Patients with acute myeloid leukaemia (AML) positive for internal tandem duplication (ITD) mutations of have poor outcomes. Quizartinib, an oral, highly potent, selective, type 2 FLT3 inhibitor, plus chemotherapy showed antitumour activity with an acceptable safety profile in patients with -ITD-positive newly diagnosed AML. The aim of the study was to compare the effect of quizartinib versus placebo on overall survival in patients with -ITD-positive newly diagnosed AML aged 18–75 years. We conducted a randomised, double-blind, placebo-controlled, phase 3 trial comparing quizartinib and placebo in combination with chemotherapy in induction and consolidation, followed by quizartinib or placebo single-agent continuation, in patients with -ITD-positive newly diagnosed AML at 193 hospitals and clinics in 26 countries in Europe; North America; and Asia, Australia, and South America. Patients aged 18–75 years were eligible. Patients were randomly assigned (1:1) to the quizartinib group or the placebo group by an independent biostatistician through an interactive web and voice response system, stratified by region, age, and white blood cell count at diagnosis. Patients, investigators, funders, and contract research organisations were masked to treatments assigned. Induction therapy comprised a standard 7 + 3 induction regimen of cytarabine 100 mg/m per day (or 200 mg/m per day allowed if institutional or local standard) by continuous intravenous infusion from day 1 to day 7 and anthracycline (daunorubicin 60 mg/m per day or idarubicin 12 mg/m per day) by intravenous infusion on days 1, 2, and 3, then quizartinib 40 mg orally or placebo once per day, starting on day 8, for 14 days. Patients with complete remission or complete remission with incomplete neutrophil or platelet recovery received standard consolidation with high-dose cytarabine plus quizartinib (40 mg per day orally) or placebo, allogeneic haematopoietic cell transplantation (allo-HCT), or both as consolidation therapy, followed by continuation of single-agent quizartinib or placebo for up to 3 years. The primary outcome was overall survival, defined as time from randomisation until death from any cause and assessed in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of quizartinib or placebo. This study is registered with (). Between Sept 27, 2016, and Aug 14, 2019, 3468 patients with AML were screened and 539 patients (294 [55%] male patients and 245 [45%] female patients) with -ITD-positive AML were included and randomly assigned to the quizartinib group (n=268) or placebo group (n=271). 148 (55%) of 268 patients in the quizartinib group and 168 (62%) of 271 patients in the placebo group discontinued the study, primarily because of death (133 [90%] of 148 in the quizartinib group 158 [94%] of 168 in the placebo group) or withdrawal of consent (13 [9%] of 148 in the quizartinib group 9 [5%] of 168 in the placebo group). Median age was 56 years (range 20–75, IQR 46·0–65·0). At a median follow-up of 39·2 months (IQR 31·9–45·8), median overall survival was 31·9 months (95% CI 21·0–not estimable) for quizartinib versus 15·1 months (13·2–26·2) for placebo (hazard ratio 0·78, 95% CI 0·62–0·98, p=0·032). Similar proportions of patients in the quizartinib and placebo groups had at least one adverse event (264 [100%] of 265 in the quizartinib group and 265 [99%] of 268 in the placebo group) and one grade 3 or higher adverse event (244 [92%] of 265 in the quizartinib group and 240 [90%] of 268 in the placebo group). The most common grade 3 or 4 adverse events were febrile neutropenia, hypokalaemia, and pneumonia in both groups and neutropenia in the quizartinib group. The addition of quizartinib to standard chemotherapy with or without allo-HCT, followed by continuation monotherapy for up to 3 years, resulted in improved overall survival in adults aged 18–75 years with -ITD-positive newly diagnosed AML. Based on the results from the QuANTUM-First trial, quizartinib provides a new, effective, and generally well tolerated treatment option for adult patients with -ITD-positive newly diagnosed AML. Daiichi Sankyo.

