title: Phase I clinical and pharmacokinetic evaluation of high-dose mitoxantrone in combination with cytarabine in patients with acute leukemia.
abstract: OBJECTIVE
  To determine the maximally tolerated dose of mitoxantrone in combination with cytarabine in patients with acute leukemia and advanced phases of chronic myelogenous leukemia (CML), and to assess the pharmacokinetics of high-dose mitoxantrone in this patient population.
  
  
  METHODS
  In a phase I study, 68 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and accelerated- and blastic-phase CML received induction therapy consisting of cytarabine 3 g/m2 by infusion over 3 hours daily for 5 days, with escalating doses of mitoxantrone 40 to 80 mg/m2 over 1 to 2 days by intravenous infusion over 15 minutes. Mitoxantrone pharmacokinetics were evaluated by high-performance liquid chromatography (HPLC) in 15 patients given a single dose of mitoxantrone ranging from 40 to 80 mg/m2 in combination with cytarabine.
  
  
  RESULTS
  Severe, but reversible hyperbilirubinemia (> three times normal) was considered the dose-limiting toxicity, and was observed in 25% of all patients and in 35% of those who received 70 to 80 mg/m2 of mitoxantrone. Other extramedullary toxicity, including cardiac dysfunction, was mild. Myelosuppression was universal and the median time to complete remission (CR) was 28 days (range, 19 to 77). The CR rate for previously untreated and relapsed patients with AML was 85% (17 of 20) and 38% (seven of 18), respectively. Eighty-three percent (15 of 18) of patients with ALL achieved a CR, including all patients with previously untreated disease. Eight of 12 patients with advanced-phase CML achieved a CR. No significant changes in mean mitoxantrone plasma elimination rates (ie, terminal plasma half-life and total-body clearance rate) occurred as the mitoxantrone dose doubled, indicating linear pharmacokinetics.
  
  
  CONCLUSIONS
  The recommended phase II dose of mitoxantrone is 80 mg/m2 administered over 15 minutes as a single intravenous infusion in combination with cytarabine 3 g/m2/d for 5 days. At this dose, high concentrations of mitoxantrone are achievable in vivo to levels that have been shown to be extremely cytotoxic in vitro.
authors.affiliation: Division of Neoplastic Diseases, New York Medical College, Valhalla 10595.
authors.forename: E J
authors.initials: EJ
authors.lastname: Feldman
authors.forename: D S
authors.initials: DS
authors.lastname: Alberts
authors.forename: Z
authors.initials: Z
authors.lastname: Arlin
authors.forename: T
authors.initials: T
authors.lastname: Ahmed
authors.forename: A
authors.initials: A
authors.lastname: Mittelman
authors.forename: P
authors.initials: P
authors.lastname: Baskind
authors.forename: Y M
authors.initials: YM
authors.lastname: Peng
authors.forename: M
authors.initials: M
authors.lastname: Baier
authors.forename: P
authors.initials: P
authors.lastname: Plezia
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001752:Blast Crisis / Q000188:drug therapy*; D056486:Chemical and Drug Induced Liver Injury; D003561:Cytarabine / Q000008:administration & dosage / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D015465:Leukemia, Myeloid, Accelerated Phase / Q000188:drug therapy*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage / Q000493:pharmacokinetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*
chemical_list: D003561:Cytarabine; D008942:Mitoxantrone