Update on Idelalisib + Rituximab in Relapsed and Elderly CLL Patients

The combination of idelalisib with rituximab prolonged progression-free survival (PFS) for patients with relapsed chronic lymphocytic leukemia (CLL), according to an oral presentation at the 56th ASH Annual Meeting.

In frail patients with relapsed CLL – especially those with adverse prognostic factors such as chromosome 17p deletion or TP53 gene mutations – there is an unmet need for more effective therapies, noted lead study author Jeffrey P. Sharman, MD, in his presentation of the results. “Patients with CLL who are considered inappropriate candidates for traditional chemotherapy can derive substantial benefit from the addition of idelalisib to rituximab,” he added.

Idelalisib, a first-in-class, targeted, oral inhibitor of PI3K delta, a protein that is over-expressed in many B-cell malignancies, was recently approved by the FDA in combination with rituximab for treatment of relapsed CLL.

“There have been other PI3K drugs in development affecting all of the isoforms, but what is unique about idelalisib is its selectivity for the PI3K-delta isoform,” said Steven E. Coutre, MD, in his discussion of the newly approved drug during the Special Education Session on Newly Approved Drugs. “The delta isoform is not ubiquitously expressed, but seems to be limited to the leukocytes.”

Idelalisib received FDA approval for the treatment of relapsed chronic lymphocytic leukemia based on a results from a clinical trial of 220 patients who were randomly assigned to receive idelalisib + rituximab or placebo + rituximab. The trial was stopped early after investigators observed “a rather dramatic difference between the two arms” in terms of progression-free survival (PFS), noted Dr. Coutre: 10.7 months vs. 5.5 months with placebo + rituxmab (hazard ratio [HR] = 0.18 [95% CI 0.10–0.32]; p<0.0001).

Dr. Sharman, from the Willamette Valley Cancer Institute/US Oncology Research in Springfield, Oregon, presented results from a second interim analysis of a phase 3 study evaluating idelalisib + rituximab in patients with CLL that had progressed sooner than 24 months a previous therapy.

The 220 enrolled patients were randomized to receive either 150 mg idelalisib twice daily (n=110) or placebo (n=110), plus rituximab (375 mg/m2 [first dose] and then 500 mg/m2 every 2 weeks for four cycles, followed by every 4 weeks for three cycles, for a total of 8 doses).

The trial was stopped after the first interim analysis due to overwhelming evidence of efficacy of the idelalisib. The secondary interim analysis was conducted at the end of the blinded phase, and the updated analysis, reported here, was conducted after a median follow-up of about 1 year.

Median age of enrolled patients was 71 years, with median time since diagnosis of 8.5 years. Patients had received a median of three prior therapies. In terms of adverse risk factors, 43 percent of patients had del(17p)/TP53 mutation and 84 percent had unmutated IGHV (immunoglobulin heavy chain variable). About 85 percent of patients had total CIRS scores >6.

Seventy-six percent of patients receiving idelalisib + rituximab and 46 percent of patients on placebo + rituximab continued to the open-label extension study, during which all patients received idelalisib (300 mg twice-daily for the original active therapy group, and 150 mg twice-daily for crossover patients).

After 12 months, patients initially randomized to idelalisib had significantly higher rates of PFS (the study’s primary endpoint) and overall survival:

  • Median PFS: 19.4 months with idelalisib versus 7.3 months in the placebo group (HR=0.25; p<0.0001)
  • Overall survival: not yet reached in the idelalisib group, versus 20.8 months in the placebo group (HR=0.34; 95% CI 0.19–0.6; p=0.0001).

Differences in PFS between IGHV-mutated and IGHV-unmutated patients were not statistically significant; neither were differences in PFS of patients with high-risk genomic markers del7p/TP53 and del11q mutations. In the IGHV-unmutated subgroup, median overall survival was similarly improved with idelalisib versus placebo (not yet reached vs. 18.1 months; HR=0.35 [95% CI 0.19–0.6]; p=0.0003).

In his presentation of the results, Dr. Sharman characterized the safety profile as “acceptable,” with the most common adverse events being diarrhea and hepatic transaminase levels.

“This is the first presentation in which the presence or absence of the 17p deletion did not influence the outcome for patients who received experimental therapy,” Dr. Sharman said, supporting the use of combination therapy over the routine use of rituximab monotherapy in these patients.


  • Sharman JP, Coutre SE, Furman RR, et al. “Second interim analysis of a phase 3 study of idelalisib (ZYDELIG®) plus rituximab (R) for relapsed chronic lymphocytic leukemia (CLL): efficacy analysis in patient subpopulations with del(17p) and other adverse prognostic factors.” Abstract #330. Presented at the American Society of Hematology Annual Meeting, December 8, 2014.