Liu Xiaoyan, Gong Yuping
Department of Hematology, West China Hospital of Sichuan University, No.37 Guo Xue Xiang, Chengdu, 610041 Sichuan Province China.
Biomark Res. 2019 Oct 22;7:22. doi: 10.1186/s40364-019-0173-z. eCollection 2019.
Isocitrate dehydrogenase (IDH) is a key enzyme involved in the conversion of isocitrate to α-ketoglutarate (α-KG) in the tricarboxylic acid (TCA) cycle. IDH mutation produces a neomorphic enzyme, which can lead to the abnormal accumulation of R-2-HG and promotes leukemogenesis. IDH mutation occurs in 20% of acute myeloid leukemia (AML) patients, mainly including IDH1 R132, IDH2 R140, and IDH2 R172. Different mutant isoforms have different prognostic values. In recent years, IDH inhibitors have shown good clinical response in AML patients. Hence, enasidenib and ivosidenib, the IDH2 and IDH1 inhibitors developed by Agios Pharmaceuticals, have been approved by the Food and Drug Administration on 1 August 2017 and 20 July 2018 for the treatment of adult relapsed or refractory (R/R) AML with IDH2 and IDH1 mutations, respectively. IDH inhibitor monotherapy for R/R AML is efficacious and safe; however, there are problems, such as primary or acquired resistance. Clinical trials of IDH inhibitors combined with hypomethylating agents or standard chemotherapy for the treatment of R/R AML or newly diagnosed AML, as well as in post hematopoietic stem cell transplantation as maintenance therapy, are ongoing. This article summarizes the use of IDH inhibitors in AML with IDH mutations.
异柠檬酸脱氢酶（IDH）是三羧酸（TCA）循环中参与异柠檬酸转化为α-酮戊二酸（α-KG）的关键酶。IDH突变产生一种新功能酶，可导致R-2-羟基戊二酸（R-2-HG）异常蓄积并促进白血病发生。IDH突变见于20%的急性髓系白血病（AML）患者，主要包括IDH1 R132、IDH2 R140和IDH2 R172。不同的突变亚型具有不同的预后价值。近年来，IDH抑制剂在AML患者中显示出良好的临床反应。因此，Agios制药公司研发的IDH2和IDH1抑制剂恩西地平（enasidenib）和艾伏尼布（ivosidenib）分别于2017年8月1日和2018年7月20日获美国食品药品监督管理局批准，用于治疗具有IDH2和IDH1突变的成人复发或难治性（R/R）AML。IDH抑制剂单药治疗R/R AML有效且安全；然而，存在原发性或获得性耐药等问题。IDH抑制剂联合去甲基化药物或标准化疗治疗R/R AML或新诊断AML以及用于造血干细胞移植后维持治疗的临床试验正在进行。本文总结了IDH抑制剂在伴有IDH突变的AML中的应用。
