Combination active in pretreated, poor-risk CLL

Combination active in pretreated, poor-risk CLL

10/12/2013

Poor-risk chronic lymphocytic leukemia (CLL) patients had much longer survival when treated with an experimental drug plus rituximab. The drug, used in a placebo-controlled trial, was a small-molecule inhibitor.

As compared with the control group, idelalisib-treated patients had a 72% reduction in the survival hazard. The trial also met the primary endpoint of progression-free survival, as patients treated with rituximab (Rituxan) plus placebo had a median PFS of 5.5 months, whereas the median had yet to be reached in the idelalisib group.

An interim analysis showed similar adverse event rates between the idelalisib and control groups, leading to termination of the trial, Richard Furman, MD, reported here at the American Society of Hematology meeting.

"Idelalisib plus rituximab provided effective, durable disease control and improved overall survival for patients with relapsed CLL who were not suitable for chemotherapy, including high-risk patients," said Furman, of Weill Cornell Medical College in New York City. "Idelalisib plus rituximab demonstrated an acceptable safety profile."

Idelalisib is a selective inhibitor of the delta isoform of phosphoinositide 3-kinase (PI3K), which is found primarily in leukocytes and has a central role in activation, proliferation, migration, and survival of B lymphocytes. The isoform appears to be hyperactivated in a variety of B-cell malignancies, said Furman.

Preliminary studies showed that idelalisib inhibits proliferation and induces apoptosis in CLL cells. The drug also blocks homing and retention of CLL cells in lymphoid tissues to shorten cell survival.

On the basis of favorable results from early-stage clinical trials, investigators at sites in North America and Europe initiated a phase III, randomized, placebo-controlled trial to evaluate idelalisib in patients with previously treated CLL.

Subsequently, 220 patients were randomized to rituximab plus idelalisib or placebo for 6 months of treatment. At progression, patients could continue treatment in a single-agent extension study. Patients initially randomized to idelalisib received a higher dose (300 mg BID) in the extension study, whereas patients randomized to placebo received the randomized dose (150 mg BID).

The primary endpoint was PFS as assessed by independent review. Secondary endpoints included objective response rate, lymph node response, and overall survival.

The study population had a median age of 71. The median disease duration was 8 to 9 years, and two-thirds of the patients had Rai stage III-IV disease at enrollment. About 90% of the patients had previously received rituximab, and 50% or more had received cyclophosphamide, fludarabine, and bendamustine.

On average, the patients had received three prior regimens and were considered ineligible for chemotherapy.

Furman reported that 80% to 90% of the patients had a Cumulative Illness Rating Score >6; 40% to 45% had 17p deletion (del), IGHV mutations, or p53 mutations; and about 40% of the patients had a creatinine clearance of <60 mL/min.

The difference in PFS at the end of the trial represented an 85% reduction in the hazard for the idelalisib group versus the placebo group (HR 0.15, 95% CI 0.08-0.28, P<0.0001). The 24-week PFS was 93% with idelalisib-rituximab and 46% for placebo-rituximab. The PFS benefit was consistent across all prespecified subgroups, including sex, age, and mutation status.

The idelalisib regimen resulted in an objective response rate of 81% versus 13% for the placebo group.

Every patient in the idelalisib arm had some improvement in adenopathy, and 93% of the patients had at least 50% improvement, the criterion for lymph node response. In contrast, 4% of patients in the placebo arm had lymph node responses.

Analysis of overall survival showed a 72% reduction in the hazard with idelalisib versus placebo (HR 0.28, 95% CI 0.09-0.86 P=0.018).

More than 90% of patients in each group had one or more adverse events. The incidence of grade ≥3 adverse events was 56.4% with idelalisib versus 47.7% with placebo. Serious adverse events occurred in 40% of the idelalisib group and 34.6% of the placebo group.

The discontinuation rate associated with adverse events was 8.2% in the idelalisib arm and 10.3% in the placebo group. Additionally, four (3.6%) deaths occurred in idelalisib group as did 12 (11.2% in the placebo group).

The development of new therapies and therapeutic targets makes for an exciting time in the field of CLL, said Jennifer Brown, MD, PhD, of the Dana-Farber Cancer Institute in Boston. At the same time, the wealth of choices will complicate decisions about when to use idelalisib and other new and emerging options for CLL.

"That's the $64,000 question, isn't it?" said Brown, who moderated a press briefing about CLL but was not involved in the study. "I don't think we know yet. That's going to depend to some extent on emerging patterns of resistance and whether some agents may work better than others based on those emerging patterns of resistance.

"Certainly combinations of these agents will be of great interest, and I think that's what we'll be evaluating over the next 5 years or so. Stay tuned."

Furman expressed hope that use of targeted agents will expand beyond the heavily treated, poor-risk populations to healthier patients, a development that could help hematologists reach the goal of eliminating chemotherapy and its associated toxicities and "making long-term survival a reality for these patients."

 

Source: MedPage Today: http://www.medpagetoday.com/MeetingCoverage/ASHHematology/43336