Idelalisib and rituximab in relapsed chronic lymphocytic leukemia

  • N Engl J Med. 2014 Mar 13;370(11):997-1007. doi: 10.1056/NEJMoa1315226.
Richard R Furman  #  1 ,  Jeff P Sharman  #  1 ,  Steven E Coutre  #  1 ,  Bruce D Cheson  1 ,  John M Pagel  1 ,  Peter Hillmen  1 ,  Jacqueline C Barrientos  1 ,  Andrew D Zelenetz  1 ,  Thomas J Kipps  1 ,  Ian Flinn  1 ,  Paolo Ghia  1 ,  Herbert Eradat  1 ,  Thomas Ervin  1 ,  Nicole Lamanna  1 ,  Bertrand Coiffier  1 ,  Andrew R Pettitt  1 ,  Shuo Ma  1 ,  Stephan Stilgenbauer  1 ,  Paula Cramer  1 ,  Maria Aiello  1 ,  Dave M Johnson  1 ,  Langdon L Miller  1 ,  Daniel Li  1 ,  Thomas M Jahn  1 ,  Roger D Dansey  1 ,  Michael Hallek  1 ,  Susan M O'Brien  1
Affiliations
  • 1. Weill Cornell Medical College (R.R.F.), Memorial Sloan-Kettering Cancer Center (A.D.Z.), the Department of Medicine, and Columbia University Medical Center (N.L.) - all in New York; U.S. Oncology Research, Springfield, OR (J.P.S.); Stanford University School of Medicine, Stanford (S.E.C.), and Gilead Sciences, Foster City (M.A., D.M.J., L.L.M., D.L., T.M.J., R.D.D.) - both in California; Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC (B.D.C.); Fred Hutchinson Cancer Research Center, University of Washington, Seattle (J.M.P.); St. James's University Hospital, Leeds (P.H.), and Royal Liverpool University Hospital, Liverpool (A.R.P.) - both in the United Kingdom; Hofstra North Shore-LIJ School of Medicine, New Hyde Park, New York (J.C.B.); University of California San Diego, Moores Cancer Center, La Jolla (T.J.K.); Sarah Cannon Research Institute, Nashville (I.F.); Universita Vita-Salute San Raffaele, Instituto Scientifico San Raffaele, Milan (P.G.); David Geffen School of Medicine, University of California Los Angeles, Los Angeles (H.E.); Florida Cancer Specialists, Englewood (T.E.); Centre Hospitalier Lyon-Sud, Pierre-Bénite, France (B.C.); Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago (S.M.); University of Ulm, Ulm (S.S.), and University of Cologne, Cologne (P.C., M.H.) - both in Germany; and University of Texas M.D. Anderson Cancer Center, Houston (S.M.O.).
  • # Contributed equally.
PMID: 24450857 DOI: 10.1056/NEJMoa1315226
Abstract

Background: Patients 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.

Methods: In 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.

Results: The 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.

Conclusions: The 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.).