Impact of Asparaginase Discontinuation on Outcome in Childhood Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group
Impact of Asparaginase Discontinuation on Outcome in Childhood Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group
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DOI：
10.1200/jco.19.03024
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发表时间：
2020-06-10
影响因子：
45.3
通讯作者：
Devidas, Meenakshi
中科院分区：
文献类型：
--
作者：
Gupta, Sumit;Wang, Cindy;Devidas, Meenakshi
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，但经常因毒性而停用。欧文氏菌ASNase（Erwinia）替代品于2011年被批准用于过敏反应。然而，由于药物供应问题，欧文氏菌一直间歇性地不可用。Erwinia替代或完全停用ASNase的影响尚不清楚。方法纳入2004年至2011年儿童肿瘤组一线B细胞急性淋巴细胞白血病试验中年龄1-30.99岁的患者（国家癌症研究所[NCI]标准风险[SR]：AALL 0331; NCI高风险：AALL 0232）。处方的培门冬酶（PEG-ASNase）给药次数因试验和分层而异。维持治疗不含ASNase。维持期的标志性分析比较了接受所有处方PEG-ASNase剂量与转换为欧文氏菌但接受所有剂量与不接受所有ASNase剂量的患者的无病生存期（DFS）。AALL 0331和AALL 0232中PEG-ASNase停药的累积发生率分别为12.2%、4.6%和25.4% ± 0.8%。在多变量分析中，与接受所有处方PEG-ASNase剂量的患者相比，未接受所有处方ASNase剂量的NCI高风险患者的DFS较差（风险比[HR]，1.5; 95% CI，1.2至1.9; P = 0.002）。完成后续疗程的欧文氏菌替代患者的风险并未增加（HR，1.1; 95% CI，0.7 - 1.6; P = 0.69）。停用ASNase的NCI SR患者的风险未升高（HR，1.2; 95% CI，0.9 - 1.6; P = 0.23），但限于早期反应缓慢的患者除外，这些患者由于治疗强化而处方了更多的ASNase（HR，1.7; 95%CI，1.1 - 2.7; P = 0.03）.结论：在高危患者中，停用ASNase与较差的DFS相关。我们的研究结果说明了欧文氏菌短缺的严重后果。
PURPOSEAsparaginase (ASNase) is an important component of acute lymphoblastic leukemia (ALL) treatment, but is often discontinued because of toxicity. Erwiniachrysanthemi ASNase (Erwinia) substitution was approved in 2011 for allergic reactions. Erwinia has, however, been intermittently unavailable because of drug supply issues. The impact of Erwinia substitution or complete ASNase discontinuation is unknown.METHODSPatients 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 Erwinia but receiving all doses versus not receiving all ASNase doses.RESULTSWe 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; P = .002) compared with those receiving all prescribed PEG-ASNase doses. Patients with Erwinia substitution who completed subsequent courses were not at increased risk (HR, 1.1; 95% CI, 0.7 to 1.6; P = .69). NCI SR patients who discontinued ASNase were not at elevated risk (HR, 1.2; 95% CI, 0.9 to 1.6; P = .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; P = .03).CONCLUSIONDiscontinuation of ASNase doses is associated with inferior DFS in higher-risk patients. Our results illustrate the severe consequences of Erwinia shortages.