• Richard R Furman, Jeff P Sharman, Steven E Coutre, Bruce D Cheson, John M Pagel, Peter Hillmen, Jacqueline C Barrientos, Andrew D Zelenetz, Thomas J Kipps, Ian Flinn, Paolo Ghia, Herbert Eradat, Thomas Ervin, Nicole Lamanna, Bertrand Coiffier, Andrew R Pettitt, Shuo Ma, Stephan Stilgenbauer, Paula Cramer, Maria Aiello, Dave M Johnson, Langdon L Miller, Daniel Li, Thomas M Jahn, Roger D Dansey, Michael Hallek, and Susan M O'Brien.
• The authors' affiliations are listed in the Appendix.
• N. Engl. J. Med.. 2014 Mar 13;370(11):997-1007.

BackgroundPatients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemotherapy. Effective therapies with acceptable side-effect profiles are needed for this patient population.MethodsIn this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta isoform of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy.ResultsThe median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P=0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab.ConclusionsThe combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemotherapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512.).

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