Phase I clinical and pharmacokinetic study of a novel schedule of flavopiridol in relapsed or refractory acute leukemias
| Autor: | 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 |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: | |
| Zdroj: | Haematologica, Vol 95, Iss 7 (2010) |
| Druh dokumentu: | article |
| ISSN: | 0390-6078 1592-8721 |
| DOI: | 10.3324/haematol.2009.017103 |
| Popis: | 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 40mg/m2 intravenous bolus plus 60mg/m2 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 (ClinicalTrials.gov Identifier: NCT00101231). |
| Databáze: | Directory of Open Access Journals |
| Externí odkaz: |
|