Department of Pharmacy Services and Clinical Sciences, Michigan Medicine and University of Michigan College of Pharmacy, Ann Arbor, MI, USA.
Department of Internal Medicine, Division of Hematology and Oncology, Michigan Medicine and University of Michigan Medical School, Ann Arbor, MI, USA.
Crit Rev Oncol Hematol. 2019 Sep;141:125-138. doi: 10.1016/j.critrevonc.2019.06.011. Epub 2019 Jun 28.
Internal tandem duplications and tyrosine kinase mutations in the fms-like tyrosine kinase 3 (FLT3) receptor can occur in acute myeloid leukemia (AML) and portend a poor prognosis. Midostaurin, a multikinase inhibitor that targets FLT3, demonstrated a survival benefit in FLT3-mutated AML in combination with front-line chemotherapy. Despite this advancement, the use of FLT3 inhibitors in clinical practice is complicated by significant drug-drug interactions and uncertainty about optimal timing, duration, and sequencing of therapy. As monotherapy, the utility of FLT3 inhibitors was initially limited by incomplete and transient clinical responses and the development of acquired resistance. This led to the development of more potent and selective FLT3 inhibitors designed to overcome common resistance mechanisms. One of these second generation FLT3 inhibitors, gilteritinib, is now FDA-approved for the treatment of relapsed or refractory AML. Now that multiple FLT3 inhibitors are commercially available, it is important to further delineate the role of these agents in the AML population. This review aims to provide a comprehensive overview of the role of FLT3 inhibitors in AML and apply the current literature to clinical practice.
内部串联重复和酪氨酸激酶突变在 fms 样酪氨酸激酶 3（FLT3）受体中可能发生在急性髓系白血病（AML）中，并预示着预后不良。米哚妥林是一种针对 FLT3 的多激酶抑制剂，与一线化疗联合使用时，在 FLT3 突变的 AML 中显示出生存获益。尽管取得了这一进展，但由于药物相互作用显著以及关于治疗的最佳时机、持续时间和顺序的不确定性，FLT3 抑制剂在临床实践中的应用变得复杂。作为单药治疗，FLT3 抑制剂的效用最初受到不完全和短暂的临床反应以及获得性耐药的限制。这导致了更有效和选择性的 FLT3 抑制剂的开发，旨在克服常见的耐药机制。这些第二代 FLT3 抑制剂中的一种，吉特替尼，现已获得 FDA 批准用于治疗复发或难治性 AML。现在有多种 FLT3 抑制剂可供商业使用，因此，有必要进一步阐明这些药物在 AML 人群中的作用。这篇综述旨在全面概述 FLT3 抑制剂在 AML 中的作用，并将当前的文献应用于临床实践。
