Garciaz Sylvain, Hospital Marie-Anne
Department of Hematology, Institut Paoli-Calmettes, Aix-Marseille Université, Centre National de la Recherche Scientifique, UMR7258, Centre de Recherche en Cancérologie de Marseille, INSERM U1068, Marseille, France.
Onco Targets Ther. 2023 Jan 19;16:31-45. doi: 10.2147/OTT.S236740. eCollection 2023.
FMS-like tyrosine kinase 3 () is one of the most frequently mutated genes in acute myeloid leukemia (AML). Approximately 30% of the adult cases harbor an internal tandem duplication (-ITD) and 5-10% a tyrosine kinase domain (TKD) amino acid substitution (). The treatment paradigm of AML patients harboring mutations (30%) has been modified by the discovery of tyrosine kinase inhibitors. First- and second-generation inhibitors classify FLT3 inhibitors according to FLT3 specificity: first-generation FLT3 inhibitors include sorafenib and midostaurin and second-generation inhibitors are represented by quizartinib, gilteritinib and crenolanib, among others. Activity of these inhibitors depends on their mechanism of receptor binding (active vs inactive conformation) and efficacy against the FLT3-ITD and -TKD mutations (type 1 inhibitors are active both on -ITD and TKD, whereas type 2 inhibitors are active only on -ITD). The FLT3 inhibitors sorafenib, midostaurin, quizartinib and gilteritinib have been tested in monotherapy in several settings including refractory or relapsed AML (R/R AML), post-transplant maintenance as well as in combination with intensive chemotherapy (ICT) or non-intensity regimens. The results of published randomized studies support the use of sorafenib in a post-transplant setting (SORMAIN trial), midostaurin in combination with ICT based (RATIFY trial) and gilteritinib for R/R AML (ADMIRAL trial). Gilteritinib in combination with hypomethylating agent as well as quizartinib are not supported by solid randomized trial results for their use in FLT3-mutated AML patients.
FMS样酪氨酸激酶3（FLT3）是急性髓系白血病（AML）中最常发生突变的基因之一。大约30%的成年AML病例存在内部串联重复（FLT3-ITD），5%-10%存在酪氨酸激酶结构域（TKD）氨基酸取代（FLT3-TKD）。酪氨酸激酶抑制剂的发现改变了携带FLT3突变（30%）的AML患者的治疗模式。第一代和第二代抑制剂根据FLT3特异性对FLT3抑制剂进行分类：第一代FLT3抑制剂包括索拉非尼和米哚妥林，第二代抑制剂以奎扎替尼、吉列替尼和克伦洛尼等为代表。这些抑制剂的活性取决于它们与受体结合的机制（活性构象与非活性构象）以及对FLT3-ITD和FLT3-TKD突变的疗效（1型抑制剂对FLT3-ITD和FLT3-TKD均有活性，而2型抑制剂仅对FLT3-ITD有活性）。FLT3抑制剂索拉非尼、米哚妥林、奎扎替尼和吉列替尼已在多种情况下进行了单药治疗试验，包括难治性或复发性AML（R/R AML）、移植后维持治疗以及与强化化疗（ICT）或非强化方案联合使用。已发表的随机研究结果支持在移植后使用索拉非尼（SORMAIN试验）、与ICT联合使用米哚妥林（RATIFY试验）以及使用吉列替尼治疗R/R AML（ADMIRAL试验）。吉列替尼与低甲基化药物联合使用以及奎扎替尼在FLT3突变的AML患者中的使用未得到可靠随机试验结果的支持。
