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Blood, 15 April 2004, Vol. 103, No. 8, pp. 2908-2913.
Prepublished online as a Blood First Edition Paper on December 4, 2003; DOI 10.1182/blood-2003-07-2195.
 Previous Article | Table of Contents | Next Article 
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
The value of fludarabine in addition to ARA-C and G-CSF in the treatment of patients with high-risk myelodysplastic syndromes and AML in elderly patients
Gert J. Ossenkoppele,
Wilfried J. Graveland,
Pieter Sonneveld,
Simon M. G. J. Daenen,
Douwe H. Biesma,
Leo F. Verdonck,
M. Ron Schaafsma,
Petra H. M. Westveer,
Godefridus J. Peters,
Paul Noordhuis,
Petra Muus,
Dominik Selleslag,
Bronnie van der Holt,
Michel Delforge,
Bob Löwenberg, and
Gregor E. G. Verhoef, Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON)
From the Departments of Hematology and Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands; HOVON Data Center and the Department of Hematology, Erasmus MC, Rotterdam, The Netherlands; Department of Hematology, Academic Hospital, Groningen, The Netherlands; Department of Hematology, St Antonius Ziekenhuis, Nieuwegein, The Netherlands; Department of Hematology, University Medical Center Utrecht, The Netherlands; Department of Hematology, Medisch Spectrum Twente, Enschede, The Netherlands; Department of Hematology, University Medical Center, Nijmegen, The Netherlands; and Department of Hematology, University Hospitals K.U. Leuven, Louvain, Belgium.
Fludarabine in addition to cytosine-arabinoside (ARA-C) increases the accumulation of ARA-C–5'-triphosphate (ARA-CTP), which is responsible for the cytotoxic effect in leukemic blasts. In a randomized phase 3 trial, patients with high-risk myelodysplastic syndrome (MDS) (n = 91) or elderly patients with acute myeloid leukemia (AML) (n = 43) were randomized to receive 2 induction courses consisting of ARA-C (2 g/m2 days 1 through 5) and granulocyte colony-stimulating factor (G-CSF) (filgrastim, 5µg/kg) during and after chemotherapy with or without fludarabine (25 mg/m2, days 1 through 5) (FLAG versus AG). Consolidation consisted of daunorubicin (45 mg/m2, days 1 through 3) and ARA-C (200 mg/m2, days 1 through 7). Complete remission (CR) rate following AG was 65% versus 71% with FLAG (P = .49). Overall survival (OS) at 24 months was 24% for AG treatment and 39% for FLAG (P = .32). Event-free survival (EFS) at 2 years was 10% and 19% (P = .31) for the AG and FLAG treatments, respectively. Platelet and granulocyte recovery times after the second cycle were prolonged in the FLAG treatment group. Grades 3 to 4 neurotoxicities were more often reported in the FLAG arm (14% versus 3%, P = .03), whereas no significant differences in other toxicities were observed. In a cohort of patients, the in vivo accumulation of ARA-CTP in leukemic cells was determined. Although ARA-CTP accumulation in leukemic cells after FLAG was enhanced, clinical outcome in terms of CR rate, OS, EFS, and disease-free survival (DFS) was not significantly improved by combining fludarabine with ARA-C. (Blood. 2004;103:2908-2913)
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