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Sequential flavopiridol, cytosine arabinoside, and mitoxantrone: a phase II trial in adults with poor-risk acute myelogenous leukemia.

AbstractPURPOSE:
Flavopiridol is a cyclin-dependent kinase inhibitor that is cytotoxic to leukemic blasts. In a phase I study of flavopiridol followed by 1-beta-d-arabinofuranosylcytosine (ara-C) and mitoxantrone, overall response rate for adults with relapsed and refractory acute myelogenous leukemias (AML) was 31%. We have now completed a phase II study of sequential flavopiridol, ara-C, and mitoxantrone in 62 adults with poor-risk AML.
EXPERIMENTAL DESIGN:
Flavopiridol (50 mg/m(2)) was given by 1-h infusion daily x 3 beginning day 1 followed by 2 gm/m(2)/72 h ara-C beginning day 6 and 40 mg/m(2) mitoxantrone on day 9.
RESULTS:
Flavopiridol caused a > or =50% decrease in peripheral blood blasts in 44% by median day 2 and > or =80% decrease in 26% by day 3. Self-limited tumor lysis occurred in 53%. Three (5%) died during therapy (2 multiorgan failure and 1 fungal pneumonia). Complete remissions (CR) were achieved in 12 of 15 (75%) newly diagnosed secondary AML, 18 of 24 (75%) first relapse after short CR (median CR, 9 months, including prior allotransplant), and 2 of 13 (15%) primary refractory but 0 of 10 multiply refractory AML. Disease-free survival for all CR patients is 40% at 2 years, with newly diagnosed patients having a 2-year disease-free survival of 50%.
CONCLUSIONS:
Flavopiridol has anti-AML activity directly and in combination with ara-C and mitoxantrone. This timed sequential regimen induces durable CRs in a significant proportion of adults with newly diagnosed secondary AML (including complex cytogenetics) and adults with AML in first relapse after short first CR.
AuthorsJudith E Karp, B Douglas Smith, Mark J Levis, Steven D Gore, Jacqueline Greer, Catherine Hattenburg, Janet Briel, Richard J Jones, John J Wright, A Dimitri Colevas
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 13 Issue 15 Pt 1 Pg. 4467-73 (Aug 01 2007) ISSN: 1078-0432 [Print] United States
PMID17671131 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Flavonoids
  • Piperidines
  • Cytarabine
  • alvocidib
  • Mitoxantrone
Topics
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
  • Cytarabine (administration & dosage)
  • Disease-Free Survival
  • Female
  • Flavonoids (administration & dosage)
  • Humans
  • Infusions, Intravenous
  • Leukemia, Myeloid, Acute (drug therapy, pathology)
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Mitoxantrone (administration & dosage)
  • Neoplasm Recurrence, Local (drug therapy, pathology)
  • Piperidines (administration & dosage)
  • Prognosis
  • Remission Induction
  • Salvage Therapy
  • Survival Rate

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