title: Phase I clinical and pharmacokinetic study of a novel schedule of flavopiridol in relapsed or refractory acute leukemias.
abstract: BACKGROUND
  A pharmacokinetically derived schedule of flavopiridol administered as a 30 min intravenous bolus followed by 4-hour continuous intravenous infusion (IVB/CIVI) is active in fludarabine-refractory chronic lymphocytic leukemia, but no studies examining the feasibility and maximum tolerated dose of this schedule have been reported in acute leukemia.
  
  
  METHODS
  We conducted a phase I dose escalation trial of single-agent flavopiridol in adults with relapsed/refractory acute leukemias, utilizing a modification of the intravenous bolus/continuous intravenous infusion approach, intensifying treatment for administration on days 1, 2, and 3 of 21-day cycles.
  
  
  RESULTS
  Twenty-four adults with relapsed/refractory acute myeloid leukemia (n=19) or acute lymphoblastic leukemia (n=5) were enrolled. The median age was 62 years (range, 23-78). The maximum tolerated dose of flavopiridol was 40 mg/m(2) intravenous bolus plus 60 mg/m(2) continuous intravenous infusion (40/60). The dose limiting toxicity was secretory diarrhea. Life-threatening hyperacute tumor lysis syndrome requiring hemodialysis on day 1 was observed in one patient. Pharmacokinetics were dose-dependent with increased clearance observed at the two highest dose levels. Diarrhea occurrence and severity significantly correlated with flavopiridol concentrations at the end of the 4-hour infusion, volume of distribution, and elimination half-life. Modest anti-leukemic activity was observed, with most patients experiencing dramatic but transient reduction/clearance of circulating blasts lasting for 10-14 days. One refractory acute myeloid leukemia patient had short-lived complete remission with incomplete count recovery.
  
  
  CONCLUSIONS
  Flavopiridol as a single agent given by intravenous bolus/continuous intravenous infusion causes marked, immediate cytoreduction in relapsed/refractory acute leukemias, but objective clinical responses were uncommon. With this schedule, the dose is limited by secretory diarrhea.
authors.affiliation: Division of Hematology and Oncology and the Comprehensive Cancer Center, Department of Medicine, The Ohio State University, B310 Starling-Loving Hall, 320 West 10 Avenue, Columbus, OH 43210, USA. william.blum@osumc.edu
authors.forename: William
authors.initials: W
authors.lastname: Blum
authors.forename: Mitch A
authors.initials: MA
authors.lastname: Phelps
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Klisovic
authors.forename: Darlene M
authors.initials: DM
authors.lastname: Rozewski
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ni
authors.forename: Katie A
authors.initials: KA
authors.lastname: Albanese
authors.forename: Brad
authors.initials: B
authors.lastname: Rovin
authors.forename: Cheryl
authors.initials: C
authors.lastname: Kefauver
authors.forename: Steven M
authors.initials: SM
authors.lastname: Devine
authors.forename: David M
authors.initials: DM
authors.lastname: Lucas
authors.forename: Amy
authors.initials: A
authors.lastname: Johnson
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Schaaf
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D004334:Drug Administration Schedule; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010599:Pharmacokinetics; D010880:Piperidines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D016879:Salvage Therapy / Q000379:methods; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib
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