ImportanceAcute myeloid leukemia (AML) is a clonal hematopoietic cancer that disrupts normal hematopoiesis, ultimately leading to bone marrow failure and death. The annual incidence rate of AML is 4.1 per 100 000 people in the US and is higher in patients older than 65 years. Acute myeloid leukemia includes numerous subgroups with heterogeneous molecular profiles, treatment response, and prognosis. This review discusses the evidence supporting frontline therapies in AML, the major principles that guide therapy, and progress with molecularly targeted therapy.ObservationsAcute myeloid leukemia is a genetically complex, dynamic disease. The most commonly altered genes include FLT3, NPM1, DNMT3A, IDH1, IDH2, TET2, RUNX1, NRAS, and TP53. The incidence of these alterations varies by patient age, history of antecedent hematologic cancer, and previous exposure to chemotherapy and/or radiotherapy for any cancer. Since 2010, molecular data have been incorporated into AML prognostication, gradually leading to incorporation of targeted therapies into the initial treatment approach of induction chemotherapy and subsequent management. The first molecularly targeted inhibitor, midostaurin, was approved to treat patients with AML with FLT3 variants in 2017. Since then, the understanding of the molecular pathogenesis of AML has expanded, allowing the identification of additional potential targets for drug therapy, treatment incorporation of molecularly targeted therapies (midostaurin, gilteritinib, and quizartinib targeting FLT3 variants; ivosidenib and olutasidenib targeting IDH1 variants, and enasidenib targeting IDH2), and identification of rational combination regimens. The approval of hypomethylating agents combined with venetoclax has revolutionized the therapy of AML in older adults, extending survival over monotherapy. Additionally, patients are now referred for hematopoietic cell transplant on a more rational basis.Conclusions and RelevanceIn the era of genomic medicine, AML treatment is customized to the patient’s comorbidities and AML genomic profile.

中文翻译：

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急性髓性白血病的当代管理


重要性急性髓性白血病 （AML） 是一种克隆性造血癌，会破坏正常的造血功能，最终导致骨髓衰竭和死亡。在美国，AML 的年发病率为 4.1/100 000 人，65 岁以上患者的年发病率更高。急性髓系白血病包括许多具有不同分子特征、治疗反应和预后的亚组。本综述讨论了支持 AML 一线治疗的证据、指导治疗的主要原则以及分子靶向治疗的进展。观察急性髓系白血病是一种遗传复杂的动态疾病。最常见的改变基因包括 FLT3、NPM1、DNMT3A、IDH1、IDH2、TET2、RUNX1、NRAS 和 TP53。这些改变的发生率因患者年龄、血液系统癌症既往史以及既往接受过任何癌症的化疗和/或放疗而异。自 2010 年以来，分子数据已被纳入 AML 预后，逐渐将靶向治疗纳入诱导化疗的初始治疗方法和后续管理。第一个分子靶向抑制剂米哚妥林于 2017 年被批准用于治疗具有 FLT3 变体的 AML 患者。从那时起，对 AML 分子发病机制的理解得到了扩展，从而能够确定药物治疗的其他潜在靶点，结合分子靶向治疗（靶向 FLT3 变体的米哚妥林、吉特替尼和奎扎替尼;靶向 IDH1 变体的 ivosidenib 和 olutasidenib，以及靶向 IDH2 的 enasidenib），并确定合理的联合方案。 低甲基化药物联合维奈托克的批准彻底改变了老年人 AML 的治疗，与单药治疗相比，延长了生存期。此外，患者现在在更合理的基础上被转诊进行造血细胞移植。结论和相关性在基因组医学时代，AML 治疗是根据患者的合并症和 AML 基因组概况定制的。