Originally published as JCO Early Release 10.1200/JCO.2006.08.0762 on February 5 2007

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Phase III Trial of Fludarabine Plus Cyclophosphamide Compared With Fludarabine for Patients With Previously Untreated Chronic Lymphocytic Leukemia: US Intergroup Trial E2997

Ian W. Flinn, Donna S. Neuberg, Michael R. Grever, Gordon W. Dewald, John M. Bennett, Elisabeth M. Paietta, Mohamad A. Hussein, Frederick R. Appelbaum, Richard A. Larson, Dennis F. Moore, Jr, Martin S. Tallman

From the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD; Dana-Farber Cancer Institute, Boston, MA; School of Medicine, Ohio State University, Columbus; Cleveland Clinic Foundation, Cleveland, OH; Mayo Clinic, Rochester, MN; University of Rochester Cancer Center, Rochester, NY; Our Lady of Mercy Medical Center, Bronx, NY; Fred Hutchinson Cancer Research Center, Seattle, WA; University of Chicago; Cancer and Leukemia Group B, Feinberg School of Medicine, Northwestern University, Chicago, IL; and the Cancer Center of Kansas, Wichita, KS

Address reprint requests to Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute, 250 25th Avenue North, Suite 110, Nashville, TN 37203; e-mail: iflinn{at}tnonc.com

Purpose The combination of fludarabine and cyclophosphamide is an effective regimen for patients with chronic lymphocytic leukemia (CLL). However, it may be accompanied by increased toxicity compared with fludarabine alone. E2997 is a phase III randomized Intergroup trial comparing fludarabine and cyclophosphamide (FC arm) versus fludarabine (F arm) alone in patients receiving their first chemotherapy regimen for CLL.

Patients and Methods Symptomatic, previously untreated patients with CLL were randomly assigned to receive either fludarabine 25 mg/m² intravenously (IV) days 1 through 5 or cyclophosphamide 600 mg/m² IV day 1 and fludarabine 20 mg/m² IV days 1 through 5. These cycles were repeated every 28 days for a maximum of six cycles.

Results A total of 278 patients were randomly assigned in this Intergroup study. Treatment with fludarabine and cyclophosphamide was associated with a significantly higher complete response (CR) rate (23.4% v 4.6%; P < .001) and a higher overall response (OR) rate (74.3% v 59.5%, P = .013) than treatment with fludarabine as a single agent. Progression-free survival (PFS) was also superior in patients treated with fludarabine and cyclophosphamide than those treated with fludarabine (31.6 v 19.2 months, P < .0001). Fludarabine and cyclophosphamide caused additional hematologic toxicity, including more severe thrombocytopenia (P = .046), but it did not increase the number of severe infections (P = .812).

Conclusion Fludarabine and cyclophosphamide produced an increase in OR and CR, and it improved PFS in patients with previously untreated CLL compared with fludarabine alone and was not associated with an increase in infectious toxicity.

published online ahead of print at www.jco.org on February 5, 2007.

Supported by the Eastern Cooperative Oncology Group and supported in part by Public Health Service Grants No. CA16116, CA23318, CA11083, CA59307, CA13650, CA15488, CA49957, CA66636, CA21115, and CA31946 from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services.

Presented in part at the 46th Annual Meeting of the American Society of Hematology, December 3-7, 2004, San Diego, CA.

This article's contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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