Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia
Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia
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DOI：
10.1182/blood-2006-05-020735
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发表时间：
2007-01-15
期刊：
影响因子：
20.3
通讯作者：
Grever, Michael R.
中科院分区：
文献类型：
--
作者：
Byrd, John C.;Lin, Thomas S.;Grever, Michael R.
尽管细胞周期蛋白依赖性激酶抑制剂flavopiridol在慢性淋巴细胞白血病（CLL）和其他疾病中的临床前研究很有希望，但以前的临床试验结果令人失望。在人和牛血清中发现差异蛋白结合的flavopiridol有助于一个有效的药代动力学衍生的时间表管理这种代理。基于使用我们的体外结果和先前试验的数据进行的药代动力学建模，我们在难治性CLL患者中启动了一项1期研究，使用30分钟负荷剂量，随后每周输注4小时，持续4/6周。一组42例患者入组3个队列（队列1，30 mg/m2负荷剂量，随后30 mg/m2输注4小时;队列2，40 mg/m2负荷剂量，随后40 mg/m2输注4小时;队列3，队列1剂量治疗1至4，然后30 mg/m2负荷剂量，随后50 mg/m2 4小时输注）。使用这种新方案的剂量限制性毒性是超急性肿瘤溶解综合征。积极的预防和排除白细胞计数大于200 × 10（9）/L的患者使该药物在队列3剂量下安全给药。在接受治疗的42例患者中，19例（45%）达到部分缓解，中位缓解持续时间超过12个月。在遗传高危疾病患者中观察到缓解，包括12例del（17p13.1）患者中的5例（42%）和18例del（11q22.3）患者中的13例（72%）。使用这种新的给药方案给药的Flavopiridol在难治性CLL中具有显著的临床活性。具有巨大疾病和高风险遗传特征的患者已经实现了持久的反应，从而证明了进一步研究flavopiridol在CLL和其他疾病中的作用。
Despite promising preclinical studies with the cyclin-dependent kinase inhibitor flavopiridol in chronic lymphocytic leukemia (CLL) and other diseases, previous clinical trials with this agent have been disappointing. The discovery of differential protein binding of flavopiridol in human and bovine serum contributed to an effective pharmacokinetic-derived schedule of administration of this agent. On the basis of pharmacokinetic modeling using our in vitro results and data from a previous trial, we initiated a phase 1 study using a 30-minute loading dose followed by 4 hours of infusion administered weekly for 4 of 6 weeks in patients with refractory CLL. A group of 42 patients were enrolled on 3 cohorts (cohort 1, 30 mg/m(2) loading dose followed by 30 mg/m(2) 4-hour infusion; cohort 2, 40 mg/m(2) loading dose followed by 40 mg/m(2) 4-hour infusion; and cohort 3, cohort 1 dose for treatments 1 to 4, then a 30 mg/m(2) loading dose followed by a 50 mg/m(2) 4-hour infusion). The dose-limiting toxicity using this novel schedule was hyperacute tumor lysis syndrome. Aggressive prophylaxis and exclusion of patients with leukocyte counts greater than 200 x 10(9)/L have made this drug safe to administer at the cohort 3 dose. Of the 42 patients treated, 19 (45%) achieved a partial response with a median response duration that exceeds 12 months. Responses were noted in patients with genetically high-risk disease, including 5 (42%) of 12 patients with del(17p13.1) and 13 (72%) of 18 patients with del(11q22.3). Flavopiridol administered using this novel schedule has significant clinical activity in refractory CLL. Patients with bulky disease and high-risk genetic features have achieved durable responses, thereby justifying further study of flavopiridol in CLL and other diseases.