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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.

Author(s): Ossenkoppele GJ, Graveland WJ, Sonneveld P, Daenen SM, Biesma DH, Verdonck LF, Schaafsma MR, Westveer PH, Peters GJ, Noordhuis P, Muus P, Selleslag D, van der Holt B, Delforge M, Lowenberg B, Verhoef GE, Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON)

Affiliation(s): Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands. g.ossenkoppele@vumc.nl

Publication date & source: 2004-04-15, Blood., 103(8):2908-13. Epub 2003 Dec 4.

Publication type: Clinical Trial; Randomized Controlled Trial

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, 5 microg/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.

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