Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
Curr Hematol Malig Rep. 2021 Apr;16(2):192-206. doi: 10.1007/s11899-021-00621-9. Epub 2021 Mar 18.
Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow that has a poor prognosis with traditional cytotoxic chemotherapy, especially in elderly patients. In recent years, small molecule inhibitors targeting AML-associated IDH1, IDH2, and FLT3 mutations have been FDA approved. However, the majority of AML cases do not have a targetable mutation. A variety of novel agents targeting both previously untargetable mutations and general pathways in AML are currently being investigated. Herein, we review selected new targeted therapies currently in early-phase clinical investigation in AML.
The DOT1L inhibitor pinometostat in KMT2A-rearranged AML, the menin inhibitors KO-539 and SYNDX-5613 in KMT2Ar and NPM1-mutated AML, and the mutant TP53 inhibitor APR-246 are examples of novel agents targeting specific mutations in AML. In addition, BET inhibitors, polo-like kinase inhibitors, and MDM2 inhibitors are promising new drug classes for AML which do not depend on the presence of a particular mutation. AML remains in incurable disease for many patients but advances in genomics, epigenetics, and drug discovery have led to the development of many potential novel therapeutic agents, many of which are being investigated in ongoing clinical trials. Additional studies will be necessary to determine how best to incorporate these novel agents into routine clinical treatment of AML.
急性髓系白血病（AML）是一种侵袭性骨髓恶性肿瘤，传统细胞毒化疗预后较差，尤其是老年患者。近年来，FDA 已批准了针对 AML 相关 IDH1、IDH2 和 FLT3 突变的小分子抑制剂。然而，大多数 AML 病例没有可靶向的突变。目前正在研究各种针对以前不可靶向的突变和 AML 一般途径的新型药物。在此，我们综述了 AML 早期临床研究中选定的新型靶向治疗方法。
DOT1L 抑制剂 pinometostat 在 KMT2A 重排 AML 中、menin 抑制剂 KO-539 和 SYNDX-5613 在 KMT2Ar 和 NPM1 突变 AML 中、以及突变型 TP53 抑制剂 APR-246 是针对 AML 特定突变的新型药物的实例。此外，BET 抑制剂、极酶样激酶抑制剂和 MDM2 抑制剂是 AML 的有前途的新药类别，不依赖于特定突变的存在。尽管 AML 对许多患者来说仍是一种不可治愈的疾病，但基因组学、表观遗传学和药物发现的进展已经导致了许多潜在的新型治疗药物的发展，其中许多正在进行临床试验研究。需要进一步的研究来确定如何将这些新型药物最好地纳入 AML 的常规临床治疗中。
