Mutations in FMS-related receptor tyrosine kinase 3 (FLT3) are among the most common alterations in acute myeloid leukemia (AML), present in ≈30% of newly diagnosed AML cases. Internal tandem duplications (ITD) in FLT3 (FLT3-ITD) occur in ≈25% of newly diagnosed AML cases and are associated with unfavorable outcomes. Quizartinib (formerly AC220) is a novel, second-generation, highly potent, and selective type II FLT3 inhibitor. Quizartinib is approved in Japan as monotherapy for the treatment of adult patients with FLT3-ITD–positive relapsed/refractory (R/R) AML. Quizartinib is also approved in the United States, Japan, Europe, and United Kingdom in combination with chemotherapy during induction and consolidation, and as maintenance monotherapy (but, in the United States, not after allogeneic hematopoietic cell transplantation [allo-HCT]), for the treatment of adult patients with newly diagnosed FLT3-ITD–positive AML. In this review, we summarize preclinical studies that established quizartinib as a potent and selective type II FLT3 inhibitor as well as early and pivotal phase 3 clinical studies (QuANTUM-R and QuANTUM-First) that led to the approvals of quizartinib. We also summarize mechanisms of resistance to quizartinib along with its safety profile. Furthermore, we review the ongoing post hoc analyses of the QuANTUM-First data elucidating the impact of allo-HCT, the presence of measurable residual disease, and number and length of ITD on the clinical outcomes of quizartinib. We also describe the impact of quizartinib on patient-reported outcomes. Finally, we highlight some of the ongoing studies that test quizartinib in patients with FLT3-ITD–positive AML, patients with FLT3-ITD–negative AML, in both the first-line and R/R settings, in patients fit or unfit for intensive chemotherapy, including studies for quizartinib-based combination with other compounds such as decitabine and venetoclax. Future research should aim to further optimize the clinical value of quizartinib and explore its use in additional clinical settings, which could be achieved by testing quizartinib with other drugs, better characterization of the mechanisms of resistance, identification of the role of quizartinib as a maintenance therapy after allo-HCT, and investigating quizartinib in patients with FLT3-ITD–negative AML.

中文翻译：

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Quizartinib：一种有效的选择性 FLT3 抑制剂，用于治疗 FLT3-ITD 阳性 AML 患者


FMS 相关受体酪氨酸激酶 3 （FLT3） 突变是急性髓性白血病 （AML） 最常见的改变之一，在 ≈30% 的新诊断 AML 病例中存在。FLT3 内部串联重复 （ITD） （FLT3-ITD） 发生在 ≈25% 的新诊断 AML 病例中，并且与不良结果相关。Quizartinib （formerly AC220） 是一种新型的第二代高效选择性 II 型 FLT3 抑制剂。Quizartinib 在日本被批准作为单药治疗 FLT3-ITD 阳性复发/难治性 （R/R） AML 成人患者。Quizartinib 在美国、日本、欧洲和英国也被批准在诱导和巩固期间与化疗联合使用，并作为维持单药治疗（但在美国，同种异体造血细胞移植 [allo-HCT] 后未批准）用于治疗新诊断的 FLT3-ITD 阳性 AML 成人患者。在这篇综述中，我们总结了将 quizartinib 确立为有效和选择性 II 型 FLT3 抑制剂的临床前研究，以及导致 quizartinib 获得批准的早期和关键 3 期临床研究 （QuANTUM-R 和 QuANTUM-First）。我们还总结了对 quizartinib 的耐药机制及其安全性。此外，我们回顾了正在进行的 QuANTUM-First 数据的事后分析，阐明了同种异体 HCT 、可测量残留病灶的存在以及 ITD 的数量和持续时间对 quizartinib 临床结果的影响。我们还描述了 quizartinib 对患者报告结果的影响。 最后，我们重点介绍了一些正在进行的研究，这些研究在 FLT3-ITD 阳性 AML 患者、FLT3-ITD 阴性 AML 患者中、一线和 R/R 环境中、适合或不适合强化化疗的患者中测试 quizartinib，包括基于 quizartinib 与其他化合物（如地西他滨和维奈托克）联合使用的研究。未来的研究应旨在进一步优化 quizartinib 的临床价值并探索其在其他临床环境中的使用，这可以通过测试 quizartinib 与其他药物、更好地表征耐药机制、确定 quizartinib 作为同种异体 HCT 后维持治疗的作用以及研究 quizartinib 在 FLT3-ITD 阴性 AML 患者中来实现。