Pharmacy Services, Denver Health, Denver, Colorado.
Division of Hematology, University of Colorado Cancer Center, Aurora, Colorado.
Pharmacotherapy. 2017 Dec;37(12):1586-1599. doi: 10.1002/phar.2039. Epub 2017 Nov 23.
Acute myeloid leukemia (AML), a clonal hematologic malignancy that results in bone marrow failure, is the most common acute leukemia in adults (median age of diagnosis 67 yrs), and treatment options, especially in the elderly population, are limited. Induction chemotherapy with 7 + 3, the combination of continuous-infusion cytarabine and intermittent dosing of an anthracycline administered over 7 and 3 days, respectively, has remained the standard of care since its introduction in 1973 in the United States. Midostaurin is a first-generation FMS-like tyrosine kinase 3 (FLT3) inhibitor (TKI) that was approved by the U.S. Food and Drug Administration in April 2017 for the treatment of FLT3-mutant AML. We performed a search of the PubMed database (January 1990-January 2017) to review pertinent clinical trials of midostaurin. Phase I, II, and III trials reported in English evaluating the safety and efficacy of midostaurin in patients with AML or myelodysplastic syndrome were included. The ClinicalTrials.gov database was also searched for ongoing trials. In the only phase III trial that has been conducted to date, midostaurin demonstrated significant improvement compared with placebo in overall and event-free survival in patients aged 18-59 years with newly diagnosed FLT3-mutant AML treated with standard induction chemotherapy. The median overall survival for patients randomized to the midostaurin group was 74.7 months versus 25.6 months in the placebo group (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.63-0.96, p=0.009). Median event-free survival was 8.2 months with midostaurin compared with 3.0 months with placebo (HR 0.78, 95% CI 0.66-0.93, p=0.002). In addition to being evaluated in combination with conventional chemotherapy, midostaurin has been studied as monotherapy, in combination with the hypomethylating agents azacitidine and decitabine, and as single-agent maintenance. Studies evaluating midostaurin in the maintenance setting after allogeneic stem cell transplantation are underway. Midostaurin is the first oral multitargeted TKI to improve overall survival in patients with FLT3-mutant AML and represents an important addition to the limited armamentarium against AML.
急性髓系白血病（AML）是一种克隆性血液恶性肿瘤，导致骨髓衰竭，是成人中最常见的急性白血病（中位诊断年龄 67 岁），治疗选择，特别是在老年人群中，受到限制。自 1973 年在美国引入以来，含 7+3 的诱导化疗（阿糖胞苷连续输注和阿霉素间歇性给药，分别持续 7 天和 3 天）一直是治疗标准。米哚妥林是一种第一代 FMS 样酪氨酸激酶 3（FLT3）抑制剂（TKI），于 2017 年 4 月被美国食品和药物管理局批准用于治疗 FLT3 突变型 AML。我们在 PubMed 数据库中进行了检索（1990 年 1 月至 2017 年 1 月），以回顾米哚妥林的相关临床试验。纳入了以英语发表的评估 AML 或骨髓增生异常综合征患者米哚妥林安全性和疗效的 I、II 和 III 期试验。还在 ClinicalTrials.gov 数据库中搜索了正在进行的试验。在迄今为止进行的唯一一项 III 期试验中，与安慰剂相比，新诊断的 FLT3 突变型 AML 患者接受标准诱导化疗时，米哚妥林治疗组在总生存期和无事件生存期方面均有显著改善。随机分配至米哚妥林组的患者中位总生存期为 74.7 个月，而安慰剂组为 25.6 个月（风险比 [HR] 0.78，95%置信区间 [CI] 0.63-0.96，p=0.009）。米哚妥林组的中位无事件生存期为 8.2 个月，而安慰剂组为 3.0 个月（HR 0.78，95% CI 0.66-0.93，p=0.002）。除了与常规化疗联合评估外，米哚妥林还作为单药、与低甲基化剂阿扎胞苷和地西他滨联合以及作为单药维持治疗进行了研究。正在进行评估米哚妥林在异基因干细胞移植后的维持治疗中的作用的研究。米哚妥林是第一种改善 FLT3 突变型 AML 患者总生存期的口服多靶点 TKI，是对抗 AML 的有限武器库的重要补充。
