Patient-reported outcomes in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia receiving standard chemotherapy plus quizartinib or placebo (QuANTUM-First): a global, randomised, placebo-controlled, phase 3 trial.

We evaluated the impact of quizartinib on patient-reported outcomes and health-related quality of life using the European Organisation for Research and Treatment of Cancer 30-item Core Quality of Life Questionnaire.

我们使用欧洲癌症研究与治疗组织的30项核心生活质量问卷评估了quizartinib对患者报告的结果和健康相关生活质量的影响。

Methods

In this global, multicentre, randomised, placebo-controlled, phase 3 trial, we recruited adults aged 18-75 years, with FLT3-ITD-positive newly diagnosed AML or AML secondary to myelodysplastic syndrome or myeloproliferative neoplasm, and with an Eastern Cooperative Oncology Group performance status of 0-2.

在这项全球多中心、随机、安慰剂对照的III期试验中，我们招募了年龄在18-75岁之间的成人，这些患者被诊断为FLT3-ITD阳性的新发急性髓细胞性白血病（AML）或继发于骨髓增生异常综合征或骨髓增殖性肿瘤的AML，并且东部肿瘤协作组（Eastern Cooperative Oncology Group）的体能状态评分为0-2。

Participants were randomly allocated (1:1) to quizartinib (40 mg/day) or placebo plus standard 7 + 3 induction chemotherapy, and then received standard consolidation chemotherapy with high-dose cytarabine plus quizartinib (40 mg/day) or placebo, allogeneic haematopoietic cell transplantation (allo-HCT), or both, followed by maintenance with single-agent quizartinib (30-60 mg/day) or placebo for up to 36 cycles.

参与者被随机分配（1:1）接受quizartinib（每日40毫克）或安慰剂加标准的7+3诱导化疗，然后接受标准的巩固化疗，包括高剂量的阿糖胞苷加quizartinib（每日40毫克）或安慰剂，异基因造血干细胞移植（allo-HCT），或两者，随后用单药quizartinib（每日30-60毫克）或安慰剂进行维持治疗，最多36个周期。

Randomisation was managed via an interactive web and voice response system.

随机化是通过交互式网络和语音响应系统进行管理的。

Patient-reported outcome endpoints, assessed using the European Organisation for Research and Treatment of Cancer 30-item Core Quality of Life Questionnaire, were exploratory and analyses were based on the patient-reported outcome intention-to-treatanalysis set.

使用欧洲癌症研究与治疗组织的30项核心生活质量问卷评估的患者报告的结果终点是探索性的，分析基于患者报告的结果意向治疗分析集。

Treatment effects on patient-reported outcomes were assessed using the mixed-effects model for repeated measures, time to sustained improvement, and time until definitive deterioration analyses.

使用混合效应模型重复测量、持续改善时间和确定性恶化时间分析评估治疗对患者报告结果的影响。

A minimal clinically important difference score of 10 or higher for each subscale was defined as clinically meaningful.

每个子量表的最小临床重要差异分数定义为10分或更高，被认为是临床意义上的。

This trial is registered with ClinicalTrials.gov, NCT02668653, and is completed.

该试验已在ClinicalTrials.gov注册，注册号为NCT02668653，并已完成。

Results

Participants were enrolled between Sept 27, 2016, and Aug 14, 2019.

参与者在2016年9月27日至2019年8月14日期间被纳入研究。

Of 539 randomly allocated participants, 509 (278 [55%] female and 231 [45%] male) were included in the patient-reported outcome analysis set, 254 in the quizartinib group and 255 in the placebo group.

在随机分配的539名参与者中，509名（女性278名[55%]，男性231名[45%]）被纳入患者报告结果分析集，其中254名在quizartinib组，255名在安慰剂组。

The overall median follow-up was 39·2 months (IQR 31·9-45·8).

总体中位随访时间为39.2个月（四分位数间距31.9-45.8）。

Baseline patient-reported outcome scores were similar between groups.

基线患者报告的结果评分在两组之间相似。

The change in global health status and quality of life score (GHS-QoL) from baseline was above the minimal clinically important difference from consolidation onwards in both groups.

从巩固治疗开始，两组的全球健康状况和生活质量评分（GHS-QoL）的变化均超过了最小临床重要差异。

The treatment difference (quizartinib minus placebo) in change from baseline for GHS-QoL (by mixed-effects model for repeated measures) was -2·0 (95% CI -4·8 to 0·7, nominal p=0·15), indicating no substantial difference between groups, further confirmed by time to sustained improvement (subdistribution hazard ratio[SHR] 1·126 [95% CI 0·904 to 1·403], nominal p=0·28) and time until definitive deterioration (hazard ratio0·81 [95% CI 0·51 to 1·28], nominal p=0·37) analyses.

治疗差异（quizartinib 减去安慰剂）在基线变化对 GHS-QoL（通过重复测量的混合效应模型）为 -2·0（95% 置信区间 -4·8 至 0·7，名义 p=0·15），表明两组之间没有实质性差异，通过持续改善时间（亚分布风险比 [SHR] 1·126 [95% CI 0·904 至 1·403]，名义 p=0·28）和确定性恶化时间（风险比 0·81 [95% CI 0·51 至 1·28]，名义 p=0·37）分析进一步确认。

Longitudinal analyses of the functional and symptom subscales showed no substantially different patterns between groups.

功能和症状亚量表的纵向分析显示两组之间没有显著不同的模式。

For the functional subscales, the SHR ranged from 0·940 to 1·148 (0·737-1·544, nominal p=0·36-0·90).

对于功能亚量表，SHR的范围为0.940至1.148（0.737-1.544，名义p=0.36-0.90）。

For the symptom subscales, the SHR ranged from 0·965 to 1·407 (0·720-1·989, nominal p=0·28-0·99).

对于症状亚量表，SHR的范围为0.965至1.407（0.720-1.989，名义p=0.28-0.99）。

interpretation

The results indicate that quizartinib plus standard chemotherapy prolongs overall survivalwithout adversely affecting patient-reported outcomes and health-related quality of life, with no substantial differences between groups.

研究结果表明，quizartinib联合标准化疗可延长总生存期，且不会对患者报告的结果和健康相关生活质量产生不利影响，两组之间没有显著差异。

Future research in real-world settings is warranted to assess the generalisability of these patient-reported outcome results.

有必要在真实世界环境中进行未来研究，以评估这些患者报告结果的普遍适用性。

funding

Daiichi Sankyo.

第一三共株式会社。