Fred Hutchinson Cancer Research Center , 1100 Fairview Ave N. D5-360, Seattle, WA 98109-1024 , USA +1 206 667 6045 ; +1 206 667-2324 ;
Expert Opin Investig Drugs. 2013 Dec;22(12):1659-69. doi: 10.1517/13543784.2013.842973. Epub 2013 Sep 26.
Approximately one-third of the patients with acute myeloid leukemia (AML) harbor internal tandem duplication (ITD) in the gene encoding FMS-like tyrosine kinase 3 (FLT3-ITD), which is associated with poor prognosis. Over the course of the last decade, several FLT3 inhibitors have been developed. Nevertheless, the pharmacokinetic limitations of some of these compounds as well as their potency have limited their therapeutic efficacy. Quizartinib (AC220) is a second-generation FLT3 inhibitor that has shown promising activity in AML in Phase II clinical trials.
The pharmacokinetic, mechanism of action and resistance as well as clinical studies of quizartinib in AML are reported here in detail.
Quizartinib is potent and selective FLT3 tyrosine kinase inhibitor with significant activity in both FLT3-mutant and wild-type AML. The quality and duration of achievable response thus far seen with this agent is suboptimal. Quizartinib in combination with chemotherapy might result in improved outcome and results of these trials are eagerly awaited. In addition, quizartinib in combination with other agents tackling the bone marrow microenvironment and FLT3 cooperative pathways may enhance response to quizartinib.
大约三分之一的急性髓系白血病（AML）患者存在编码 FMS 样酪氨酸激酶 3（FLT3-ITD）的基因内串联重复（ITD），这与预后不良有关。在过去的十年中，已经开发了几种 FLT3 抑制剂。然而，这些化合物中的一些由于药代动力学限制及其效力限制了其治疗效果。Quizartinib（AC220）是一种第二代 FLT3 抑制剂，在 AML 的 II 期临床试验中显示出良好的疗效。
本文详细报告了 quizartinib 在 AML 中的药代动力学、作用机制和耐药性以及临床研究。
Quizartinib 是一种有效且选择性的 FLT3 酪氨酸激酶抑制剂，在 FLT3 突变型和野生型 AML 中均具有显著活性。到目前为止，该药物的反应质量和持续时间并不理想。Quizartinib 与化疗联合使用可能会改善疗效，人们急切地等待着这些试验的结果。此外，quizartinib 与其他针对骨髓微环境和 FLT3 协同途径的药物联合使用可能会增强对 quizartinib 的反应。
