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Idelalisib plus Rituximab for Relapsed Chronic Lymphocytic Leukemia

Summary and Comment |
January 29, 2014

Idelalisib plus Rituximab for Relapsed Chronic Lymphocytic Leukemia

  1. Michael E. Williams, MD, ScM

Outcomes were significantly better than with rituximab plus placebo.

  1. Michael E. Williams, MD, ScM

The PI3Kδ inhibitor idelalisib has single-agent activity in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). To assess response and safety of idelalisib in combination with the anti-CD20 monoclonal antibody rituximab in these patients, investigators conducted an industry-sponsored, phase III, multinational, randomized, placebo-controlled, double-blind trial involving 220 CLL patients (median age, 71; median Cumulative Illness Rating Scale score, 8). Eligible patients had progressive disease within 2 years of prior therapy and were clinically ineligible for cytotoxic chemotherapy.

Patients were randomized to rituximab intravenously (375 mg/m2 in week 1, then 500 mg/m2 weekly for 4 doses and 500 mg/m2 monthly for 3 doses) plus either idelalisib orally (150 mg twice daily) or placebo. Patients who progressed with placebo could receive idelalisib; those who progressed with idelalisib could escalate the dose of the drug to 300 mg twice daily.

Progression-free survival was superior with rituximab plus idelalisib (not reached vs. 5.5 months; P<0.001), as was overall response rate (81% vs. 13%; P<0.001), and 1-year overall survival (92% vs. 80%; P =0.02). Both treatment groups experienced similar rates of serious adverse events, including infusion reactions to rituximab and infrequent grade 3 or higher transaminase elevations and diarrhea; grade 3 or higher neutropenia was observed in 34% of idelalisib recipients and 22% of placebo recipients.

Comment

The significantly improved outcomes with rituximab plus idelalisib versus rituximab plus placebo led to a recommendation by the trial's Data Safety Monitoring Board to stop the trial at the first planned interim analysis. Responses were observed in patients with poor-risk CLL, including those with del(17p) and mutations in the immunoglobulin heavy-chain variable (IGHV) gene. The expected peripheral blood lymphocytosis previously observed with single-agent idelalisib was blunted by concomitant rituximab. Further analyses of mechanisms of resistance, activity in previously untreated CLL, other combination regimens, and strategies to maximize early response and maintenance of response will be of great interest.

  • Disclosures for Michael E. Williams, MD, ScM at time of publication Consultant / Advisory board Celgene; Genentech; Millennium; Pharmacyclics Speaker's bureau Educational Concepts Group; ION; Research to Practice; Xcenda Grant / research support Allos Therapeutics; AstraZeneca; Celgene; Genentech; Gilead; Millennium; Novartis; Onyx; Pharmacyclics; Janssen Editorial boards Current Treatment Options in Oncology

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