Idelalisib combination reduces risk for progression, death in refractory CLL

ORLANDO, Fla. — The addition of idelalisib to bendamustine and rituximab prolonged PFS and OS among patients with relapsed/refractory chronic lymphocytic leukemia, according to results of a late-breaking abstract presented at the ASH Annual Meeting and Exposition.

These outcomes persisted among patients with or without high-risk features such as 17p deletion and TP53 mutations; however, most patients experienced treatment-related toxicities.

Andrew D. Zelenetz

“New treatments for patients who relapse are important,” Andrew D. Zelenetz, MD, PhD, a medical oncologist and vice chair of medical informatics in the department of medicine at Memorial Sloan Kettering Cancer Center, said during the presentation. “It’s nice to be able to have people in remission longer but it’s key to find ways for people to live longer. The addition of idelalisib … resulted in a significant improvement in survival compared to the control.”

Idelalisib (Zydelig, Gilead) — a first-in-class PI3k delta inhibitor — is approved in combination with rituximab (Rituxan; Genentech, Biogen Idec) for first-line treatment of patients with relapsed CLL who are unsuitable for chemotherapy and have 17p deletion or TP53 mutations.

Zelenetz and colleagues sought to evaluate the efficacy of the addition of idelalisib to a combination of bendamustine (Treanda, Cephalon) and rituximab for relapsed/refractory CLL.

PFS served as the primary endpoint, and OS served as a secondary endpoint.

Researchers enrolled 416 patients (76% male, 58% aged younger than 65 years) between June 2012 and August 2014. Forty-six percent of patients had Rai stage III/IV disease, the median time since completion of last therapy was 16 months and patients had received a median of two (range, 1-13) prior therapies.

High-risk features in the cohort included 17p deletion or p53 mutation (32.9%), unmutated IGHV (83.2%), and refractory disease (28.9%).

Patients in the intention-to-treat analysis received six cycles of bendamustine and rituximab with 150 mg twice daily idelalisib (n = 207) or placebo (n = 209). Idelalisib or placebo was continued until disease progression, death, intolerable toxicity or withdraw from the study.

The interim analysis occurred when 75% of 260 planned events — which included CLL progression or death from any cause — occurred. The data cutoff was June 15, 2015.

Median follow-up was 12 months. Patients in both arms completed a median of six cycles.

Median PFS was 23 months in the idelalisib arm vs. 11 months in the control arm (HR = 0.33; 95% CI, 0.24-0.45). The PFS benefits of the idelalisib combination persisted in subgroup analyses, such as among patients without 17p deletion or TP53 mutation (HR = 0.22; 95% CI, 0.14-0.35), or patients who had either 17p deletion or TP53 mutation (HR = 0.5; 95% CI, 0.32-0.77).

More patients died in the placebo vs. idelalisib arm (24.4% vs. 16.4%). However, median OS was not yet reached in either arm (HR = 0.55; 95% CI 0.36-0.86).

Based on these data, the independent data monitoring committee recommended unblinding the study based on “overwhelming efficacy” of idelalisib.

More patients in the idelalisib arm experienced any adverse event (100% vs. 97%), a severe adverse event (66% vs. 44%), study drug dose reduction (11% vs. 6%) or discontinuation (26% vs. 13%), and death (10% vs. 7%).

The most common adverse events in the idelalisib arm were neutropenia (63.3%) and pyrexia (41.5%), whereas the most common adverse events in the placebo arm were neutropenia (53.6%) and nausea (34.4%). The most common grade 3 or worse adverse events included neutropenia (59.9%) and febrile neutropenia (20.3%) in the experimental arm and neutropenia (45.9%) and anemia (12%) in the placebo arm.

More patients in the idelalisib cohort also experienced grade 3 or worse diarrhea (7.2% vs. 1.9%), pneumonitis (1.4% vs. 0%), and all-grade alanine transaminase abnormalities (59.9% vs. 30.6%) and aspartate transaminase abnormalities (52.2% vs. 30.6%). – by Anthony SanFilippo

Reference:

Zelenetz AD, et al. Abstract LBA5. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.

Disclosure: The study included off-label use of idelalisib for relapsed/refractory CLL. Zelenetz reports research funding from Gilead Sciences. Please see the abstract for a list of all other researchers’ relevant financial disclosures.