www.thelancet.com/haematology Vol 4 March 2017 e114 Articles Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial Jeffrey A Jones, Tadeusz Robak, Jennifer R Brown, Farrukh T Awan, Xavier Badoux, Steven Coutre, Javier Loscertales, Kerry Taylor, Elisabeth Vandenberghe, Malgorzata Wach, Nina Wagner-Johnston, Loic Ysebaert, Lyndah Dreiling, Ronald Dubowy, Guan Xing, Ian W Flinn, Carolyn Owen Summary Background Idelalisib, a selective inhibitor of PI3Kδ, is approved for the treatment of patients with relapsed chronic lymphocytic leukaemia (CLL) in combination with rituximab. We aimed to assess the efficacy and safety of idelalisib in combination with a second-generation anti-CD20 antibody, ofatumumab, in a similar patient population. Methods In this global, open-label, randomised, controlled phase 3 trial, we enrolled patients with relapsed CLL progressing less than 24 months from last therapy. Patients refractory to ofatumumab were excluded. Patients were stratified by relapsed versus refractory disease, presence or absence of del(17p) or TP53 mutation, or both, and IGHV mutated versus unmutated. We randomised patients in a 2:1 ratio using a web-based interactive system that generated a unique treatment code, and assigned patients to receive either idelalisib plus ofatumumab (oral idelalisib 150 mg twice daily continuously plus ofatumumab 300 mg intravenously in week 1, then 1000 mg intravenously weekly for 7 weeks, and every 4 weeks for 16 weeks) or ofatumumab alone (ofatumumab dosing as per the combination group, except 2000 mg was substituted for the 1000 mg dose). An independent review committee assessed response, including progressive disease, based on imaging using modified International Workshop on Chronic Lymphocytic Leukaemia 2008 criteria. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat population. We did a primary analysis (data cutoff Jan 15, 2015) and an updated analysis (data cutoff Sept 1, 2015). This trial is registered with Clinicaltrials.gov, number NCT01659021. Findings Between Dec 17, 2012, and March 31, 2014, we enrolled 261 patients (median age 68 years [IQR 61–74], median previous therapies three [IQR 2–4]). At the primary analysis, median progression-free survival was 16·3 months (95% CI 13·6–17·8) in the idelalisib plus ofatumumab group and 8·0 months (5·7–8·2) in the ofatumumab group (adjusted hazard ratio [HR] 0·27, 95% CI 0·19–0·39, p<0·0001). The most frequent grade 3 or worse adverse events in the idelalisib plus ofatumumab group were neutropenia (59 [34%] patients vs 14 [16%] in the ofatumumab group), diarrhoea (34 [20%] vs one [1%]), and pneumonia (25 [14%] vs seven [8%]). The most frequent grade 3 or worse adverse events in the ofatumumab group were neutropenia (14 [16%]), pneumonia (seven [8%]), and thrombocytopenia (six [7%] vs 19 [11%] in the idelalisib plus ofatumumab group). Serious infections were more common in the idelalisib plus ofatumumab group and included pneumonia (23 [13%] patients in the idelalisib plus ofatumumab group vs nine [10%] in the ofatumumab group), sepsis (11 [6%] vs one [1%]), and Pneumocystis jirovecii pneumonia (eight [5%] vs one [1%]). 22 treatment-related deaths occurred in the idelalisib plus ofatumumab group (the most common being sepsis, septic shock, viral sepsis, and pneumonia). Six treatment-related deaths occurred in the ofatumumab group (the most common being progressive multifocal leukoencephalopathy and pneumonia). Interpretation The idelalisib plus ofatumumab combination resulted in better progression-free survival compared with ofatumumab alone in patients with relapsed CLL, including in those with high-risk disease, and thus might represent a new treatment alternative for this patient population. Funding Gilead Sciences, Inc. Introduction Chronic lymphocytic leukaemia (CLL) is the most prevalent adult leukaemia in Europe and the USA. 1 Chemoimmunotherapy is considered standard first-line therapy for most patients with CLL and results in durable remission in most cases. 2,3 Recently, small- molecule drugs that target the components of the B-cell receptor pathway, such as Bruton’s tyrosine kinase and PI3Kδ, have been approved and their role in therapy is evolving. Treatment is not curative in most cases, and most patients require further treatment at relapse. Patients with refractory disease (ie, progression <6 months from completion of previous therapy), patients whose CLL cells have high-risk genetic features (eg, deletion of the short group of chromosome 17 [del(17p)], or mutation of the TP53 tumour suppressor gene), and patients with persisting toxicity from previous therapy or clinically significant comorbid medical illnesses have few options for effective therapy. 4–9 Identification of therapies with novel mechanisms of Lancet Haematol 2017; 4: e114–26 See Comment page e397 Division of Haematology, The Ohio State University, Columbus, OH, USA (J A Jones MD, F T Awan MD); Medical University of Lodz and Copernicus Memorial Hospital, Lodz, Poland (Prof T Robak MD); Dana-Farber Cancer Institute, Boston, MA, USA (J R Brown MD); St George Hospital, Kogarah, NSW, Australia (X Badoux MBBS); Stanford University School of Medicine, Stanford, CA, USA (Prof S Coutre MD); Hospital Universitario de La Princesa, IIS-IP, Madrid, Spain (J Loscertales MD); Haematology and Oncology Clinics of Australia at Mater, South Brisbane, QLD, Australia (K Taylor MBBS); St James’s Hospital, Dublin, Ireland (Prof E Vandenberghe MD); Medical University of Lublin, Lublin, Poland (M Wach MD); The Johns Hopkins University, Baltimore, MD, USA (Prof N Wagner-Johnston MD); Hôpital Purpan, Toulouse, France (L Ysebaert MD); Gilead Sciences, Foster City, CA, USA (L Dreiling MD, R Dubowy MD, G Xing PhD); Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA (I W Flinn MD); and Alberta Health Services, Calgary, Alberta, Canada (C Owen MD) Correspondence to: Dr Jeffrey Jones, Division of Haematology, The Ohio State University, Columbus, OH 43210, USA jeffrey.jones@osumc.edu