Phase 1 and pharmacokinetic study of bolus-infusion flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukemias
Phase 1 and pharmacokinetic study of bolus-infusion flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukemias
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DOI：
10.1182/blood-2010-09-310862
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发表时间：
2011-03-24
期刊：
影响因子：
20.3
通讯作者：
Rudek, Michelle A.
中科院分区：
文献类型：
--
作者：
Karp, Judith E.;Smith, B. Douglas;Rudek, Michelle A.
Flavopiridol是一种蛋白结合的细胞毒性细胞周期蛋白依赖性激酶抑制剂。Flavopiridol以50 mg/m2每日3次，每次1小时推注，随后是阿糖胞苷和米托蒽醌（FLAM），对低风险急性白血病成人有效。在难治性慢性淋巴细胞性白血病中，一种源自FDA的"混合"方案（30分钟推注，随后4小时输注）比推注给药更有效。我们在55名复发/难治性急性白血病成人中进行的I期试验"混合FLAM"开始时，总flavopiridol剂量为50 mg/m2/天，共3次（20 mg/m2推注，30 mg/m2输注）。剂量限制性毒性发生在水平6（30 mg/m2推注，70 mg/m2输注），伴有肿瘤溶解、高胆红素血症和粘膜炎。死亡5例（9%）。在所有剂量中，22例（40%）患者完全缓解。完全缓解患者的总生存率和无病生存率在2年以上时超过60%。药代动力学表明，总血浆和未结合血浆flavopiridol的剂量反应与总蛋白、白蛋白、外周原始细胞计数或毒性无关。药效学上，flavopiridol抑制多种细胞周期调节因子的mRNA，但bcl-2的均匀增加。"混合FLAM"在复发/难治性急性白血病中有效，推荐的"混合"剂量为推注30 mg/m2，然后每天输注60 mg/m2，持续3天。本临床试验在www.example.com注册为#NCT00470197。（血。2011; 117（12）：3302 - 3310）
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)