Kiyoi Hitoshi
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Nagoya J Med Sci. 2015 Feb;77(1-2):7-17.
FLT3, a type III receptor tyrosine kinase, expresses on most acute leukemia cells as well as normal hematopoietic stem/progenitor cells. Mutation in the 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. 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 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.
FLT3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/祖细胞中表达。该基因的突变是急性髓系白血病（AML）中最常见的基因改变，并且是髓系恶性肿瘤发生发展的重要驱动突变。FLT3突变是AML患者长期生存的一个强烈不良预后因素，而大剂量化疗和异基因造血干细胞移植都无法克服不良预后。因此，人们迫切期待开发一种FLT3抑制剂。迄今为止，已经开发了几种有效的FLT3抑制剂，其中一些在临床试验中进行了疗效评估，尽管尚无FLT3抑制剂获得批准。此外，临床应用中的几个问题，如不良反应、血药浓度和耐药性已经显现出来。最近开发的AC220是一种高度选择性和敏感性的FLT3抑制剂。在I期和II期试验中，AC220在临床评估的FLT3抑制剂中，对携带FLT3突变的AML细胞显示出迄今为止最好的疗效，然而，严重的骨髓抑制和QTc延长问题有待解决以便临床应用。在这篇综述中，我总结了处于临床开发阶段的FLT3抑制剂的特点，并讨论了临床应用中有待解决的重要问题。
