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Phase III Intergroup Study of Fludarabine Phosphate Compared With Cyclophosphamide, Vincristine, and Prednisone Chemotherapy in Newly Diagnosed Patients With Stage III and IV Low-Grade Malignant Non-Hodgkin's Lymphoma

Anton Hagenbeek, Houchingue Eghbali, Silvio Monfardini, Umberto Vitolo, Peter J. Hoskin, Christiane de Wolf-Peeters, Ken MacLennan, Elvira Staab-Renner, Joachim Kalmus, Astrid Schott, Ivana Teodorovic, Anastassia Negrouk, Martine van Glabbeke, Robert Marcus

From the European Organisation for Research and Treatment of Cancer (EORTC) Lymphoma Group, the British National Lymphoma Investigation Group, and the Dutch-Belgian Working Party on Hemato-Oncology, Academic Medical Center Amsterdam, Amsterdam, the Netherlands; Institut Bergonie Cancer Center, Bordeaux, France; Ospedale Civile di Padova, Padova; S Giovanni Battista Hospital, Torino, Italy; Mount Vernon Hospital, Northwood; St James's University Hospital, Leeds; Addenbrooke's Hospital, Cambridge, United Kingdom; University of Leuven Medical Center, Leuven; EORTC Data Center, Brussels, Belgium; and Schering AG, Berlin, Germany.

Address reprint requests to Anton Hagenbeek, MD, PhD, Academic Medical Center, Department of Hematology (F4-224), PO Box 22660, 1100 DD Amsterdam, the Netherlands; e-mail: a.hagenbeek{at}amc.uva.nl

PURPOSE: To compare the efficacy and safety of fludarabine phosphate with cyclophosphamide, vincristine, and prednisone (CVP) in 381 previously untreated, advanced-stage, low-grade (lg) non-Hodgkin's lymphoma (NHL) patients in a phase III, multicenter study.

PATIENTS AND METHODS: Between 1993 and 1997, patients were randomly assigned to treatment with either fludarabine (25 mg/m² intravenously [IV] daily for 5 days every 4 weeks) or CVP (cyclophosphamide 750 mg/m² IV on day 1; vincristine, 1.4 mg/m² IV on day 1; and prednisone, 40 mg/m² orally on days 1 through 5 every 4 weeks).

RESULTS: Overall response (OR) rates were significantly improved in the fludarabine arm versus the CVP arm, both for the intent-to-treat (ITT) population and assessable patients (P < .001). Complete response (CR) rates in the ITT population were also higher after fludarabine treatment. The CR rate was 38.6% for fludarabine compared with 15.0% for CVP. There were no statistically significant differences in time to progression (TTP), time to treatment failure (TTF), and overall survival (OS) between treatment groups. WHO grades 3 and 4 hematologic adverse events were more common in the fludarabine arm. However, concerning the higher incidence of granulocytopenia, this did not translate to more infections in fludarabine-treated patients.

CONCLUSION: Newly diagnosed lgNHL patients who received fludarabine achieved higher OR and CR rates compared with CVP-treated patients. No differences in TTP, TTF, and OS were noted. Fludarabine is a highly active single agent in lgNHL. Combination therapies incorporating fludarabine are now being further evaluated as first-line therapy in follicular NHL.

Supported by Schering AG, Berlin, Germany.

Presented in part at the 43rd Annual Meeting of the American Society of Hematology, Orlando, FL, December 7-11, 2001.

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

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