中文翻译：

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Quizartinib 联合化疗治疗新诊断的 FLT3 内部串联重复阳性急性髓系白血病患者 (QuANTUM-First)：一项随机、双盲、安慰剂对照 3 期试验

内部串联重复 (ITD) 突变呈阳性的急性髓系白血病 (AML) 患者预后较差。Quizartinib 是一种口服、高效、选择性 2 型 FLT3 抑制剂，联合化疗在新诊断的 -ITD 阳性 AML 患者中显示出抗肿瘤活性和可接受的安全性。该研究的目的是比较 quizartinib 与安慰剂对 18-75 岁新诊断 AML 患者总体生存率的影响。我们进行了一项随机、双盲、安慰剂对照的 3 期试验，比较了 quizartinib 和安慰剂联合化疗的诱导和巩固作用，然后继续使用 quizartinib 或安慰剂单药治疗，治疗时间为 2019 年 2 月 1 日新诊断的 -ITD 阳性 AML 患者。欧洲26个国家的193家医院和诊所；北美; 以及亚洲、澳大利亚和南美洲。年龄 18-75 岁的患者符合资格。独立生物统计学家通过交互式网络和语音应答系统将患者随机分配 (1:1) 到 quizartinib 组或安慰剂组，并按诊断时的地区、年龄和白细胞计数进行分层。患者、研究人员、资助者和合同研究组织对指定的治疗方法不知情。诱导治疗包括标准的 7 + 3 诱导方案，阿糖胞苷每天 100 mg/m2（如果机构或当地标准允许，每天 200 mg/m2），从第 1 天到第 7 天持续静脉输注和蒽环类药物（柔红霉素 60 mg/ m每天或伊达比星12 mg/m每天），在第1、2和3天静脉输注，然后口服quizartinib 40 mg或安慰剂，每天一次，从第8天开始，持续14天。完全缓解或完全缓解但中性粒细胞或血小板恢复不完全的患者接受标准巩固治疗，即大剂量阿糖胞苷加奎扎替尼（每天口服 40 mg）或安慰剂、同种异体造血细胞移植（allo-HCT）或两者作为巩固治疗，随后进行持续使用单药 quizartinib 或安慰剂长达 3 年。主要结局是总体生存率，定义为从随机分组到任何原因死亡的时间，并在意向治疗人群中进行评估。对所有接受至少一剂 quizartinib 或安慰剂的患者进行安全性评估。本研究已注册（）。2016年9月27日至2019年8月14日期间，对3468名AML患者进行了筛查，其中539名-ITD阳性AML患者（294名[55%]男性患者和245名[45%]女性患者）被纳入并随机分配到quizartinib 组 (n=268) 或安慰剂组 (n=271)。quizartinib 组 268 名患者中的 148 名患者 (55%) 和安慰剂组 271 名患者中的 168 名患者 (62%) 终止了研究，主要是因为死亡（quizartinib 组 148 名患者中的 133 名患者 [90%] 158 名患者 [94%]安慰剂组 168 人中的 13 人 [9%]（quizartinib 组 148 人中的 13 人 [9%]；安慰剂组 168 人中的 9 人 [5%]）。中位年龄为 56 岁（范围 20–75，IQR 46·0–65·0）。中位随访时间为 39·2 个月（IQR 31·9–45·8），奎扎替尼的中位总生存期为 31·9 个月（95% CI 21·0 – 不可估计），而奎扎替尼的中位总生存期为 15·1 个月（13 ·2–26·2) 安慰剂（风险比 0·78，95% CI 0·62–0·98，p=0·032）。quizartinib 组和安慰剂组中发生至少一种不良事件的患者比例相似（quizartinib 组 265 例患者中有 264 例 [100%]，安慰剂组 268 例患者中有 265 例 [99%]）和 1 例 3 级或以上不良事件（ quizartinib 组 265 人中有 244 人 [92%]，安慰剂组 268 人中有 240 人 [90%]。两组最常见的 3 级或 4 级不良事件均为发热性中性粒细胞减少症、低钾血症和肺炎，奎扎替尼组为中性粒细胞减少症。在有或没有同种异体 HCT 的标准化疗中添加 quizartinib，然后继续单药治疗长达 3 年，可改善 18-75 岁新诊断 AML 阳性的 18-75 岁成人的总体生存率。根据 QuANTUM-First 试验的结果，quizartinib 为新诊断的 -ITD 阳性 AML 成年患者提供了一种新的、有效的、总体耐受性良好的治疗选择。第一三共.