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.

DESIGN AND 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: William Blum, Mitch A Phelps, Rebecca B Klisovic, Darlene M Rozewski, Wenjun Ni, Katie A Albanese, Brad Rovin, Cheryl Kefauver, Steven M Devine, David M Lucas, Amy Johnson, Larry J Schaaf, John C Byrd, Guido Marcucci, Michael R Grever
• Journal: Haematologica (Haematologica) Vol. 95 Issue 7 Pg. 1098-105 (Jul 2010) ISSN: 1592-8721 [Electronic] Italy
• PMID: 20460644 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Flavonoids
• Piperidines
• alvocidib

Topics

• Acute Disease
• Adult
• Aged
• Drug Administration Schedule
• Female
• Flavonoids (administration & dosage, pharmacokinetics, toxicity)
• Humans
• Leukemia (drug therapy)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Pharmacokinetics
• Piperidines (administration & dosage, pharmacokinetics, toxicity)
• Salvage Therapy (methods)
• Treatment Outcome
• Young Adult