title: Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial.
abstract: Bendamustine plus rituximab is a standard of care for the management of patients with relapsed or refractory chronic lymphocytic leukaemia. New therapies are needed to improve clinically relevant outcomes in these patients. We assessed the efficacy and safety of adding idelalisib, a first-in-class targeted phosphoinositide-3-kinase δ inhibitor, to bendamustine plus rituximab in this population.
  
  
  
  For this international, multicentre, double-blind, placebo-controlled trial, adult patients (≥18 years) with relapsed or refractory chronic lymphocytic leukaemia requiring treatment who had measurable lymphadenopathy by CT or MRI and disease progression within 36 months since their last previous therapy were enrolled. Patients were randomly assigned (1:1) by a central interactive web response system to receive bendamustine plus rituximab for a maximum of six cycles (bendamustine: 70 mg/m2intravenously on days 1 and 2 for six 28-day cycles; rituximab: 375 mg/m2on day 1 of cycle 1, and 500 mg/m2on day 1 of cycles 2-6) in addition to either twice-daily oral idelalisib (150 mg) or placebo until disease progression or intolerable study drug-related toxicity. Randomisation was stratified by high-risk features (IGHV, del[17p], or TP53 mutation) and refractory versus relapsed disease. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat population. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01569295.
  
  
  
  Between June 26, 2012, and Aug 21, 2014, 416 patients were enrolled and randomly assigned to the idelalisib (n=207) and placebo (n=209) groups. At a median follow-up of 14 months (IQR 7-18), median progression-free survival was 20·8 months (95% CI 16·6-26·4) in the idelalisib group and 11·1 months (8·9-11·1) in the placebo group (hazard ratio [HR] 0·33, 95% CI 0·25-0·44; p<0·0001). The most frequent grade 3 or worse adverse events in the idelalisib group were neutropenia (124 [60%] of 207 patients) and febrile neutropenia (48 [23%]), whereas in the placebo group they were neutropenia (99 [47%] of 209) and thrombocytopenia (27 [13%]). An increased risk of infection was reported in the idelalisib group compared with the placebo group (grade ≥3 infections and infestations: 80 [39%] of 207 vs 52 [25%] of 209). Serious adverse events, including febrile neutropenia, pneumonia, and pyrexia, were more common in the idelalisib group (140 [68%] of 207 patients) than in the placebo group (92 [44%] of 209). Treatment-emergent adverse events leading to death occurred in 23 (11%) patients in the idelalisib group and 15 (7%) in the placebo group, including six deaths from infections in the idelalisib group and three from infections in the placebo group.
  
  
  
  Idelalisib in combination with bendamustine plus rituximab improved progression-free survival compared with bendamustine plus rituximab alone in patients with relapsed or refractory chronic lymphocytic leukaemia. However, careful attention needs to be paid to management of serious adverse events and infections associated with this regimen during treatment selection.
  
  
  
  Gilead Sciences Inc.
authors.affiliation: Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. Electronic address: zeleneta@mskcc.org.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Zelenetz
authors.affiliation: Hofstra Northwell School of Medicine, Hofstra University, New Hyde Park, NY, USA.
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Barrientos
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: Department of Haematology, Centre Hospitalier Lyon Sud, Pierre-Bénite, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Coiffier
authors.affiliation: Department of Haematology, Hospital Clínic, Barcelona, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Delgado
authors.affiliation: Department of Haematology, Somogy County Kaposi Mór Hospital, Kaposvar, Hungary.
authors.forename: Miklós
authors.initials: M
authors.lastname: Egyed
authors.affiliation: Division of Experimental Oncology and Department of Onco-Haematology, IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghia
authors.affiliation: Department of Haematology, University of Debrecen, Debrecen, Hungary.
authors.forename: Árpád
authors.initials: Á
authors.lastname: Illés
authors.affiliation: Department of Haematology, Jagiellonian University, Krakow, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Jurczak
authors.affiliation: Department of Haematology, Princess Alexandra Hospital, University of Queensland, School of Medicine, Brisbane, Australia.
authors.forename: Paula
authors.initials: P
authors.lastname: Marlton
authors.affiliation: Department of Haematology, Niguarda Cancer Center, Niguarda Hospital, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Montillo
authors.affiliation: CHRU Lille, Unité GRITA, Department of Haematology, Université de Lille, Lille, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Morschhauser
authors.affiliation: Department of Haematology, Ryazan Regional Clinical Hospital, Ryazan, Russia.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Pristupa
authors.affiliation: Department of Haematology, Medical University of Lodz and Copernicus Memorial Hospital, Lodz, Poland.
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Robak
authors.affiliation: US Oncology Research, Willamette Valley Cancer Institute and Research Center, Eugene, OR, USA.
authors.forename: Jeff P
authors.initials: JP
authors.lastname: Sharman
authors.affiliation: North Shore Hospital, Takapuna, Auckland, New Zealand.
authors.forename: David
authors.initials: D
authors.lastname: Simpson
authors.affiliation: 4th Department of Internal Medicine-Haematology, University Hospital and Charles University in Prague, Faculty of Medicine in Hradec Králové, Hradec Králové, Czech Republic.
authors.forename: Lukáš
authors.initials: L
authors.lastname: Smolej
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany.
authors.forename: Eugen
authors.initials: E
authors.lastname: Tausch
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Adeboye H
authors.initials: AH
authors.lastname: Adewoye
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Lyndah K
authors.initials: LK
authors.lastname: Dreiling
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Yeonhee
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
authors.affiliation: Department of Haematology/Oncology, St James's University Hospital, Leeds, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Hillmen
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000069461:Bendamustine Hydrochloride / Q000008:administration & dosage; D004311:Double-Blind Method; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D011687:Purines / Q000008:administration & dosage; D052999:Quinazolinones / Q000008:administration & dosage; D000069283:Rituximab / Q000008:administration & dosage; D016879:Salvage Therapy; D015996:Survival Rate
chemical_list: D011687:Purines; D052999:Quinazolinones; D000069283:Rituximab; D000069461:Bendamustine Hydrochloride; C552946:idelalisib