天冬酰胺酶停用对儿童急性淋巴细胞白血病预后的影响：来自儿童肿瘤学组的报告
Impact of Asparaginase Discontinuation on Outcome in Childhood Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group.
作者信息
Gupta Sumit, Wang Cindy, Raetz Elizabeth A, Schore Reuven, Salzer Wanda L, Larsen Eric C, Maloney Kelly W, Mattano Len A, Carroll William L, Winick Naomi J, Hunger Stephen P, Loh Mignon L, Devidas Meenakshi
机构信息
Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Department of Biostatistics, University of Florida, Gainesville, FL.
出版信息
J Clin Oncol. 2020 Jun 10;38(17):1897-1905. doi: 10.1200/JCO.19.03024. Epub 2020 Apr 10.
PURPOSE
Asparaginase (ASNase) is an important component of acute lymphoblastic leukemia (ALL) treatment, but is often discontinued because of toxicity. ASNase () substitution was approved in 2011 for allergic reactions. has, however, been intermittently unavailable because of drug supply issues. The impact of substitution or complete ASNase discontinuation is unknown.
METHODS
Patients aged 1-30.99 years in frontline Children's Oncology Group trials for B-cell acute lymphoblastic leukemia between 2004 and 2011 (National Cancer Institute [NCI] standard risk [SR]: AALL0331; NCI high risk: AALL0232) were included. The number of prescribed pegaspargase (PEG-ASNase) doses varied by trial and strata. Maintenance therapy did not contain ASNase. Landmark analyses at maintenance compared disease-free survival (DFS) among those receiving all prescribed PEG-ASNase doses versus switching to but receiving all doses versus not receiving all ASNase doses.
RESULTS
We included 5,195 AALL0331 and 3,001 AALL0232 patients. The cumulative incidence of PEG-ASNase discontinuation was 12.2% ± 4.6% in AALL0331 and 25.4% ± 0.8% in AALL0232. In multivariable analyses, NCI high-risk patients not receiving all prescribed ASNase doses had inferior DFS (hazard ratio [HR], 1.5; 95% CI, 1.2 to 1.9; = .002) compared with those receiving all prescribed PEG-ASNase doses. Patients with substitution who completed subsequent courses were not at increased risk (HR, 1.1; 95% CI, 0.7 to 1.6; = .69). NCI SR patients who discontinued ASNase were not at elevated risk (HR, 1.2; 95% CI, 0.9 to 1.6; = .23), except when restricted to those with slow early response, who were prescribed more ASNase because of therapy intensification (HR, 1.7; 95% CI, 1.1 to 2.7; = .03).
CONCLUSION
Discontinuation of ASNase doses is associated with inferior DFS in higher-risk patients. Our results illustrate the severe consequences of shortages.
目的
天冬酰胺酶（ASNase）是急性淋巴细胞白血病（ALL）治疗的重要组成部分，但常因毒性而停药。聚乙二醇化天冬酰胺酶（PEG - ASNase）替代疗法于2011年获批用于治疗过敏反应。然而，由于药物供应问题，PEG - ASNase曾间歇性缺货。PEG - ASNase替代或完全停用ASNase的影响尚不清楚。
方法
纳入2004年至2011年间在儿童肿瘤协作组进行的B细胞急性淋巴细胞白血病一线试验中年龄在1至30.99岁的患者（美国国立癌症研究所[NCI]标准风险[SR]：AALL0331；NCI高风险：AALL0232）。所开PEG - ASNase剂量的数量因试验和分层而异。维持治疗不含ASNase。在维持阶段进行的标志性分析比较了接受所有规定剂量PEG - ASNase的患者、改用PEG - ASNase但接受了所有剂量的患者以及未接受所有ASNase剂量的患者的无病生存期（DFS）。
结果
我们纳入了5195例AALL0331患者和3001例AALL0232患者。AALL0331中PEG - ASNase停药的累积发生率为12.2%±4.6%，AALL0232中为25.4%±0.8%。在多变量分析中，与接受所有规定剂量PEG - ASNase的患者相比，未接受所有规定ASNase剂量的NCI高风险患者的DFS较差（风险比[HR]，1.5；95%置信区间[CI]，1.2至1.9；P = 0.002）。完成后续疗程的接受PEG - ASNase替代的患者风险未增加（HR，1.1；95%CI，0.7至1.6；P = 0.69）。停用ASNase 的NCI SR患者风险未升高（HR，1.2；95%CI，0.9至1.6；P = 0.23），但仅限于那些早期反应缓慢的患者，由于治疗强化他们被开了更多的ASNase（HR，1.7；95%CI，1.1至2.7；P = 0.03）。
结论
停用ASNase剂量与高风险患者较差的DFS相关。我们的结果说明了PEG - ASNase短缺的严重后果。
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