Pulse therapy with vincristine and dexamethasone for childhood acute lymphoblastic leukaemia (CCCG-ALL-2015): an open-label, multicentre, randomised, phase 3, non-inferiority trial.
Pulse therapy with vincristine and dexamethasone for childhood acute lymphoblastic leukaemia (CCCG-ALL-2015): an open-label, multicentre, randomised, phase 3, non-inferiority trial.
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DOI：
10.1016/s1470-2045(21)00328-4
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发表时间：
2021-09
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影响因子：
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通讯作者：
Pui CH
中科院分区：
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作者：
Yang W;Cai J;Shen S;Gao J;Yu J;Hu S;Jiang H;Fang Y;Liang C;Ju X;Wu X;Zhai X;Tian X;Wang N;Liu A;Jiang H;Jin R;Sun L;Yang M;Leung AWK;Pan K;Zhang Y;Chen J;Zhu Y;Zhang H;Li C;Yang JJ;Cheng C;Li CK;Tang J;Zhu X;Pui CH
长春新碱加地塞米松脉冲通常用于儿童急性淋巴细胞白血病(ALL)的持续治疗。我们试图确定这种疗法是否可以安全地省略超过一年的治疗。我们在0至18岁的初诊ALL儿童中进行了一项随机、开放、非自卑的研究。对持续缓解1年的患者进行分层随机分组，在第2年期间接受或不接受长春新碱(1.5 mg/m2)加地塞米松(6 mg/m2，每日6 mg/m2，共7天)冲击治疗。分别在低风险和中/高风险队列中进行随机化和分析。分层因素包括参与中心、性别和确诊时的年龄；低风险组还被分层为ETV6-RUNX1状态，以及中/高风险队列的细胞谱系。随机化在领先的机构集中进行，分配序列由方案生物统计员生成。主要终点是5年无事件生存，非劣势边缘预设为0.05(5%)。按意向处理进行分析。我们在此报告在完成登记和完成特定方案的随访后的结果。该试验在中国临床试验注册中心注册(CHICCTR-IPR-14005706)。从2015年1月1日至2019年2月20日，入选6108名可评估患者。分析时还活着的随机患者的中位随访时间为3.7年(IQR，2.8-4.7)。在低危ALL患者中，接受治疗的1442例患者与未加用脉冲治疗的1481例患者的5年无事件生存率(90.3%[95%CI，88.4%−92.2%]vs 90.2%[95%CI，88.2%−92.2%]，P=0.9)。5年无事件生存概率差异的单边95%可信区间为0.024，建立在预先设定的标准0.05的基础上的非劣势。在中高危ALL患者中，接受治疗的1071例患者的5年无事件生存率为82.8%[95%CI，80.0%−85.6%]，而未加脉冲治疗的1060例患者的5年无事件生存率为80.8%[95%CI，77.7%−83.90%](P=0.9)。5年无事件生存概率差异的单边95%可信区间为0.055，对于那些没有接受额外脉冲治疗的患者来说，这是一个边缘较差的结果。所有接受额外脉冲治疗的中/高风险患者明显更有可能发展为3/4级肺炎和周围神经病变。7例低风险ALL患者和11例中/高风险ALL患者发生了致命感染，随机分组之间的发生率没有显着差异。对于低风险ALL儿童，长春新碱加地塞米松脉冲治疗可在一年后省略。对于中/高风险ALL，还需要进行额外的研究。中国万岁儿童癌症基金会、中国国家自然科学基金、中国第四轮公共卫生三年行动计划(2015年-2017年)、中国医学科学院医学科学创新基金、美国国家癌症研究所、圣鲍德里克基金会以及美国黎巴嫩叙利亚联合慈善机构。
Vincristine plus dexamethasone pulses are generally used throughout continuation treatment for childhood acute lymphoblastic leukemia (ALL). We sought to determine if this therapy can be safely omitted beyond 1 year of treatment. We conducted a randomized, open-label, non-inferiority study in children between 0 and 18 years old with newly diagnosed ALL. Patients in continuous remission for 1 year were stratified and randomized to receive or not receive seven pulses of vincristine (1.5 mg/m2) plus dexamethasone (6 mg/m2 per day for 7 days) during the second year of treatment. Randomization and analyses were performed in low-risk and intermediate-/high-risk cohorts separately. Stratification factors included participating center, sex, and age at diagnosis; the low-risk group was additionally stratified for ETV6–RUNX1 status, and the intermediate-/high-risk cohort for cell lineage. Randomizations were performed centrally at the leading institution with assignment sequences generated by the protocol biostatistician. The primary endpoint was 5-year event-free survival, with the non-inferiority margin preset at 0.05 (5%). The analysis was done by intention to treat. We herein report the findings after completion of enrollment and completion of protocol-specified follow-up. The trial is registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-14005706). From January 1, 2015 to February 20, 2019, 6108 evaluable patients were enrolled. The median follow-up time for the randomized patients who were alive at the time of analysis was 3.7 years (IQR, 2.8–4.7). Among patients with low-risk ALL, there was no difference in 5-year event-free survival between the 1442 patients treated with and the 1481 treated without additional pulse therapy (90.3% [95% CI, 88.4%−92.2%] vs. 90.2% [95% CI, 88.2%−92.2%], P=0.90). The one-sided 95% upper confidence bound for the difference in 5-year event-free survival probability was 0.024, establishing non-inferiority based on the preset criterion of 0.05. Among patients with intermediate-/high-risk ALL, the 5-year event-free survival was 82.8% [95% CI, 80.0%−85.6%] for the 1071 patients treated with and 80.8% [95% CI, 77.7%−83.90%] for the 1060 patients treated without additional pulse therapy (P=0.90). The one-sided 95% upper confidence bound for the difference in probability of 5-year event-free survival was 0.055, a borderline inferior result for those treated without additional pulse therapy. Patients with intermediate-/high-risk ALL receiving additional pulse therapy were significantly more likely to develop grade 3/4 pneumonia and peripheral neuropathy. Fatal infection occurred in 7 patients with low-risk ALL and in 11 with intermediate-/high-risk ALL with no significant difference in the rate between randomized groups. Vincristine plus dexamethasone pulses can be omitted beyond 1 year of treatment for children with low-risk ALL. Additional studies are needed for intermediate-/high-risk ALL. VIVA China Children’s Cancer Foundation, the National Natural Science Foundation of China, the China fourth round of Three-Year Public Health Action Plan (2015–2017), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, U.S. National Cancer Institute, St. Baldrick’s Foundation, and the American Lebanese Syrian Associated Charities.