Hawkins Douglas S, Park Julie R, Thomson Blythe G, Felgenhauer Judy L, Holcenberg John S, Panosyan Eduard H, Avramis Vassilios I
Children's Hospital and Regional Medical Center, Seattle, Washington 98105-0371, USA.
Clin Cancer Res. 2004 Aug 15;10(16):5335-41. doi: 10.1158/1078-0432.CCR-04-0222.
Asparaginase therapy is an important component in the treatment of children with acute lymphoblastic leukemia. Polyethylene glycol-conjugated asparaginase (PEG-ASNase) has significant pharmacological advantages over native Escherichia coli asparaginase. We investigated the pharmacokinetics of PEG-ASNase, presence of antibodies to PEG-ASNase, and concentrations of asparagine in serum and cerebrospinal fluid (CSF) in combination chemotherapy for relapsed pediatric acute lymphoblastic leukemia.
Twenty-eight pediatric patients with relapsed medullary (n = 16) and extramedullary (n = 11) acute lymphoblastic leukemia were enrolled at three pediatric institutions and had at least two serum and CSF samples obtained for analysis. Patients received induction therapy (including PEG-ASNase 2500 IU/m2 intramuscularly weekly on days 2, 9, 16, and 23) and intensification therapy (including PEG-ASNase 2500 IU/m2 intramuscularly once on day 7). Serum samples were obtained weekly during induction and intensification. CSF samples were obtained during therapeutic lumbar punctures during induction and intensification.
Weekly PEG-ASNase therapy resulted in PEG-ASNase activity of >0.1 IU/ml in 91-100% of patients throughout induction. During intensification, PEG-ASNase on day 7 resulted in PEG-ASNase activity >0.1 IU/ml in 94% and 80% of patients on days 14 and 21, respectively. Serum and CSF asparagine depletion was observed and maintained during induction and intensification in the majority of samples. PEG-ASNase antibody was observed in only 3 patients.
Intensive PEG-ASNase therapy in the treatment of relapsed acute lymphoblastic leukemia reliably results in high-level serum PEG-ASNase activity, and asparagine depletion in serum and CSF is usually achieved. Incorporation of intensive PEG-ASNase in future trials for recurrent acute lymphoblastic leukemia is warranted.
天冬酰胺酶疗法是治疗儿童急性淋巴细胞白血病的重要组成部分。聚乙二醇化天冬酰胺酶（PEG - ASNase）相较于天然大肠杆菌天冬酰胺酶具有显著的药理学优势。我们研究了复发型小儿急性淋巴细胞白血病联合化疗中PEG - ASNase的药代动力学、抗PEG - ASNase抗体的存在情况以及血清和脑脊液（CSF）中天冬酰胺的浓度。
三家儿科机构招募了28例复发型髓性（n = 16）和髓外（n = 11）急性淋巴细胞白血病患儿，并获取至少两份血清和脑脊液样本进行分析。患者接受诱导治疗（包括在第2、9、16和23天每周一次肌肉注射PEG - ASNase 2500 IU/m²）和强化治疗（包括在第7天一次肌肉注射PEG - ASNase 2500 IU/m²）。诱导期和强化期每周采集血清样本。诱导期和强化期治疗性腰椎穿刺时采集脑脊液样本。
在整个诱导期，每周的PEG - ASNase治疗使91 - 100%的患者的PEG - ASNase活性>0.1 IU/ml。在强化期，第7天使用PEG - ASNase后，分别在第14天和第21天使94%和80%的患者的PEG - ASNase活性>0.1 IU/ml。在大多数样本的诱导期和强化期观察到并维持了血清和脑脊液中天冬酰胺的消耗。仅在3例患者中观察到PEG - ASNase抗体。
在复发型急性淋巴细胞白血病治疗中，强化PEG - ASNase治疗可可靠地导致血清中高水平的PEG - ASNase活性，并且通常能实现血清和脑脊液中天冬酰胺的消耗。在未来复发性急性淋巴细胞白血病的试验中纳入强化PEG - ASNase治疗是有必要的。
