Effect of Dasatinib vs Imatinib in the Treatment of Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia A Randomized Clinical Trial
Effect of Dasatinib vs Imatinib in the Treatment of Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia A Randomized Clinical Trial
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达沙替尼与伊马替尼治疗儿童费城染色体阳性急性淋巴细胞白血病的随机临床试验
DOI：
10.1001/jamaoncol.2019.5868
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发表时间：
2020-03-01
期刊：
影响因子：
28.4
通讯作者：
Pui, Ching-Hon
中科院分区：
文献类型：
--
作者：
Shen, Shuhong;Chen, Xiaojuan;Pui, Ching-Hon
需要进行一项随机临床试验，以确定第二代酪氨酸激酶抑制剂达沙替尼是否比第一代抑制剂甲磺酸伊马替尼更有效地治疗儿童费城染色体阳性急性淋巴细胞白血病（ALL）。目的确定在不进行预防性头颅照射的情况下，在强化化疗的背景下，达沙替尼每日剂量80 mg/m2是否比甲磺酸伊马替尼每日剂量300 mg/m2更有效地改善费城染色体阳性ALL儿童的无事件生存率。设计、设置和参与者这项开放标签、3期随机临床试验在中国的20家医院进行。入组时间为2015年1月1日至2018年9月18日，随机化于2018年10月4日停止，当时符合试验的提前停止标准。招募了0至18岁的患者。在225例确诊患者中，35例拒绝参与，1例在治疗前死亡，剩下189例患者可供分析。分析了2019年1月1日至8月4日的数据。干预措施患者被随机分配接受每日达沙替尼（n = 92）或伊马替尼（n = 97），从缓解诱导期间诊断的时间到继续治疗结束的整个ALL治疗期间连续。主要结局和指标主要结局是基于治疗意向分析的无事件生存率，次要结局是复发、毒性反应导致的死亡和总生存率。结果189名受试者中，男性136例，占72.0%;中位年龄，7.8 [四分位距（IQR），5.2-11.3]岁），中位随访时间为26.4（IQR，16.3-34.1）个月，4年无事件生存率和总生存率为71.0%（95% CI，56.2%-89.6%）和88.4%（95% CI，81.3%-96.1%），达沙替尼组和48.9%（95% CI，32.0%-74.5%; P = 0.005，对数秩检验）和69.2%（95% CI，55.6%-86.2%; P = 0.04，对数秩检验）。4年累积复发风险为19.8%达沙替尼组（95% CI，4.2%-35.4%）和34.4%伊马替尼组（95% CI，15.6%-53.2%）（P = .01，Gray检验），而孤立性中枢神经系统复发的4年累积风险为2.7%达沙替尼组为8.4%（95% CI，0.0%-8.1%），伊马替尼组为8.4%（95% CI，1.2%-15.6%）（P = 0.06，Gray检验）。两个治疗组之间重度毒性反应的频率无显著差异。结论和相关性与剂量为300 mg/m2的甲磺酸伊马替尼相比，每日剂量为80 mg/m2的达沙替尼强化化疗对费城染色体阳性ALL的治疗效果上级在不使用预防性颅照射的情况下，达沙替尼对中枢神经系统白血病的控制效果非常好。费城染色体阳性急性淋巴细胞白血病？在这项对189名费城染色体阳性急性淋巴细胞白血病儿童进行的随机临床试验中，92例患者接受达沙替尼80 mg/m2/d治疗，4年无事件生存率显著升高，（71.0% vs 48.9%）和总生存率（88.4% vs 69.2%）以及较低的复发率（19.8% vs 34.4%）。两组之间的严重毒性反应无显著差异。这些发现支持在费城染色体阳性急性淋巴细胞白血病患儿中使用达沙替尼80 mg/m2/d的剂量。这项3期随机临床试验评估了达沙替尼80 mg/m2是否比甲磺酸伊马替尼300 mg/m2更有效地改善费城染色体阳性急性淋巴细胞白血病患儿的无事件生存率。
Importance A randomized clinical trial is needed to determine whether the second-generation Abl-tyrosine kinase inhibitor dasatinib is more effective than the first-generation inhibitor imatinib mesylate for childhood Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). Objective To determine whether dasatinib given at a daily dosage of 80 mg/m(2) is more effective than imatinib mesylate at a daily dosage of 300 mg/m(2) to improve event-free survival of children with Philadelphia chromosome-positive ALL in the context of intensive chemotherapy without prophylactic cranial irradiation. Design, Setting, and Participants This open-label, phase 3 randomized clinical trial was conducted at 20 hospitals in China. Enrollment occurred from January 1, 2015, through September 18, 2018, and randomization was stopped on October 4, 2018, when the early stopping criterion of the trial was met. Patients aged 0 to 18 years were recruited. Of the 225 patients with the diagnosis, 35 declined participation and 1 died before treatment, leaving 189 