title: A phase I and pharmacodynamic study of fludarabine, carboplatin, and topotecan in patients with relapsed, refractory, or high-risk acute leukemia.
abstract: OBJECTIVE
  A novel regimen designed to maximize antileukemia activity of carboplatin through inhibiting repair of platinum-DNA adducts was conducted in poor prognosis, acute leukemia patients.
  
  
  METHODS
  Patients received fludarabine (10 to 15 mg/m(2) x 5 days), carboplatin (area under the curve 10 to 12 by continuous infusion over 5 days), followed by escalated doses of topotecan infused over 72 hours (fludarabine, carboplatin, topotecan regimen). Twenty-eight patients had acute myelogenous leukemia (7 untreated secondary acute myelogenous leukemia, 11 in first relapse, and 10 in second relapse or refractory), 1 patient had refractory/relapsed acute lymphoblastic leukemia, and 2 patients had untreated chronic myelogenous leukemia blast crisis. Six patients had failed an autologous stem cell transplant. Patients ranged from 19 to 76 (median 54) years. Measurement of platinum-DNA adducts were done in serial bone marrow specimens.
  
  
  RESULTS
  Fifteen of 31 patients achieved bone marrow aplasia. Clinical responses included 2 complete response, 4 complete response with persistent thrombocytopenia, and 2 partial response. Prolonged myelosuppression was observed with median time to blood neutrophils >/=200/microl of 28 (0 to 43) days and time to platelets >/=20,000/microl (untransfused) of 40 (24 to 120) days. Grade 3 or greater infections occurred in all of the patients, and there were 2 infection-related deaths. The nonhematologic toxicity profile was acceptable. Five patients subsequently received allografts without early transplant-related mortality. Maximum tolerated dose of fludarabine, carboplatin, topotecan regimen was fludarabine 15 mg/m(2) x 5, carboplatin area under the curve 12, and topotecan 2.55 mg/m(2) over 72 hours. An increase in bone marrow, platinum-DNA adduct formation between the end of carboplatin infusion and 48 hours after the infusion correlated with bone marrow response.
  
  
  CONCLUSIONS
  Fludarabine, carboplatin, topotecan regimen is a promising treatment based on potential pharmacodynamic interactions, which merits additional study in poor prognosis, acute leukemia patients.
authors.affiliation: Department of Medicine, University Hospitals of Cleveland, Ireland Cancer Center, Case Western Reserve University, Cleveland, Ohio 44109, USA. bxc12@po.cwru.edu
authors.forename: Brenda W
authors.initials: BW
authors.lastname: Cooper
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Veal
authors.forename: Tomas
authors.initials: T
authors.lastname: Radivoyevitch
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Tilby
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Meyerson
authors.forename: Hillard M
authors.initials: HM
authors.lastname: Lazarus
authors.forename: Omer N
authors.initials: ON
authors.lastname: Koc
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Creger
authors.forename: Graham
authors.initials: G
authors.lastname: Pearson
authors.forename: Geoff M
authors.initials: GM
authors.lastname: Nowell
authors.forename: David
authors.initials: D
authors.lastname: Gosky
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Ingalls
authors.forename: Charles L
authors.initials: CL
authors.lastname: Hoppel
authors.forename: Stanton L
authors.initials: SL
authors.lastname: Gerson
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D018736:DNA Adducts; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D011379:Prognosis; D012008:Recurrence; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D014740:Vidarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D018736:DNA Adducts; D019772:Topotecan; D016190:Carboplatin; D014740:Vidarabine; C024352:fludarabine