Idelalisib and rituximab in relapsed chronic lymphocytic leukemia

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.).

Figure 1. Progression-free and Overall Survival

At the time the study was stopped, the median duration of progression-free survival among 110 patients receiving idelalisib and rituximab had not yet been reached; among the 110 patients receiving placebo and rituximab, the median duration of progression-free survival was 5.5 months (hazard ratio for progression or death in the idelalisib group, 0.15; 95% confidence interval [CI], 0.08 to 0.28; P<0.001) (Panel A). The median duration of overall survival in the two study groups had also not been reached; the overall survival rate was 92% in the idelalisib group versus 80% in the placebo group at 12 months (hazard ratio for death, 0.28; 95% CI, 0.09 to 0.86; P = 0.02) (Panel B).

Figure 2. Forest Plot of Progression-free Survival in Prespecified Subgroups

Hazard ratios of less than 1.00 for disease progression or death indicate better results in the idelalisib group.

Figure 3. Changes in Lymph Nodes and Lymphocytes

Shown are the greatest percentage changes in the sum of the products of the perpendicular diameters of measured lymph nodes for each study patient (Panel A) and the median absolute lymphocyte counts over a period of 48 weeks (Panel B). The I bars represent interquartile ranges.