patients available for analysis. Data were analyzed from January 1 through August 4, 2019. Interventions Patients were randomized to receive daily dasatinib (n = 92) or imatinib (n = 97) continuously for the entire duration of ALL therapy from the time of diagnosis made during remission induction to the end of continuation therapy. Main Outcomes and Measures The primary outcome was event-free survival, analyzed based on intention to treat. The secondary outcomes were relapse, death due to toxic effects, and overall survival. Results Among the 189 participants (136 male [72.0%]; median age, 7.8 [interquartile range (IQR), 5.2-11.3] years) and a median follow-up of 26.4 (IQR, 16.3-34.1) months, the 4-year event-free survival and overall survival rates were 71.0% (95% CI, 56.2%-89.6%) and 88.4% (95% CI, 81.3%-96.1%), respectively, in the dasatinib group and 48.9% (95% CI, 32.0%-74.5%; P = .005, log-rank test) and 69.2% (95% CI, 55.6%-86.2%; P = .04, log-rank test), respectively, in the imatinib group. The 4-year cumulative risk of any relapse was 19.8% (95% CI, 4.2%-35.4%) in the dasatinib group and 34.4% (95% CI, 15.6%-53.2%) in the imatinib group (P = .01, Gray test), whereas the 4-year cumulative risk of an isolated central nervous system relapse was 2.7% (95% CI, 0.0%-8.1%) in the dasatinib group and 8.4% (95% CI, 1.2%-15.6%) in the imatinib group (P = .06, Gray test). There were no significant differences in the frequency of severe toxic effects between the 2 treatment groups. Conclusions and Relevance Intensive chemotherapy including dasatinib at a dosage of 80 mg/m(2) per day yielded superior results in the treatment of Philadelphia chromosome-positive ALL compared with imatinib mesylate at a dosage of 300 mg/m(2) per day and provided excellent control of central nervous system leukemia without the use of prophylactic cranial irradiation.Question Is dasatinib more effective than imatinib mesylate for childhood Philadelphia chromosome-positive acute lymphoblastic leukemia? Findings In this randomized clinical trial of 189 children with Philadelphia chromosome-positive acute lymphoblastic leukemia, the 92 patients treated with dasatinib at 80 mg/m(2) per day had significantly higher rates of 4-year event-free survival (71.0% vs 48.9%) and overall survival (88.4% vs 69.2%) and lower relapse rates (19.8% vs 34.4%) than the 97 treated with imatinib mesylate at 300 mg/m(2) per day. There were no significant differences in severe toxic effects between the 2 groups. Meaning These findings support the use of dasatinib at a dosage of 80 mg/m(2) per day in children with Philadelphia chromosome-positive acute lymphoblastic leukemia.This phase 3 randomized clinical trial assesses whether dasatinib given at 80 mg/m(2) is more effective than imatinib mesylate at 300 mg/m(2) to improve event-free survival in children with Philadelphia chromosome-positive acute lymphoblastic leukemia.