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.
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.
Ossenkoppele
Gert J
GJ
Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands. g.ossenkoppele@vumc.nl
Graveland
Wilfried J
WJ
Sonneveld
Pieter
P
Daenen
Simon M G J
SM
Biesma
Douwe H
DH
Verdonck
Leo F
LF
Schaafsma
M Ron
MR
Westveer
Petra H M
PH
Peters
Godefridus J
GJ
Noordhuis
Paul
P
Muus
Petra
P
Selleslag
Dominik
D
van der Holt
Bronnie
B
Delforge
Michel
M
Löwenberg
Bob
B
Verhoef
Gregor E G
GE
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D003561:Cytarabine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018572:Disease-Free Survival; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage* / Q000009:adverse effects; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000378:metabolism; D011379:Prognosis; D011994:Recombinant Proteins; D012307:Risk Factors; D015996:Survival Rate; D014740:Vidarabine / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives*
D011994:Recombinant Proteins; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D016179:Granulocyte Colony-Stimulating Factor; D014740:Vidarabine; C024352:fludarabine; D000069585:Filgrastim