Originally published as JCO Early Release 10.1200/JCO.2009.22.0442 on August 24 2009

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Rituximab, Fludarabine, Cyclophosphamide, and Mitoxantrone: A New, Highly Active Chemoimmunotherapy Regimen for Chronic Lymphocytic Leukemia

From the Department of Hematology, Hospital Clínic, Institut de Investigacions Biomèdiques "August Pi i Sunyer"; Department of Hematopathology, Hospital Clinic; Hospital "Duran y Reynals," L'Hospitalet; Hospital del Mar; Hospital de Sant Pau, Barcelona; Departments of Hematology, Hospital Clínic; Hospital General Universitario; Hospital Dr Peset; Hospital "Arnau de Vilanova"; Hospital "La Fe," Valencia; Hospital "Germans Trias y Pujol," Badalona; Hospital Clínico Universitario, Salamanca; Hospital Universitario Puerta de Hierro, Madrid; Hospital Joan XXIII, Tarragona; Hospital "Josep Trueta," Girona; and Hospital Mutua de Terrassa, Terrassa, Spain.

Corresponding author: Francesc Bosch, MD, PhD, Department of Hematology, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain; e-mail: fbosch{at}clinic.ub.es.

Purpose The addition of monoclonal antibodies to chemotherapy has significantly improved treatment of chronic lymphocytic leukemia (CLL). Based on excellent results with the chemotherapy-only regimen fludarabine, cyclophosphamide, and mitoxantrone (FCM), we built a new chemoimmunotherapy combination—rituximab plus FCM (R-FCM). We report a phase II clinical trial consisting of an initial treatment with R-FCM followed by rituximab maintenance.

Patients and Methods Seventy-two untreated CLL patients age 70 years or younger received rituximab 500 mg/m² on day 1 (375 mg/m² the first cycle), fludarabine 25 mg/m² IV on days 1 to 3, cyclophosphamide 200 mg/m² on days 1 to 3, and mitoxantrone 6 mg/m² IV on day 1, given at 4-week intervals with up to six cycles supported with colony-stimulating factor. Patients achieving response received maintenance with rituximab 375 mg/m² every 3 months for 2 years.

Results The overall response, minimal residual disease (MRD) –negative complete response (CR), MRD-positive CR, and partial response rates were 93%, 46%, 36%, and 11%, respectively. Severe neutropenia developed in 13% of patients. Major and minor infections were reported in 8% and 5% of cycles, respectively. Advanced clinical stage, del(17p), or increased serum β2-microglobulin levels correlated with a lower CR rate.

Conclusion R-FCM is highly effective in previously untreated CLL, with an 82% CR rate and a high proportion of MRD-negative CRs (46%). Treatment toxicity is acceptable. Parameters correlating with a lower response rate were advanced clinical stage, high serum β2-microglobulin levels, and del(17p). Based on these results, R-FCM warrants further investigation in randomized clinical trials.

Supported in part by Grants No. 05/0213, 08/0211, and 08/0304 from the Spanish Ministry of Health; Grant No. 05/1810 from Marató de TV3; Grant No. RTICC-2006; and Grants No. EM/08 and CR/08 from the José Carreras Foundation.

Written on behalf of the Spanish Group for Chronic Lymphocytic Leukemia.

Presented in part at the 43rd Annual Meeting of the American Society of Hematology, December 8-11, 2007, Atlanta, GA.

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

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