Pharmacology of cytarabine given as a continuous infusion followed by mitoxantrone with and without amsacrine/etoposide as reinduction chemotherapy for relapsed or refractory pediatric acute myeloid leukemia.
BACKGROUND
The outcome of patients with acute myeloid leukemia (AML) who relapse or fail to achieve an initial remission has been dismal.


METHODS
Fifteen pediatric patients with AML, 4 relapsed and 11 primary refractory, were reinduced with a loading bolus of 0.5 g/m2 cytarabine (ara-C) followed immediately by a continuous infusion of ara-C (130 mg/m2/day) for 72 hours, followed with four daily doses (12 mg/m2/day) of mitoxantrone. Eight of 15 patients received an additional course of amsacrine and etoposide.


RESULTS
Ten of 15 (66%) achieved complete response (CR) and 3 achieved partial response (PR) (20%), with an objective response rate of 86% after ara-C/mitoxantrone. One patient died before disease assessment, and one had no response after ara-C/mitoxantrone. Pharmacokinetic studies of ara-C and ara-U were performed in 13 of 15 patients. A steady-state (Css) ara-C concentration was achieved at 2 hours after the bolus ara-C dose and was maintained up to 72 hours. The Css plasma concentrations of ara-C and ara-U averaged 10.33 +/- 0.81 microM and 139.14 +/- 17.8 microM, respectively. Also, cellular pharmacokinetic studies of ara-CTP were performed on circulating leukemic cells from 5 patients. Four patients who had a significant increase (P = 0.0041) in their Css ara-CTP concentrations achieved CR, whereas one patient with an insignificant increase achieved PR.


CONCLUSIONS
Continuous infusion of ara-C followed by mitoxantrone is an active reinduction regimen in refractory or relapsed pediatric AML patients. The addition of amsacrine and etoposide did not improve the remission induction rate. Further studies are needed in a larger patient population to confirm these observations.
Ozkaynak
M F
MF
Department of Pediatrics, New York Medical College, Valhalla 10595, USA. mehmet-ozkaynak@nymc.edu
Avramis
V I
VI
Carcich
S
S
Ortega
J A
JA
D000208:Acute Disease; D000293:Adolescent; D000677:Amsacrine / Q000008:administration & dosage; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001853:Bone Marrow / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D003561:Cytarabine / Q000097:blood / Q000493:pharmacokinetics*; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D007951:Leukemia, Myeloid / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008942:Mitoxantrone / Q000008:administration & dosage; D012008:Recurrence; D012074:Remission Induction
D000964:Antimetabolites, Antineoplastic; D000677:Amsacrine; D003561:Cytarabine; D005047:Etoposide; D008942:Mitoxantrone