Intermittent Versus Continuous PEG-Asparaginase to Reduce Asparaginase-Associated Toxicities: A NOPHO ALL2008 Randomized Study
Intermittent Versus Continuous PEG-Asparaginase to Reduce Asparaginase-Associated Toxicities: A NOPHO ALL2008 Randomized Study
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DOI：
10.1200/jco.18.01877
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发表时间：
2019-07-01
影响因子：
45.3
通讯作者：
Schmiegelow, Kjeld
中科院分区：
文献类型：
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作者：
Albertsen, Birgitte Klug;Grell, Kathrine;Schmiegelow, Kjeld
目的：天冬酰胺酶是儿童急性淋巴细胞白血病（ALL）治疗的一种必需药物，经常使用数月以获得持续的天冬酰胺耗竭。我们随机分配患者连续或间歇聚乙二醇-天冬酰胺酶（PEG-asp）治疗，假设毒性降低，疗效不变。方法：根据北欧儿童血液学和肿瘤学学会ALL2008方案，接受非高危ALL治疗的儿童（中位年龄4.2岁）每两周接受5次肌内PEG-asp注射（1,000 IU/m(2)），然后随机分配到另外3次剂量（间隔6周[实验组]，n = 309）和10次剂量（间隔2周[标准组]，n = 316）。主要终点是非劣势（6%）无病生存期。毒性降低是次要终点。发生的天冬酰胺酶相关的过敏，胰腺炎，骨坏死，血栓栓塞前瞻性登记。结果：中位随访4.1年，实验组和标准组的5年无病生存率分别为92.2% （95% CI, 88.6 ~ 95.8）和90.8% （95% CI, 87.0 ~ 94.6）。任何首次天冬酰胺酶相关毒性（过敏[n = 13]；骨坏死[n = 29]；胰腺炎[n = 24]；血栓栓塞[n = 17]）的3年累积发生率在实验组为9.3%，在标准组为18.1% （P = 0.001）。按年龄分层的性别和风险组校正Cox回归分析证实了天冬酰胺酶相关毒性降低（>= 10和< 10岁；风险比，0.48;P = .001）。实验组所有四种毒性的发生率最低，在胰腺炎方面达到显著性（6个月风险，5.8% vs 1.3%; P = 0.002）。结论：良好的治愈率和降低的毒性风险支持在未来儿童ALL试验中采用延长PEG-asp治疗的前10周后使用间歇性PEG-asp治疗。
PURPOSE Asparaginase is an essential drug in childhood acute lymphoblastic leukemia (ALL) therapy and is frequently given for months to obtain continuous asparagine depletion. We randomly assigned patients to continuous versus intermittent pegylated-asparaginase (PEG-asp) treatment, hypothesizing there would be decreased toxicity with unchanged efficacy.METHODS Children (median age, 4.2 years) treated for non-high-risk ALL according to the Nordic Society for Pediatric Hematology and Oncology ALL2008 protocol received five intramuscular PEG-asp injections (1,000 IU/m(2)) every two weeks and were then randomly assigned to additional three doses (6-week intervals [experimental arm], n = 309) versus 10 doses (2-week intervals [standard arm], n = 316). The primary end point was noninferior (6% margin) disease-free survival. Toxicity reduction was a secondary end point. Occurrence of asparaginase-associated hypersensitivity, pancreatitis, osteonecrosis, and thromboembolism were prospectively registered.RESULTS After a median follow-up of 4.1 years, the 5-year disease-free survival was 92.2% (95% CI, 88.6 to 95.8) and 90.8% (95% CI, 87.0 to 94.6) in the experimental and standard arms, respectively. The 3-year cumulative incidence of any first asparaginase-associated toxicity (hypersensitivity [n = 13]; osteonecrosis [n = 29]; pancreatitis [n = 24]; thromboembolism [n = 17]) was 9.3% in the experimental arm and 18.1% in the standard arm (P = .001). Asparaginase-associated toxicity reduction was confirmed in sex- and risk-group-adjusted Cox regression analysis stratified by age (>= 10 and < 10 years; hazard ratio, 0.48; P = .001). The experimental arm had the lowest incidences of all four toxicities, reaching significance for pancreatitis (6-month risk, 5.8% v 1.3%; P = .002).CONCLUSION The excellent cure rates and reduced toxicity risk support the use of intermittent PEG-asp therapy after the first 10 weeks in future childhood ALL trials that apply prolonged PEG-asp therapy.