New Orleans—Patients with heavily pretreated, relapsed chronic lymphocytic leukemia (CLL) not suitable for chemotherapy had a significant increase in progression-free survival, overall survival, and overall response rate if they received idelalisib plus rituximab compared with a group that took placebo plus rituximab, according to a prespecified interim analysis of a phase 3 randomized, double-blind, placebo-controlled study. The groups had similar rates of adverse events.
Richard Furman, MD, the study’s lead author, presented the results during a late-breaking oral abstract session at the ASH meeting. The analysis was performed after 50% of patients died, had disease progression, or discontinued treatment because of an adverse event.
Rituximab is FDA-approved in combination with fludarabine plus cyclophosphamide chemotherapy to treat CD-20 positive CLL as an initial treatment or after disease relapse. In September, Gilead Sciences, Inc., submitted an application to the FDA for the approval of idelalisib to treat patients with indolent non-Hodgkin’s lymphoma. The drug is also being tested for other lymphoid and hematological malignancies, according to the company. Idelalisib is a targeted, highly selective, oral inhibitor of the phosphoinositide 3-kinase-delta isoform.
In this study, the authors randomized 220 patients in a 1:1 ratio to receive rituximab plus 150 mg of idelalisib twice daily or rituximab plus placebo twice daily. They received 375 mg/m2 of rituximab during the first week, followed by 500 mg/m2 of rituximab every 2 weeks for 4 doses, and then 500 mg/m2 of rituximab every 4 weeks for 3 doses. They remained on the combination treatment for 6 months and then took a single agent (idelalisib or placebo) until disease progression, death, or discontinuation due to adverse events.
The median progression-free survival had not been reached in the idelalisib group and was 5.5 months in the placebo group (hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.08-0.28; P<.0001). At 24 weeks, 93% of patients receiving idelalisib plus rituximab and 46% of patients taking placebo plus rituximab remained progression-free. Dr. Furman noted that progression-free survival favored the idelalisib group in all prespecified subgroups.
The overall survival also favored the idelalisib group (HR, 0.28; 95% CI, 0.09-0.86; P=.018). The overall response rate was 81% in the idelalisib group and 13% in the placebo group (P<.0001), while 93% of patients in the idelalisib group and 4% of patients in the placebo group had at least a 50% reduction in lymph node size (P<.0001).
Grade 3 or higher adverse events were found in 56% of patients taking idelalisib plus rituximab and 48% of patients receiving placebo plus rituximab, while serious adverse events were found in 40% and 35% of patients, respectively. The most common adverse events in the idelalisib group were pyrexia (29%), fatigue (24%), nausea (24%), and chills (22%).
There were 4 deaths in the idelalisib group, including 3 from disease progression and 1 from infection. There were 12 deaths in the placebo group, including 6 from infection and 1 from progressive disease.
Patients were included if their CLL progressed <24 months since their last therapy, had measurable lymphadenopathy, and previously received ≥1 anti-CD20 antibody containing therapy or ≥2 cytotoxic therapies. Dr. Furman added that the most important criteria for eligibility was that patients had to be considered unfit for receiving additional chemo-immunotherapy.
At baseline, the median age was 71 years in both groups, while the median time to diagnosis was 7.8 years for patients receiving idelalisib plus rituximab and 8.6 years for patients taking placebo plus rituximab. Patients in each group received a median of 3 previous therapies before enrolling in the trial.
The authors found that 19% of patients in the idelalisib group and 48% of patients in the placebo group discontinued treatment, including 5% and 31%, respectively, after their disease progressed.
The median exposure to the drug was 3.8 months for patients taking idelalisib and 2.9 months for patients receiving placebo.