TY - JOUR AU - William Blum, AU - Mitch A. Phelps, AU - Rebecca B. Klisovic, AU - Darlene M. Rozewski, AU - Wenjun Ni, AU - Katie A. Albanese, AU - Brad Rovin, AU - Cheryl Kefauver, AU - Steven M. Devine, AU - David M. Lucas, AU - Amy Johnson, AU - Larry J. Schaaf, AU - John C. Byrd, AU - Guido Marcucci, AU - Michael R. Grever, PY - 2010/06/30 Y2 - 2024/03/29 TI - Phase I clinical and pharmacokinetic study of a novel schedule of flavopiridol in relapsed or refractory acute leukemias JF - Haematologica JA - haematol VL - 95 IS - 7 SE - Articles DO - 10.3324/haematol.2009.017103 UR - https://haematologica.org/article/view/5651 SP - 1098-1105 AB - 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). ER -