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

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Clinical Cancer Research 14, 155-161, January 1, 2008. doi:

10.1158/1078-0432.CCR-07-1371

Fludarabine, Cyclophosphamide, and Mitoxantrone as Initial Therapy of Chronic

Lymphocytic Leukemia: High Response Rate and Disease Eradication

Francesc Bosch1, Ana Ferrer2, Neus Villamor3, Marcos González7, Briones4,

Eva González-Barca5, Eugenia Abella2, Santiago Gardella8, Lourdes Escoda9, Elena

Pérez-Ceballos10, Antoni Asensi11, Ma José Sayas12, Llorenç Font13, Albert

Altés4,6, Ana Muntañola1, Paola Bertazzoni1, María Rozman3, Marta Aymerich3, Eva

Giné1 and Emili Montserrat1

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 " p

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@... .

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 IgVH 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.