聚乙二醇化大肠杆菌L-天冬酰胺酶卡拉斯帕酶治疗急性淋巴细胞白血病患者的药代动力学和药效学特性：儿童肿瘤学组AALL07P4研究结果
Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children's Oncology Group Study AALL07P4.
作者信息
Angiolillo Anne L, Schore Reuven J, Devidas Meenakshi, Borowitz Michael J, Carroll Andrew J, Gastier-Foster Julie M, Heerema Nyla A, Keilani Taha, Lane Ashley R, Loh Mignon L, Reaman Gregory H, Adamson Peter C, Wood Brent, Wood Charlotte, Zheng Hao W, Raetz Elizabeth A, Winick Naomi J, Carroll William L, Hunger Stephen P
机构信息
Anne L. Angiolillo, Reuven J. Schore, Ashley R. Lane, and Gregory H. Reaman, Children's National Medical Center, Washington, DC; Meenakshi Devidas, Colleges of Medicine, Public Health and Health Professions, University of Florida; Charlotte Wood and Hao W. Zheng, Children's Oncology Group, Gainesville, FL; Michael J. Borowitz, Johns Hopkins Medical Institutions, Baltimore; Taha Keilani, Sigma-Tau Pharmaceuticals, Gaithersburg, MD; Andrew J. Carroll, University of Alabama at Birmingham, Birmingham, AL; Julie M. Gastier-Foster and Nyla A. Heerema, Ohio State University Wexner Medical Center; Julie M. Gastier-Foster, Ohio State University College of Medicine and Nationwide Children's Hospital, Columbus, OH; Mignon L. Loh, University of California at San Francisco, San Francisco, CA; Peter C. Adamson, Children's Hospital of Philadelphia, Philadelphia, PA; Brent Wood, University of Washington, Seattle, WA; Elizabeth A. Raetz and William L. Carroll, New York University Cancer Institute, New York University Langone Medical Center, New York, NY; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; and Stephen P. Hunger, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO.
出版信息
J Clin Oncol. 2014 Dec 1;32(34):3874-82. doi: 10.1200/JCO.2014.55.5763. Epub 2014 Oct 27.
PURPOSE
Asparaginase is a critical agent used to treat acute lymphoblastic leukemia (ALL). Pegaspargase (SS-PEG), a pegylated form of Escherichia coli L-asparaginase with a succinimidyl succinate (SS) linker, is the first-line asparaginase product used in Children's Oncology Group (COG) ALL trials. Calaspargase pegol (SC-PEG) replaces the SS linker in SS-PEG with a succinimidyl carbamate linker, creating a more stable molecule. COG AALL07P4 was designed to determine the pharmacokinetic and pharmacodynamic comparability of SC-PEG to SS-PEG in patients with newly diagnosed high-risk (HR) B-cell ALL.
PATIENTS AND METHODS
A total of 165 evaluable patients were randomly assigned at a 2:1 ratio to receive SC-PEG at 2,100 (SC-PEG2100; n = 69) or 2,500 IU/m(2) (SC-PEG2500; n = 42) versus SS-PEG 2,500 IU/m(2) (SS-PEG2500; n = 54) as part of an otherwise identical chemotherapy regimen. The groups were similar demographically, except more female patients received SC-PEG2500.
RESULTS
The mean half-life of plasma asparaginase activity for both SC-PEG doses was approximately 2.5× longer than that of SS-PEG2500. The total systemic exposure, as defined by induction area under the curve from time 0 to 25 days, was greater with SC-PEG2500 than with SS-PEG2500 or SC-PEG2100. The proportion of patients with plasma asparaginase activity ≥ 100 mIU/mL and ≥ 400 mIU/mL was higher in patients who received SC-PEG as compared with SS-PEG2500. After one dose of pegylated asparaginase on induction day 4, plasma asparagine was undetectable for 11 days for SS-PEG2500 and 18 days for both SC-PEG groups.
CONCLUSION
SC-PEG2500 achieves a significantly longer period of asparaginase activity above defined thresholds and asparagine depletion compared with SS-PEG2500 and has a comparable toxicity profile in children with HR B-cell ALL.
目的
天冬酰胺酶是治疗急性淋巴细胞白血病（ALL）的关键药物。培门冬酶（SS-PEG）是一种经聚乙二醇化修饰的大肠杆菌L-天冬酰胺酶，带有琥珀酰亚胺琥珀酸酯（SS）连接子，是儿童肿瘤协作组（COG）ALL试验中使用的一线天冬酰胺酶产品。卡拉斯帕酶聚乙二醇（SC-PEG）用氨基甲酸琥珀酰亚胺酯连接子取代了SS-PEG中的SS连接子，形成了一个更稳定的分子。COG AALL07P4旨在确定新诊断的高危（HR）B细胞ALL患者中SC-PEG与SS-PEG的药代动力学和药效学可比性。
患者与方法
总共165例可评估患者按2:1的比例随机分组，接受2100（SC-PEG2100；n = 69）或2500 IU/m²（SC-PEG2500；n = 42）的SC-PEG，与2500 IU/m²的SS-PEG（SS-PEG2500；n = 54）相比，作为其他方面相同的化疗方案的一部分。各治疗组在人口统计学上相似，只是接受SC-PEG2500的女性患者更多。
结果
两种SC-PEG剂量的血浆天冬酰胺酶活性的平均半衰期比SS-PEG2500长约2.5倍。由第0天至第25天曲线下诱导面积定义的全身总暴露量，SC-PEG2500高于SS-PEG2500或SC-PEG2100。与SS-PEG2500相比，接受SC-PEG治疗的患者血浆天冬酰胺酶活性≥100 mIU/mL和≥400 mIU/mL的比例更高。在诱导第4天给予一剂聚乙二醇化天冬酰胺酶后，SS-PEG2500组血浆天冬酰胺在11天内检测不到，而两个SC-PEG组均为18天。
结论
与SS-PEG2500相比，SC-PEG2500在定义阈值以上实现了显著更长的天冬酰胺酶活性持续时间和天冬酰胺消耗，并且在HR B细胞ALL儿童中的毒性特征相当。
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