First-Line Fludarabine, Cyclophosphamide, and Rituximab vs Bendamustine/Rituximab in Advanced CLL
In a European phase III noninferiority trial reported in The Lancet Oncology, Eichhorst et al found that progression-free survival was better with standard first-line fludarabine/cyclophosphamide/rituximab vs bendamustine/rituximab in fit patients with advanced chronic lymphocytic leukemia (CLL) without del(17p).
Study Details
In the trial, 561 patients from sites in Germany, Austria, Switzerland, Denmark, and the Czech Republic were randomized between October 2008 and July 11 2011 to receive six 28-day cycles of fludarabine, cyclophosphamide, and rituximab (n = 282) or bendamustine and rituximab (n = 279). Treatment consisted of fludarabine at 25 mg/m²/d and cyclophosphamide at 250 mg/m²/d for the first 3 days or bendamustine at 90 mg/m²/d for the first 2 days of each cycle and rituximab at 375 mg/m² on day 0 of cycle 1 and 500 mg/m² during the next five cycles on day 1. The primary endpoint was progression-free survival.
Progression-Free Survival
Median follow-up was 37.1 months. Median progression-free survival was 55.2 months (95% confidence interval [CI] = not evaluable) in the standard-therapy group vs 41.7 months (95% CI = 34.9–45.3 months) in the bendamustine/rituximab group (hazard ratio [HR] = 1.643, 90.4% CI = 1.308–2.064; noninferiority not rejected). Hazard ratios were 1.789 (95% CI = 1.290–2.480) among patients aged < 65 years and 1.388 (95% CI = 0.867–2.222) among those aged ≥ 65 years. Overall response rates were 95% vs 96%, with complete response in 40% vs 31% (P = .034).
Toxicity
Severe neutropenia (84% vs 59%) and infection (39% vs 25%) were more common with standard treatment, with the difference in infectious complications being greater among patients aged ≥ 65 years. Treatment was discontinued due to adverse events in 23% vs 13% of patients (P = .003).
The investigators concluded: “The combination of fludarabine, cyclophosphamide, and rituximab remains the standard front-line therapy in fit patients with chronic lymphocytic leukaemia, but bendamustine and rituximab is associated with less toxic effects.”
The study was funded by Roche Pharma AG, Mundipharma, and the German Federal Ministry of Education and Research.
Barbara Eichhorst, MD, of the University of Cologne, Germany, is the corresponding author of The Lancet Oncology article.
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