Rosin
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Iris
authors.initials: I
authors.lastname: de Weerdt
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ghayathri
authors.initials: G
authors.lastname: Jeyakumar
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferrajoli
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Marylou
authors.initials: M
authors.lastname: Cardenas-Turanzas
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Lerner
authors.affiliation: Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Jorgensen
authors.affiliation: Department of Biostatistics, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Graciela M
authors.initials: GM
authors.lastname: Nogueras-González
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Gracy
authors.initials: G
authors.lastname: Zacharian
authors.affiliation: Department of Biostatistics, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xuelin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.affiliation: Department of Diagnostic Radiology, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Naveen
authors.initials: N
authors.lastname: Garg
authors.affiliation: Institute of Pathology, University of Würzburg, Würzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D018579:Patient Selection; D010880:Piperidines; D011379:Prognosis; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D000069283:Rituximab; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000069283:Rituximab; D000225:Adenine