Journal
BLOOD
Volume 117, Issue 12, Pages 3302-3310Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-09-310862
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Funding
- National Institutes of Health [2U01CA70095]
- National Cancer Institute [U01 CA70095]
- National Cancer Institute Cancer Center [2P30 CA069773-45]
- National Center for Research [UL1 RR025005]
- J.P. McCarthy Foundation
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Flavopiridol is a protein bound, cytotoxic, cyclin-dependent kinase inhibitor. Flavopiridol given by 1-hour bolus at 50 mg/m(2) daily 3 times followed by cytosine arabinoside and mitoxantrone (FLAM) is active in adults with poor-risk acute leukemias. A pharmacologically 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/m(2) per day 3 times (20-mg/m(2) bolus, 30-mg/m(2) infusion). Dose-limiting toxicity occurred at level 6 (30-mg/m(2) bolus, 70-mg/m(2) 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/m(2) followed by infusion of 60 mg/m(2) daily for 3 days. This clinical trial is registered at www.clinicaltrials.gov as #NCT00470197. (Blood. 2011;117(12):3302-3310)
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