Clofarabine Can Replace Anthracyclines and Etoposide in Remission Induction Therapy for Childhood Acute Myeloid Leukemia: The AML08 Multicenter, Randomized Phase III Trial
Clofarabine Can Replace Anthracyclines and Etoposide in Remission Induction Therapy for Childhood Acute Myeloid Leukemia: The AML08 Multicenter, Randomized Phase III Trial
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DOI：
10.1200/jco.19.00327
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发表时间：
2019-08-10
影响因子：
45.3
通讯作者：
Pui, Ching-Hon
中科院分区：
文献类型：
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作者：
Rubnitz, Jeffrey E.;Lacayo, Norman J.;Pui, Ching-Hon
为了确定对急性髓性白血病儿童有效且毒性较小的治疗方法，我们将氯法拉滨引入缓解诱导的第一个疗程，以减少柔红霉素和依托泊苷的暴露。262例随机分配接受氯法拉滨和阿糖胞苷（Clo+AraC，n = 129）或大剂量阿糖胞苷、柔红霉素和依托泊苷（HD-ADE，n = 133）作为诱导I。诱导II包括低剂量ADE单独给药或与索拉非尼或伏立诺他联合给药。巩固治疗包括两个或三个额外疗程的化疗或造血细胞移植。遗传异常和诱导缓解第22天的微小残留病（MRD）水平决定了最终的风险分类。主要终点是第22天的MRD。在285例患者中，263例（92.3%）在两个疗程后诱导完全缓解;诱导失败包括4例早期死亡和15例耐药白血病。第22天，接受Clo+AraC治疗的121例随机分配的可评价患者中有57例（47%）MRD阳性，接受HD-ADE治疗的121例患者中有42例（35%）MRD阳性（比值比，1.86; 95% CI，1.03 - 3.41; P = 0.04）。尽管如此，3年无事件生存率（Clo+AraC组为52.9% [44.6%至62.8%]，HD-ADE组为52.4% [44.0%至62.4%]，P = 0.94）和总生存率（Clo+AraC为74.8% [67.1%至83.3%]，HD-ADE为64.6% [56.2%至74.2%]，P = .1）结论：我们的研究结果表明，在缓解诱导期间使用氯法拉滨和阿糖胞苷可能会减少对蒽环类药物和依托泊苷的需要，急性髓性白血病患者，并可能降低心肌病和治疗相关癌症的发病率。
PURPOSETo identify effective and less toxic therapy for children with acute myeloid leukemia, we introduced clofarabine into the first course of remission induction to reduce exposure to daunorubicin and etoposide.PATIENTS AND METHODSFrom 2008 through 2017, 285 patients were enrolled at eight centers; 262 were randomly assigned to receive clofarabine and cytarabine (Clo+AraC, n = 129) or high-dose cytarabine, daunorubicin, and etoposide (HD-ADE, n = 133) as induction I. Induction II consisted of low-dose ADE given alone or combined with sorafenib or vorinostat. Consolidation therapy comprised two or three additional courses of chemotherapy or hematopoietic cell transplantation. Genetic abnormalities and the level of minimal residual disease (MRD) at day 22 of initial remission induction determined final risk classification. The primary end point was MRD at day 22.RESULTSComplete remission was induced after two courses of therapy in 263 (92.3%) of the 285 patients; induction failures included four early deaths and 15 cases of resistant leukemia. Day 22 MRD was positive in 57 of 121 randomly assigned evaluable patients (47%) who received Clo+AraC and 42 of 121 patients (35%) who received HD-ADE (odds ratio, 1.86; 95% CI, 1.03 to 3.41; P = .04). Despite this result, the 3-year event-free survival rate (52.9% [44.6% to 62.8%] for Clo+AraC v 52.4% [44.0% to 62.4%] for HD-ADE, P = .94) and overall survival rate (74.8% [67.1% to 83.3%] for Clo+AraC v 64.6% [56.2% to 74.2%] for HD-ADE, P = .1) did not differ significantly across the two arms.CONCLUSIONOur findings suggest that the use of clofarabine with cytarabine during remission induction might reduce the need for anthracycline and etoposide in pediatric patients with acute myeloid leukemia and may reduce rates of cardiomyopathy and treatment-related cancer.