Phase 1 and pharmacokinetic study of bolus-infusion flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukemias

Judith E. Karp, B. Douglas Smith, Linda S. Resar, Jacqueline M. Greer, Amanda Blackford, Ming Zhao, Dwella Moton-Nelson, Katrina Alino, Mark J. Levis, Steven D. Gore, Biju Joseph, Hetty Carraway, Michael A. McDevitt, Lorena Bagain, Karen Mackey, Janet Briel, L. Austin Doyle, John J. Wright, Michelle A. Rudek

Research output: Contribution to journalArticlepeer-review

Abstract

Flavopiridol is a protein bound, cytotoxic, cyclin-dependent kinase inhibitor. Flavopiridol given by 1-hour bolus at 50 mg/m2 daily 3 times followed by cytosine arabinoside and mitoxantrone (FLAM) is active in adults with poor-risk acute leukemias.Apharmacologically derived "hybrid" schedule (30-minute bolus followed by 4-hour infusion) of flavopiridol was more effective than bolus administration in refractory chronic lymphocytic leukemia. Our phase 1 trial "hybrid FLAM" in 55 adults with relapsed/refractory acute leukemias began at a total flavopiridol dose of 50 mg/m2 per day 3 times (20-mg/m2 bolus, 30-mg/m2 infusion). Dose-limiting toxicity occurred at level 6 (30-mg/m2 bolus, 70-mg/m2 infusion) with tumor lysis, hyperbilirubinemia, and mucositis. Death occurred in 5 patients (9%). Complete remission occurred in 22 (40%) across all doses. Overall and disease-free survivals for complete remission patients are more than 60% at more than 2 years. Pharmacokinetics demonstrated a dose-response for total and unbound plasma flavopiridol unrelated to total protein, albumin, peripheral blast count, or toxicity. Pharmacodynamically, flavopiridol inhibited mRNAs of multiple cell cycle regulators, but with uniform increases in bcl-2. "Hybrid FLAM" is active in relapsed/refractory acute leukemias, with a recommended "hybrid" dose of bolus 30 mg/m2 followed by infusion of 60 mg/m2 daily for 3 days. This clinical trial is registered at www.clinicaltrials. gov as #NCT00470197.

Original languageEnglish (US)
Pages (from-to)3302-3310
Number of pages9
JournalBlood
Volume117
Issue number12
DOIs
StatePublished - Mar 24 2011

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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