Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial.
Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial.
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DOI：
10.1016/s1470-2045(10)70090-5
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发表时间：
2010-06
期刊：
影响因子：
51.1
通讯作者：
Campana, Dario
中科院分区：
文献类型：
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作者：
Rubnitz, Jeffrey E.;Inaba, Hiroto;Dahl, Gary;Ribeiro, Raul C.;Bowman, W. Paul;Taub, Jeffrey;Pounds, Stanley;Razzouk, Bassem I.;Lacayo, Norman J.;Cao, Xueyuan;Meshinchi, Soheil;Degar, Barbara;Airewele, Gladstone;Raimondi, Susana C.;Onciu, Mihaela;Coustan-Smith, Elaine;Downing, James R.;Leung, Wing;Pui, Ching-Hon;Campana, Dario
我们试图通过应用基于白血病细胞遗传异常的风险导向治疗和治疗期间通过流式细胞术测定的微小残留病（MRD）来改善儿童急性髓性白血病（AML）的结局。从2002年10月13日至2008年6月19日，232例初治AML（n=206）、治疗或骨髓增生异常相关AML（n=12）或混合系白血病（n=14）患者在8个中心入组。区组、非盲随机化，按细胞遗传学或形态学亚型分层，将患者分配至高剂量（18 g/m2，n=113）或低剂量（2 g/m2，n=117）阿糖胞苷（A），与柔红霉素（D）和依托泊苷（E）联合给药（诱导I）;实现MRD阴性状态是主要终点。诱导II期包括ADE联合或不联合吉妥珠单抗（GO）;巩固治疗包括3个额外疗程的化疗或造血干细胞移植（HSCT）。MRD水平用于分配GO并确定诱导II的时间;诊断时的MRD和遗传异常用于确定最终风险分类。低风险患者（n=68）接受了5个疗程的化疗，而高风险患者（n=79）以及具有匹配同胞供体的标准风险患者（n=69）有资格进行HSCT（在48例高风险患者和8例标准风险患者中进行）。对所有随机化患者（n=230）进行主要终点分析。其他分析仅限于216例AML患者，不包括混合系白血病。本试验已在ClinicalTrial.gov上注册，注册号为NCT 00136084，不进行累积。诱导I后完全缓解率为80%（173/216），诱导II后完全缓解率为94%（203/216）。诱导失败包括2例中毒死亡和10例耐药白血病。引入高剂量阿糖胞苷并未显著降低诱导I治疗后MRD阳性率（34% vs. 42%，P=0.17）。高剂量组或低剂量组治疗患者的3级或以上感染的累积发生率分别为79.3% ± 4.0%和75.5% ± 4.2%。无事件生存率和总生存率的3年估计值（± SE）分别为63.0% ± 4.1%和71.1% ± 3.8%。诱导II期后MRD < 0.1%的实现确定了一大组患者（80%）的累积复发率仅为17% ± 3%。诱导I期后MRD ≥ 1%是无事件（HR，2.41; CI 1.36-4.26; P=0.003）和总生存期（HR，2.11; CI 1.09-4.11; P=0.028）具有统计学显著性（P < 0.05）的唯一独立不良预后因素。我们的研究结果表明，在基于遗传特征和MRD结果的综合风险分层策略的背景下，使用靶向化疗和HSCT可以改善儿童AML的结局。
We sought to improve outcome of childhood acute myeloid leukemia (AML) by applying risk-directed therapy based on the genetic abnormalities of the leukemic cells and measurements of minimal residual disease (MRD) as determined by flow cytometry during treatment. From October 13, 2002 to June 19, 2008, 232 patients with de novo AML (n=206), therapy- or myelodysplasia-related AML (n=12), or mixed-lineage leukemia (n=14) were enrolled at eight centers. Block, nonblinded randomization, stratified by cytogenetic or morphologic subtype, assigned patients to high-dose (18 g/m2, n=113) or low-dose (2 g/m2, n=117) cytarabine (A), given together with daunorubicin (D) and etoposide (E) (Induction I); achievement of MRD negative status was the primary endpoint. Induction II consisted of ADE with or without gemtuzumab ozogamicin (GO); consolidation therapy included three additional courses of chemotherapy or hematopoietic stem cell transplantation (HSCT). Levels of MRD were used to allocate GO and determine the timing of Induction II; both MRD and genetic abnormalities at diagnosis were used to determine final risk classification. Low-risk patients (n=68) received 5 courses of chemotherapy, whereas high-risk patients (n=79), as well as standard-risk patients (n=69) with matched sibling donors, were eligible for HSCT (performed in 48 high and 8 standard-risk patients). All randomized patients (n=230) were analyzed for the primary endpoint. The other analyses were limited to the 216 patients with AML, excluding mixed-lineage leukemia. This trial, closed to accrual, is registered with ClinicalTrial.gov, number NCT00136084. The complete remission rates were 80% (173 of the 216) after Induction I and 94% (203 of 216) after Induction II. Induction failures included two toxic deaths and 10 cases of resistant leukemia. The introduction of high-dose cytarabine did not significantly lower the rate of MRD positivity after Induction I therapy (34% vs. 42%, P=0.17). The cumulative incidences of grade 3 or greater infection were 79.3% ± 4.0% and 75.5% ± 4.2% for patients treated on the high-dose or low-dose arms. The 3-year estimates (± SE) of event-free and overall survival were 63.0% ± 4.1% and 71.1% ± 3.8%, respectively. Achievement of MRD < 0.1% after Induction II identified a large group of patients (80%) with a cumulative incidence of relapse of only 17% ± 3%. Post-Induction I MRD ≥ 1% was the only independent adverse prognostic factor that was statistically significant (P < 0.05) for both event-free (HR, 2.41; CI 1.36–4.26; P=0.003) and overall survival (HR, 2.11; CI 1.09–4.11; P=0.028). Our findings suggest that the use of targeted chemotherapy and HSCT, in the context of a comprehensive risk-stratification strategy based on genetic features and MRD findings, can improve the outcome of childhood AML.