Adding Idelalisib to Rituximab Improves Progression-Free and Overall Survival in Patients With Difficult-to-Treat, Relapsed CLL


Key Points

  • Idelalisib/rituximab was associated with significantly better progression-free and overall survival vs rituximab alone in difficult-to-treat relapsed CLL.
  • The combination had an acceptable safety profile.

Use of standard chemotherapy is difficult in patients with relapsed chronic lymphocytic leukemia (CLL) who have significant coexisting medical conditions. In a phase III trial reported in The New England Journal of Medicine, Furman et al found that the combination of idelalisib, an oral inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3K), and rituximab (Rituxan) was associated with significantly improved progression-free and overall survival compared with rituximab alone in this setting.

Study Details

In this double-blind trial, 220 patients with relapsed CLL who had decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses were randomly assigned to receive rituximab (375 mg/m2 followed by 500 mg/m2  every 2 weeks for four doses and then every 4 weeks for three doses) plus either idelalisib at 150 mg twice daily (n = 110) or placebo twice daily (n = 110). The primary endpoint was progression-free survival.

The combination group and the rituximab group were generally balanced for age (median, 71 years in both), Rai stage (1 or 2 in 31% vs 26%, 3 or 4 in 64% vs 65%), extent of CLL (any grade and grade ≥ 3 anemia in 75% vs 72% and 6% vs 11%, neutropenia in 34% vs 35% and 17% vs 16%, and thrombocytopenia in 62% vs 61% and 16% vs 29%), median absolute lymphocyte count (31, 960 vs 30,880/µL) median estimated creatinine clearance (62 vs 67 mL/min), genetic factors (unmutated IGHV in 83% vs 85%, 17p deletion or TP53 mutation in 42% vs 45%), median Cumulative Illness Rating Scale score (8 in both), and previous CLL treatment (median of three drugs in both; rituximab in 91% vs 88%, cyclophosphamide in 64% vs 70%, fludarabine in 56% vs 64%, bendamustine in 58% vs 54%, and chlorambucil in 31% vs 22%).

Study Stopped Early

The study was stopped early at the first prespecified interim analysis on the recommendation of the data and safety monitoring board due to overwhelming efficacy of combination treatment. At that time, 81% of patients in the combination group and 52% of the rituximab group were still receiving study medication.

At 24 weeks, median progression-free survival was not reached in the combination group vs 5.5 months in the rituximab group (adjusted hazard ratio [HR] = 0.15, P < .001). The treatment effect of combination therapy was similar and significant in analyses for all prespecified subgroups of IGHV mutation status, 17p deletion or TP53 mutation, 17p deletion, sex, and age.

Objective response rates (all partial responses) were 81% in the combination group vs 13% in the rituximab group (odds ratio [OR] = 29.92, P < .001). Overall survival at 12 months was 92% vs 80% (HR = 0.28, P =.02).

Adverse Events

The most common adverse events of any grade were pyrexia, fatigue, nausea, chills, and diarrhea in the combination group and infusion-related reactions, fatigue, cough, nausea, and dyspnea in the rituximab group. Grade ≥ 3 adverse events occurred in 56% vs 48% of patients; the most common in the combination group were neutropenia (34% vs 22% in the rituximab group), thrombocytopenia (10% vs 16%), anemia (5% vs 14%), and ALT/AST elevation (5% vs 1%).

Serious adverse events occurred in 40% vs 35%, with the most common in both groups being  pneumonia (6% vs 8%), pyrexia (6% vs 3%), and febrile neutropenia (5% vs 6%). Adverse events led to study drug discontinuation in 8% of the combination group (gastrointestinal and skin disorders in 5%) and 10% of the rituximab group (infections and respiratory disorders in 7%).

The investigators concluded, “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…. Although the follow-up in this study was short, combination therapy with idelalisib had an acceptable safety profile. Further follow-up is needed to assess whether idelalisib is safe for long-term use.”

Richard R. Furman, MD, of Weill Cornell Medical College, Jeff P. Sharman, MD, of US Oncology Research, Springfield, Oregon, and Steven E. Coutre, MD, of Stanford University School of Medicine, contributed equally to The New England Journal of Medicine article.

The trial was funded by Gilead. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.