BACKGROUND: 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. METHODS: 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 ClinicalTrials.gov, number NCT01569295. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Gilead Sciences Inc.

4th Department of Internal Medicine Haematology University Hospital and Charles University Prague Faculty of Medicine in Hradec Králové Hradec Králové Czech Republic

CHRU Lille Unité GRITA Department of Haematology Université de Lille Lille France

Department of Haematology Centre Hospitalier Lyon Sud Pierre Bénite France

Department of Haematology Hospital Clínic Barcelona Spain

Department of Haematology Jagiellonian University Krakow Poland

Department of Haematology Medical University of Lodz and Copernicus Memorial Hospital Lodz Poland

Department of Haematology Niguarda Cancer Center Niguarda Hospital Milan Italy

Department of Haematology Oncology St James's University Hospital Leeds UK

Department of Haematology Princess Alexandra Hospital University of Queensland School of Medicine Brisbane Australia

Department of Haematology Ryazan Regional Clinical Hospital Ryazan Russia

Department of Haematology Somogy County Kaposi Mór Hospital Kaposvar Hungary

Department of Haematology University of Debrecen Debrecen Hungary

Department of Internal Medicine 3 Ulm University Ulm Germany

Department of Medical Oncology Dana Farber Cancer Institute Harvard Medical School Boston MA USA

Department of Medicine Lymphoma Service Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College New York NY USA

Division of Experimental Oncology and Department of Onco Haematology IRCCS Ospedale San Raffaele and Università Vita Salute San Raffaele Milan Italy

Gilead Sciences Foster City CA USA

Hofstra Northwell School of Medicine Hofstra University New Hyde Park NY USA

North Shore Hospital Takapuna Auckland New Zealand

US Oncology Research Willamette Valley Cancer Institute and Research Center Eugene OR USA

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ClinicalTrials.gov
NCT01569295