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Lancet Oncol. 2017 Mar;18(3):297-311. doi: 10.1016/S1470-2045(16)30671-4. Epub 2017 Jan 28.

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.

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Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. Electronic address:
Hofstra Northwell School of Medicine, Hofstra University, New Hyde Park, NY, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Department of Haematology, Centre Hospitalier Lyon Sud, Pierre-Bénite, France.
Department of Haematology, Hospital Clínic, Barcelona, Spain.
Department of Haematology, Somogy County Kaposi Mór Hospital, Kaposvar, Hungary.
Division of Experimental Oncology and Department of Onco-Haematology, IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele, Milan, Italy.
Department of Haematology, University of Debrecen, Debrecen, Hungary.
Department of Haematology, Jagiellonian University, Krakow, Poland.
Department of Haematology, Princess Alexandra Hospital, University of Queensland, School of Medicine, Brisbane, Australia.
Department of Haematology, Niguarda Cancer Center, Niguarda Hospital, Milan, Italy.
CHRU Lille, Unité GRITA, Department of Haematology, Université de Lille, Lille, France.
Department of Haematology, Ryazan Regional Clinical Hospital, Ryazan, Russia.
Department of Haematology, Medical University of Lodz and Copernicus Memorial Hospital, Lodz, Poland.
US Oncology Research, Willamette Valley Cancer Institute and Research Center, Eugene, OR, USA.
North Shore Hospital, Takapuna, Auckland, New Zealand.
4th Department of Internal Medicine-Haematology, University Hospital and Charles University in Prague, Faculty of Medicine in Hradec Králové, Hradec Králové, Czech Republic.
Department of Internal Medicine III, Ulm University, Ulm, Germany.
Gilead Sciences, Foster City, CA, USA.
Department of Haematology/Oncology, St James's University Hospital, Leeds, UK.



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/m2 intravenously on days 1 and 2 for six 28-day cycles; rituximab: 375 mg/m2 on day 1 of cycle 1, and 500 mg/m2 on 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, 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.

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