Molecular monitoring versus standard clinical care in younger adults with acute myeloid leukaemia: results from the UK NCRI AML17 and AML19 randomised, controlled, phase 3 trials.

This study aimed to identify whether altering treatment based on MRD results can improve survival.

本研究旨在确定基于MRD结果改变治疗方案是否能改善生存率。

Methods

In the UK NCRI AML17 and AML19 randomised, controlled, phase 3 trials, performed in the UK, Denmark, and New Zealand, we screened patients aged 16-60 years with newly diagnosed acute myeloid leukaemia for molecular markers suitable for disease monitoring, including NPM1 mutations and fusion genes.

在英国NCRI AML17和AML19的随机对照的III期临床试验中，该试验在英国、丹麦和新西兰进行，我们对16-60岁新诊断的急性髓细胞性白血病患者进行了分子标记物筛查，以用于疾病监测，包括NPM1突变和融合基因。

Patients with a marker were randomly assigned (2:1) to either sequential molecular MRD monitoring during treatment and for 3 years after, or standard clinical care only with no molecular monitoring.

带有标记的患者被随机分配（2:1）到两组，一组在治疗期间和治疗后3年内进行序列分子最小残留病灶（MRD）监测，另一组仅接受标准的临床护理，不进行分子监测。

In the monitoring group, treating physicians decided whether and how to incorporate the MRD results into the patient's therapy, including in cases of MRD relapse.

在监测组中，治疗医生决定是否以及如何将微小残留病灶（MRD）结果纳入患者的治疗中，包括在MRD复发的情况下。

The primary endpoint was overall survival. Prespecified subgroup analysis of the primary outcome included analysis by molecular group (NPM1mut with FLT3-ITD, NPM1mut without FLT3-ITD, and fusion gene transcripts).

主要终点是总生存期。主要结果的预定亚组分析包括按分子分组（NPM1突变伴FLT3-ITD、NPM1突变不伴FLT3-ITD和融合基因转录本）进行的分析。

Both trials were registered with ISRCTN, ISRCTN55675535 and ISRCTN78449203, and are completed.

这两项试验已在ISRCTN登记，注册号分别为ISRCTN55675535和ISRCTN78449203，并且已经完成。

Results

In the AML17 trial, 1836 patients were enrolled between June 1, 2012 and Dec 31, 2014.

在AML17试验中，从2012年6月1日至2014年12月31日，共有1836名患者被纳入研究。

In the AML19 trial, 965 patients were enrolled between Nov 9, 2015, and Jan 23, 2018. 637 patients were randomly assigned across both trials (289 to MRD monitoring and 144 to no monitoring in AML17 and 136 to MRD monitoring and 68 to no monitoring in AML19).

在AML19试验中，从2015年11月9日至2018年1月23日，共有965名患者被纳入。在两个试验中，共有637名患者被随机分配（AML17中289名接受MRD监测，144名未接受监测；AML19中136名接受MRD监测，68名未接受监测）。

With a median follow-up time of 4·9 years (IQR 3·6-5·9), overall survivalat 3 years was 70% (95% CI 66-75) in patients in the monitoring group and 73% (68-80) in patients in the no-monitoring group.

中位随访时间为4.9年（四分位数间距3.6-5.9），监测组患者的3年总生存率为70%（95%置信区间66-75），未监测组患者的3年总生存率为73%（68-80）。

Meta analysis of the two studies showed no difference in overall survival(hazard ratio[HR] 1·11, 95% CI 0·83-1·49; p=0·25).

两项研究的荟萃分析显示总生存无差异（风险比[HR] 1.11, 95% 置信区间 0.83-1.49; p=0.25）。

In the pre-specified subgroup analysis of the primary endpoint, overall survivalat 3 years in patients with both NPM1 and FLT3 internal tandem duplication (ITD) mutations was 69% (95% CI 60-79) in the monitoring group and 58% (45-74) in the no-monitoring group (HR 0·53, 95% CI 0·31-0·91; p=0·021).

在主要终点的预先指定的亚组分析中，同时携带NPM1和FLT3内部串联重复（ITD）突变的患者在监测组的3年总生存率为69%（95% CI 60-79），而在无监测组为58%（95% CI 45-74）（HR 0.53, 95% CI 0.31-0.91; p=0.021）。

However there was no difference in survival by randomisation in patients with NPM1 mutations without FLT3-ITD (overall survial 69% [95% CI 62-77] in the monitoring group and 78% [70-87] in the no monitoring group; HR 1·56, 95% CI 0·96-2·52) or those with fusion gene transcripts (overall survial 72% [95% CI 65-79] in the monitoring group and 77% [68-87] in the no monitoring group; HR 1·28, 95% CI 0·80-2·18).

然而，在没有FLT3-ITD突变的NPM1突变患者中，随机分组后的生存率没有差异（监测组的总生存率为69% [95% 置信区间 62-77]，无监测组为78% [70-87]；风险比 1·56, 95% 置信区间 0·96-2·52）或者那些有融合基因转录本的患者（监测组的总生存率为72% [95% 置信区间 65-79]，无监测组为77% [68-87]；风险比 1·28, 95% 置信区间 0·80-2·18）。

interpretation

Sequential molecular MRD monitoring, coupled with MRD-guided treatment, did not improve overall survivalin the entire study population; however, in the subgroup of patients with baseline NPM1 and FLT3 ITD mutations, we observed a survival benefit for MRD monitoring.

连续的分子微小残留病（MRD）监测，结合MRD指导的治疗，并没有改善整个研究人群的总生存期；然而，在基线时具有NPM1和FLT3 ITD突变的患者亚组中，我们观察到MRD监测的生存益处。

funding

National Institute for Health Research, Blood Cancer UK, and Cancer Research UK.

国家卫生研究院、英国血液癌症协会和英国癌症研究协会。