FLT3 INHIBITORS: RECENT ADVANCES AND PROBLEMS FOR CLINICAL APPLICATION
FLT3 INHIBITORS: RECENT ADVANCES AND PROBLEMS FOR CLINICAL APPLICATION
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DOI：
10.18999/nagjms.77.1-2.7
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发表时间：
2015-02
影响因子：
0.9
通讯作者：
H. Kiyoi
中科院分区：
文献类型：
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作者：
H. Kiyoi
FLT 3是一种III型受体酪氨酸激酶，在大多数急性白血病细胞以及正常造血干/祖细胞上表达。FLT 3基因突变是急性髓性白血病（AML）中最常见的遗传改变，并且众所周知是骨髓恶性肿瘤发展的重要驱动突变。FLT 3突变是AML患者长期生存的一个强有力的不良预后因素，而大剂量化疗或异基因造血干细胞移植都不能克服不良预后。因此，FLT 3抑制剂的开发等待已久。迄今为止，已经开发了几种有效的FLT 3抑制剂，其中一些在临床试验中进行了疗效评估，尽管尚未批准FLT 3抑制剂。此外，临床应用中的一些问题，如不良反应、血药浓度和耐药性已经很明显。最近开发的AC 220是一种高度选择性和敏感的FLT 3抑制剂。在I期和II期试验中，迄今为止，AC 220在临床评价的FLT 3抑制剂中显示出对携带FLT 3突变的AML细胞的最佳疗效，而临床使用应解决严重的骨髓抑制和QTc延长。在这篇综述中，我总结了FLT 3抑制剂在临床开发中的特点，并讨论了临床应用中需要解决的重要问题。
ABSTRACT FLT3, a type III receptor tyrosine kinase, expresses on most acute leukemia cells as well as normal hematopoietic stem/progenitor cells. Mutation in the FLT3 gene is the most frequent genetic alteration in acute myeloid leukemia (AML) and is well known as an important driver mutation for the development of myeloid malignancies. FLT3 mutation is a strong poor prognostic factor for the long-term survival in AML patients, while neither high-dose chemotherapy nor allogeneic hematopoietic stem cell transplantation can overcome a poor prognosis. Development of an FLT3 inhibitor is, therefore, much awaited. To date, several potent FLT3 inhibitors have been developed and some of them were evaluated for efficacy in clinical trials, although no FLT3 inhibitor has been yet approved. Moreover, several problems for clinical use, such as adverse effects, blood concentration and resistance have been apparent. Recently developed AC220 is a highly selective and sensitive FLT3 inhibitor. In Phase I and II trials, AC220 so far showed the best efficacy of AML cells harboring FLT3 mutation among clinically evaluated FLT3 inhibitors, while severe bone marrow suppression and QTc prolongation should be resolved for the clinical use. In this review, I summarize the characteristics of FLT3 inhibitors in clinical development and discuss important issues to be resolved for clinical use.