Abstract：
OBJECTIVE: Measurable residual disease (MRD) by using flow cytometry after induction therapy is strongly prognostic in pediatric AML, and hematopoietic stem-cell transplant (hSCT) may counteract a poor response. We designed a phase III study with intensified response-guided induction and MRD-based risk stratification and treated poor induction response with hSCT. The efficacy of liposomal daunorubicin (DNX) in induction was compared with mitoxantrone.
METHODS: The study planned to randomly assign 300 patients, but the production of DNX ceased in 2017. One hundred ninety-four patients were randomly assigned to mitoxantrone or experimental DNX in induction 1. Ninety-three non-randomly assigned patients served as an observation cohort. Primary end point was fraction of patients with MRD <0.1% on day 22 after induction 1. Patients with MRD ≥15% after induction 1 or ≥0.1% after induction 2 or FLT3-ITD with NPM1 wildtype were stratified to high-risk therapy, including hSCT.
RESULTS: Outcome for all 287 children was good with 5-year event-free survival (EFS5y) 66.7% (CI, 61.4 to 72.4) and 5-year overall survival (OS5y) 79.6% (CI, 75.0 to 84.4). Overall, 75% were stratified to standard-risk and 19% to high-risk. There was no difference in the proportion of patients with MRD <0.1% on day 22 after induction 1 (34% mitoxantrone, etoposide, araC [MEC], 30% DNX, P = .65), but the proportion increased to 61% for MEC versus 47% for DNX (P = .061) at the last evaluation before induction 2. EFS5y was significantly lower, 56.6% (CI, 46.7 to 66.5) versus 71.9% (CI, 63.0 to 80.9), and cumulative incidence of relapse (CIR) was higher, 35.1% (CI, 25.7 to 44.7) versus 18.8% (CI, 11.6 to 27.2) for DNX. The inferior outcome for DNX was only in standard-risk patients with EFS5y 55.3% (CI, 45.1 to 67.7) versus 79.9% (CI, 71.1 to 89.9), CIR 39.5% (CI, 28.4 to 50.3) versus 18.7% (CI, 10.5 to 28.7), and OS5y 76.2% (CI, 67.2 to 86.4) versus 88.6% (CI, 81.4 to 96.3). As-treated analyses, including the observation cohort, supported these results. For all high-risk patients, 85% received hSCT, and EFS5y was 77.7 (CI, 67.3 to 89.7) and OS5y was 83.0 (CI, 73.5 to 93.8).
CONCLUSIONS: The intensification of induction therapy with risk stratification on the basis of response to induction and hSCT for high-risk patients led to improved outcomes. Mitoxantrone had a superior anti-leukemic effect than liposomal daunorubicin.
METHODS: The study planned to randomly assign 300 patients, but the production of DNX ceased in 2017. One hundred ninety-four patients were randomly assigned to mitoxantrone or experimental DNX in induction 1. Ninety-three non-randomly assigned patients served as an observation cohort. Primary end point was fraction of patients with MRD <0.1% on day 22 after induction 1. Patients with MRD ≥15% after induction 1 or ≥0.1% after induction 2 or FLT3-ITD with NPM1 wildtype were stratified to high-risk therapy, including hSCT.
RESULTS: Outcome for all 287 children was good with 5-year event-free survival (EFS5y) 66.7% (CI, 61.4 to 72.4) and 5-year overall survival (OS5y) 79.6% (CI, 75.0 to 84.4). Overall, 75% were stratified to standard-risk and 19% to high-risk. There was no difference in the proportion of patients with MRD <0.1% on day 22 after induction 1 (34% mitoxantrone, etoposide, araC [MEC], 30% DNX, P = .65), but the proportion increased to 61% for MEC versus 47% for DNX (P = .061) at the last evaluation before induction 2. EFS5y was significantly lower, 56.6% (CI, 46.7 to 66.5) versus 71.9% (CI, 63.0 to 80.9), and cumulative incidence of relapse (CIR) was higher, 35.1% (CI, 25.7 to 44.7) versus 18.8% (CI, 11.6 to 27.2) for DNX. The inferior outcome for DNX was only in standard-risk patients with EFS5y 55.3% (CI, 45.1 to 67.7) versus 79.9% (CI, 71.1 to 89.9), CIR 39.5% (CI, 28.4 to 50.3) versus 18.7% (CI, 10.5 to 28.7), and OS5y 76.2% (CI, 67.2 to 86.4) versus 88.6% (CI, 81.4 to 96.3). As-treated analyses, including the observation cohort, supported these results. For all high-risk patients, 85% received hSCT, and EFS5y was 77.7 (CI, 67.3 to 89.7) and OS5y was 83.0 (CI, 73.5 to 93.8).
