Flavopiridol in Chronic Lymphocytic Leukemia: A Concise Review
Flavopiridol in Chronic Lymphocytic Leukemia: A Concise Review
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DOI：
10.3816/clm.2009.s.009
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发表时间：
2009-09-01
期刊：
影响因子：
--
通讯作者：
Lin, Thomas S.
中科院分区：
文献类型：
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作者：
Christian, Beth A.;Grever, Michael R.;Lin, Thomas S.
具有Del(17p13)等高危细胞遗传学特征的慢性淋巴细胞白血病(CLL)患者治疗选择有限，总体生存率下降。P53功能障碍导致对以氟达拉滨为基础的治疗产生抵抗。细胞周期蛋白依赖性激酶抑制因子(CDKi)是一类不依赖于P53突变状态而诱导CLL细胞凋亡的新型药物。人工合成的黄酮类黄烷醇具有良好的体外抗CLL活性。在最初的I期研究中，在各种恶性肿瘤中使用持续输注给药方案，没有观察到临床活动。详细的药代动力学建模导致了一种新的给药方案的开发，该方案旨在实现体内的目标药物浓度。在I期试验中，该给药方案导致急性肿瘤溶解综合征(TLS)作为剂量限制毒性。随着预防严重TLS的标准化方案的实施，黄烷醇得到了安全的使用，并观察了严重预治疗、氟达拉滨耐药患者、细胞遗传学高危患者和巨大淋巴结病患者的反应。在药代动力学分析中，黄烷醇在血药浓度-时间曲线(AUC)下的面积与临床反应和细胞因子释放综合征相关。第11阶段的研究正在进行中，取得了令人鼓舞的初步结果。目前正在积极研究与其他药物联合使用的法洛匹多，作为消除细胞减少性化疗后患者微小残留疾病的一种手段。本文还简要讨论了其他几种临床前和临床早期研究中的CDKi。
Patients with chronic lymphocytic leukemia (CLL) with high-risk cytogenetic features such as del(17p13) have limited treatment options and decreased overall survival. Dysfunction of p53 leads to resistance to fludarabine-based therapies. Cyclin-dependent kinase inhibitors (CDKi) are a novel class of agents that induce apoptosis in CLL cells independent of p53 mutational status. The synthetic flavone flavopiridol demonstrated promising in vitro activity in CLL. In initial phase I studies using a continuous infusion dosing schedule in a variety of malignancies, no clinical activity was observed. Detailed pharmacokinetic modeling led to the development of a novel dosing schedule designed to achieve target drug concentrations in vivo. In phase I testing, this dosing schedule resulted in acute tumor lysis syndrome (TLS) as the doselimiting toxicity. With the implementation of a standardized protocol to prevent severe TLS, flavopiridol was administered safely, and responses were observed in heavily pretreated, fludarabine-refractory patients, cytogenetically high-risk patients, and patients with bulky lymphadenopathy. In a pharmacokinetic analysis, flavopiridol area under the plasma concentration-time curve (AUC) correlated with clinical response and cytokine release syndrome. Phase 11 studies are under way with encouraging preliminary results. Flavopiridol is currently under active investigation in combination with other agents and as a means to eradicate minimal residual disease in patients following cytoreductive chemotherapy. Several other investigational CDKi in preclinical and early clinical development are briefly discussed in this review.