TY - JOUR
T1 - Phase 1 and pharmacokinetic study of bolus-infusion flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukemias
AU - Karp, Judith E.
AU - Smith, B. Douglas
AU - Resar, Linda S.
AU - Greer, Jacqueline M.
AU - Blackford, Amanda
AU - Zhao, Ming
AU - Moton-Nelson, Dwella
AU - Alino, Katrina
AU - Levis, Mark J.
AU - Gore, Steven D.
AU - Joseph, Biju
AU - Carraway, Hetty
AU - McDevitt, Michael A.
AU - Bagain, Lorena
AU - Mackey, Karen
AU - Briel, Janet
AU - Doyle, L. Austin
AU - Wright, John J.
AU - Rudek, Michelle A.
PY - 2011/3/24
Y1 - 2011/3/24
N2 - Flavopiridol is a protein bound, cytotoxic, cyclin-dependent kinase inhibitor. Flavopiridol given by 1-hour bolus at 50 mg/m2 daily 3 times followed by cytosine arabinoside and mitoxantrone (FLAM) is active in adults with poor-risk acute leukemias.Apharmacologically 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/m2 per day 3 times (20-mg/m2 bolus, 30-mg/m2 infusion). Dose-limiting toxicity occurred at level 6 (30-mg/m2 bolus, 70-mg/m2 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/m2 followed by infusion of 60 mg/m2 daily for 3 days. This clinical trial is registered at www.clinicaltrials. gov as #NCT00470197.
AB - Flavopiridol is a protein bound, cytotoxic, cyclin-dependent kinase inhibitor. Flavopiridol given by 1-hour bolus at 50 mg/m2 daily 3 times followed by cytosine arabinoside and mitoxantrone (FLAM) is active in adults with poor-risk acute leukemias.Apharmacologically 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/m2 per day 3 times (20-mg/m2 bolus, 30-mg/m2 infusion). Dose-limiting toxicity occurred at level 6 (30-mg/m2 bolus, 70-mg/m2 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/m2 followed by infusion of 60 mg/m2 daily for 3 days. This clinical trial is registered at www.clinicaltrials. gov as #NCT00470197.
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U2 - 10.1182/blood-2010-09-310862
DO - 10.1182/blood-2010-09-310862
M3 - Article
C2 - 21239698
AN - SCOPUS:79953126542
SN - 0006-4971
VL - 117
SP - 3302
EP - 3310
JO - Blood
JF - Blood
IS - 12
ER -