FLT3 is the most frequently mutated gene in acute myeloid leukemia (AML), with FLT3 internal tandem duplication (ITD) mutations being associated with a more aggressive clinical course. While two large, randomized clinical trials have shown a survival benefit with the frontline use of an oral FLT3 inhibitor (midostaurin or quizartinib) in patients with FLT3-mutated AML, the role of FLT3 inhibitors in older adults with newly diagnosed FLT3-mutated AML remains unclear. A definitive improvement in survival has not been observed in intensively treated patients over 60 years of age receiving frontline FLT3 inhibitors. Furthermore, many patients with FLT3-mutated AML are unsuitable for intensive chemotherapy due to age and/or comorbidities, and this population represents a particular unmet need. For these older patients who are unfit for intensive approaches, azacitidine + venetoclax is a new standard of care and is used by many clinicians irrespective of FLT3 mutation status. However, FLT3-ITD mutations confer resistance to venetoclax and are a well-established mechanism of relapse to lower-intensity venetoclax-based regimens, leading to short durations of remission and poor survival. Preclinical and clinical data suggest synergy between FLT3 inhibitors and venetoclax, providing rationale for their combination. Novel strategies to safely incorporate FLT3 inhibitors into the standard hypomethylating agent + venetoclax backbone are now being explored in this older, less fit population with newly diagnosed FLT3-mutated AML, with encouraging early results. Herein, we discuss the frontline use of FLT3 inhibitors in older adults with FLT3-mutated AML, including the potential role of FLT3 inhibitors in combination with intensive chemotherapy and as part of novel, lower-intensity doublet and triplet regimens in this older population.
FLT3是急性髓系白血病（AML）中最常发生突变的基因，其中FLT3内部串联重复（ITD）突变与更具侵袭性的临床病程相关。尽管两项大型随机临床试验已显示，在FLT3突变的AML患者中一线使用口服FLT3抑制剂（米哚妥林或奎扎替尼）可带来生存获益，但FLT3抑制剂在新诊断FLT3突变AML老年患者中的作用尚不明确。在接受一线FLT3抑制剂强化治疗的60岁以上患者中，并未观察到明确的生存改善。此外，许多FLT3突变AML患者因年龄和/或合并症不适合接受强化化疗，这部分人群存在显著未满足的临床需求。对于这些不适合强化治疗的老年患者，阿扎胞苷联合维奈克拉已成为新的标准治疗方案，且被许多临床医生使用而不考虑FLT3突变状态。然而，FLT3-ITD突变会导致对维奈克拉的耐药性，并已成为基于维奈克拉的低强度治疗方案后复发的明确机制，导致缓解期短和生存率低。临床前和临床数据表明FLT3抑制剂与维奈克拉具有协同作用，这为两者联合应用提供了理论依据。目前正在新诊断FLT3突变AML的老年体弱人群中探索将FLT3抑制剂安全整合至标准低甲基化药物联合维奈克拉方案的新型策略，早期结果令人鼓舞。本文讨论了FLT3抑制剂在FLT3突变AML老年患者中的一线使用，包括FLT3抑制剂联合强化化疗的潜在作用，以及其作为新型低强度双联和三联方案组成部分在该老年人群中的应用前景。
肿瘤(癌症)患者之家