Luskin Marlise R, DeAngelo Daniel J
a Department of Medical Oncology , Dana-Farber Cancer Institute , Boston , MA , USA.
b Harvard Medical School , Boston , MA , USA.
Expert Rev Hematol. 2017 Dec;10(12):1033-1045. doi: 10.1080/17474086.2017.1397510. Epub 2017 Oct 30.
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with inadequate treatment options. Approximately one-third of cases have a FLT3-ITD or FLT3-TKD mutation which leads to constitutive tyrosine kinase activation which contributes to leukemogenesis. The FLT3-ITD mutation is associated with a particularly poor prognosis. Midostaurin is a multi-kinase inhibitor active against the FLT3 receptor. Midostaurin was approved by the US FDA in April 2017 for treatment of newly diagnosed FLT3-mutant AML in combination with chemotherapy. Areas covered: Standard treatment of FLT3-mutant AML and outcomes. Early clinical development of midostaurin including pharmacokinetics and metabolism. The development of midostaurin in FLT3-mutant AML is then outlined including review of the phase I, II, and III trials of midostaurin as a single agent and in combination with chemotherapy. Expert commentary: The approval of midostaurin represents the first new therapy for AML in several decades. It is also the first targeted therapy approved for AML. Future studies will focus on defining mechanisms of resistance to midostaurin as well as establishing the role of midostaurin in combination with hypomethylating agents and as maintenance therapy. Second generation, more potent and selective FLT3 inhibitors are also in development; these agents need to be compared to midostaurin.
急性髓系白血病（AML）是一种侵袭性血液系统恶性肿瘤，治疗选择有限。大约三分之一的病例存在FLT3-ITD或FLT3-TKD突变，这会导致组成型酪氨酸激酶激活，进而促进白血病发生。FLT3-ITD突变与特别差的预后相关。米哚妥林是一种对FLT3受体有活性的多激酶抑制剂。2017年4月，米哚妥林被美国食品药品监督管理局（FDA）批准与化疗联合用于治疗新诊断的FLT3突变型AML。涵盖领域：FLT3突变型AML的标准治疗及预后。米哚妥林的早期临床开发，包括药代动力学和代谢。接着概述了米哚妥林在FLT3突变型AML中的开发情况，包括对米哚妥林作为单药及与化疗联合应用的I期、II期和III期试验的综述。专家评论：米哚妥林的获批代表了几十年来AML的首个新疗法。它也是首个获批用于AML的靶向疗法。未来的研究将集中于确定对米哚妥林耐药的机制，以及确立米哚妥林与去甲基化药物联合应用及作为维持治疗的作用。第二代更有效且更具选择性的FLT3抑制剂也在研发中；需要将这些药物与米哚妥林进行比较。