CONCLUSIONS: The intensification of induction therapy with risk stratification on the basis of response to induction and hSCT for high-risk patients led to improved outcomes. Mitoxantrone had a superior anti-leukemic effect than liposomal daunorubicin.
摘要：
目的：诱导治疗后使用流式细胞术可测量的残留病（MRD）在小儿AML中具有强烈的预后，和造血干细胞移植（hSCT）可能抵消不良反应。我们设计了一项III期研究，以强化反应引导诱导和基于MRD的风险分层，并使用hSCT治疗不良诱导反应。将脂质体柔红霉素（DNX）在诱导中的功效与米托蒽醌进行了比较。
方法：该研究计划随机分配300名患者，但DNX的生产在2017年停止。在诱导1中，有一百九十四名患者被随机分配到米托蒽醌或实验性DNX。93名非随机分配的患者作为观察队列。主要终点为诱导1后第22天MRD<0.1%的患者分数。诱导1后MRD≥15％或诱导2后≥0.1％或NPM1野生型FLT3-ITD的患者被分层为高风险治疗，包括hSCT。
结果：所有287名儿童的结果均良好，5年无事件生存率（EFS5y）为66.7％（CI，61.4至72.4），5年总生存率（OS5y）为79.6％（CI，75.0至84.4）。总的来说,75%被分层为标准风险，19%被分层为高风险。诱导1后第22天MRD<0.1％的患者比例无差异（34％米托蒽醌，依托泊苷,araC[MEC]，30%DNX,P=.65），但在诱导2之前的最后一次评估中，MEC的比例增加到61％，而DNX的比例为47％（P=0.061）。EFS5y显著降低，56.6%（CI，46.7至66.5）与71.9%（CI，63.0至80.9），累积复发率（CIR）较高，DNX的35.1%（CI，25.7至44.7）与18.8%（CI，11.6至27.2）。DNX的不良结局仅在EFS5y的标准风险患者中55.3％（CI，45.1至67.7）与79.9％（CI，71.1至89.9），CIR39.5%（CI，28.4至50.3）与18.7%（CI，10.5至28.7），OS5y为76.2%（CI，67.2至86.4）和88.6%（CI，81.4至96.3）。经处理的分析，包括观察队列，支持这些结果。对于所有高危患者，85%接受hSCT，EFS5y为77.7（CI，67.3至89.7），OS5y为83.0（CI，73.5至93.8）。
结论：在高危患者对诱导和hSCT反应的基础上加强诱导治疗并进行风险分层可改善预后。米托蒽醌的抗白血病作用优于脂质体柔红霉素。
方法：该研究计划随机分配300名患者，但DNX的生产在2017年停止。在诱导1中，有一百九十四名患者被随机分配到米托蒽醌或实验性DNX。93名非随机分配的患者作为观察队列。主要终点为诱导1后第22天MRD<0.1%的患者分数。诱导1后MRD≥15％或诱导2后≥0.1％或NPM1野生型FLT3-ITD的患者被分层为高风险治疗，包括hSCT。
结果：所有287名儿童的结果均良好，5年无事件生存率（EFS5y）为66.7％（CI，61.4至72.4），5年总生存率（OS5y）为79.6％（CI，75.0至84.4）。总的来说,75%被分层为标准风险，19%被分层为高风险。诱导1后第22天MRD<0.1％的患者比例无差异（34％米托蒽醌，依托泊苷,araC[MEC]，30%DNX,P=.65），但在诱导2之前的最后一次评估中，MEC的比例增加到61％，而DNX的比例为47％（P=0.061）。EFS5y显著降低，56.6%（CI，46.7至66.5）与71.9%（CI，63.0至80.9），累积复发率（CIR）较高，DNX的35.1%（CI，25.7至44.7）与18.8%（CI，11.6至27.2）。DNX的不良结局仅在EFS5y的标准风险患者中55.3％（CI，45.1至67.7）与79.9％（CI，71.1至89.9），CIR39.5%（CI，28.4至50.3）与18.7%（CI，10.5至28.7），OS5y为76.2%（CI，67.2至86.4）和88.6%（CI，81.4至96.3）。经处理的分析，包括观察队列，支持这些结果。对于所有高危患者，85%接受hSCT，EFS5y为77.7（CI，67.3至89.7），OS5y为83.0（CI，73.5至93.8）。
结论：在高危患者对诱导和hSCT反应的基础上加强诱导治疗并进行风险分层可改善预后。米托蒽醌的抗白血病作用优于脂质体柔红霉素。
