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Fludarabine, Cyclophosphamide, and Mitoxantrone as Initial Therapy of Chronic Lymphocytic Leukemia: High Response Rate and Disease Eradication

Authors' Affiliations: Departments of Haematology from ¹ Hospital Clínic de Barcelona and ² Hospital del Mar, Barcelona; ³ Hematopathology Unit, Hospital Clínic de Barcelona; ⁴ Hospital de Sant Pau; ⁵ Hospital Durán y Reynalds, L'Hospitalet del Llobregat; ⁶ Hospital de l'Esperit Sant, Barcelona, Spain; ⁷ Hospital Universitario de Salamanca, Salamanca, Spain; ⁸ Hospital "Josep Trueta," Girona, Spain; ⁹ Hospital "Joan XXIII," Tarragona, Spain; ¹⁰ Hospital Morales Meseguer, Murcia, Spain; ¹¹ Hospital "Els Camils," St. Pere de Ribes, Spain; ¹² Hospital "Dr. Peset," Valencia, Spain; and ¹³ Hospital Verge de la Cinta, Tortosa, Spain

Requests for reprints: Francesc Bosch, Department of Haematology, Hospital Clínic, Villarroel, 170, 08036 Barcelona, Spain. Phone: 34-9-322-75428; Fax: 34-9-322-75484; E-mail: fbosch{at}clinic.ub.es.

Purpose: Fludarabine, cyclophosphamide, and mitoxantrone (FCM) results in a high response rate in previously treated patients with chronic lymphocytic leukemia (CLL). The aim of this study was to investigate FCM as frontline therapy in CLL.

Experimental Design: Sixty-nine patients under the age of 65 years with active CLL were treated. Patients received six cycles of fludarabine 25 mg/m² i.v. x 3 days, cyclophosphamide 200 mg/m² i.v. x 3 days, and mitoxantrone 6 mg/m² i.v. x 1 day. Treatment outcome was correlated with clinical and biological variables. The clinical significance of eradicating minimal residual disease (MRD) was also analyzed.

Results: The overall response, MRD-negative complete response (CR), MRD-positive CR, nodular partial response (PR), and PR rates were 90%, 26%, 38%, 14%, and 12%, respectively. Severe (grades 3 or 4) neutropenia developed in 10% of the patients. Major and minor infections were reported in 1% and 8% of cases, respectively. Median response duration was 37 months. Patients with del(17p) failed to attain CR. Patients achieving MRD-negative CR had a longer response duration and overall survival than patients with an inferior response. Low serum lactate dehydrogenase levels, low ZAP-70 expression, and mutated IgV_H genes predicted longer response duration. Finally, both low ZAP-70 and CD38 expression in leukemic cells correlated with MRD-negativity achievement.

Conclusion: FCM induces a high response rate, including MRD-negative CRs in untreated patients with active CLL. Treatment toxicity is acceptable. Both high ZAP-70 and increased CD38 expression predict failure to obtain MRD-negative response. Patients in whom MRD can be eradicated have longer response duration and overall survival than those with inferior response. These results indicate that FCM can be an ideal companion for chemoimmunotherapy of patients with CLL.

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