title: High single dose of mitoxantrone and cytarabine in acute non-lymphocytic leukemia: a pharmacokinetic and clinical study.
abstract: In a phase I-II study, the authors evaluated the intracellular pharmacokinetics, toxicity, and efficiency of a high dose of mitoxantrone given as first induction in acute non-lymphocytic leukemia. Twenty-two patients with previously untreated de novo ANLL were included and received 30 or 40 mg/m2 mitoxantrone on day 1 by intravenous infusion over 1 hour and 500 mg/m2 ara-C twice a day for 5 days. If there was no complete remission (CR), a second induction with ara-C, etoposide, and amsacrine was given. The CR rate after two courses with this regimen was 77%. Median duration of severe neutropenia was 18 days in the 30-mg/m2 group and 25 days in the 40-mg/m2 group. Two patients had fatal lung complications probably unrelated to mitoxantrone. A third patient had a possible mitoxantrone-induced reversible lung complication. In the leukemic cells, we found a high accumulation of mitoxantrone which, in contrast to the plasma concentration, remained stable during the 48 hours studied. Compared with previous results with 12 mg/m2 mitoxantrone, the AUC for intracellular concentrations versus time for the first 20 hours studied was increased by 150% to 0.638 nmol/mg cell protein x hour with 30 mg/m2 mitoxantrone and by 260% to 1.103 nmol/mg cell protein x hour with 40 mg/m2 mitoxantrone. In conclusion, a high dose of mitoxantrone results in a high intracellular exposure of the leukemic cells, which may be an advantage in improving survival of these patients.
authors.affiliation: Department of Medicine, Orebro Medical Centre Hospital, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Möllgård
authors.forename: U
authors.initials: U
authors.lastname: Tidefelt
authors.forename: B
authors.initials: B
authors.lastname: Sundman-Engberg
authors.forename: C
authors.initials: C
authors.lastname: Löfgren
authors.forename: S
authors.initials: S
authors.lastname: Lehman
authors.forename: C
authors.initials: C
authors.lastname: Paul
mesh_terms: D000328:Adult; D000368:Aged; D000677:Amsacrine / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003561:Cytarabine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D004334:Drug Administration Schedule; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D009503:Neutropenia / Q000139:chemically induced; D013997:Time Factors
chemical_list: D000677:Amsacrine; D003561:Cytarabine; D005047:Etoposide; D008942:Mitoxantrone