Division of Pediatric Hematology/Oncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas.
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
Pediatr Blood Cancer. 2018 Mar;65(3). doi: 10.1002/pbc.26873. Epub 2017 Nov 1.
Erwinia asparaginase is a Food and Drug Administration approved agent for the treatment of acute lymphoblastic leukemia (ALL) for patients who develop hypersensitivity to Escherichia coli derived asparaginases. Erwinia asparaginase is efficacious, but has a short half-life, requiring six doses to replace one dose of the most commonly used first-line asparaginase, pegaspargase, a polyethylene glycol (PEG) conjugated E. coli asparaginase. Pegcristantaspase, a recombinant PEGylated Erwinia asparaginase with improved pharmacokinetics, was developed for patients with hypersensitivity to pegaspargase. Here, we report a series of patients treated on a pediatric phase 2 trial of pegcrisantaspase.
Pediatric patients with ALL or lymphoblastic lymphoma and hypersensitivity to pegaspargase enrolled on Children's Oncology Group trial AALL1421 (Jazz 13-011) and received intravenous pegcrisantaspase. Serum asparaginase activity (SAA) was monitored before and after dosing; immunogenicity assays were performed for antiasparaginase and anti-PEG antibodies and complement activation was evaluated.
Three of the four treated patients experienced hypersensitivity to pegcrisantaspase manifested as clinical hypersensitivity reactions or rapid clearance of SAA. Immunogenicity assays demonstrated the presence of anti-PEG immunoglobulin G antibodies in all three hypersensitive patients, indicating a PEG-mediated immune response.
This small series of patients, nonetheless, provides data, suggesting preexisting immunogenicity against the PEG moiety of pegaspargase and poses the question as to whether PEGylation may be an effective strategy to optimize Erwinia asparaginase administration. Further study of larger cohorts is needed to determine the incidence of preexisting antibodies against PEG-mediated hypersensitivity to pegaspargase.
欧文氏菌 asparaginase 是一种经美国食品药品监督管理局批准的药物，用于治疗对大肠杆菌来源的 asparaginase 产生过敏反应的急性淋巴细胞白血病 (ALL) 患者。欧文氏菌 asparaginase 有效，但半衰期短，需要 6 剂才能替代最常用的一线 asparaginase（聚乙二醇（PEG）缀合的大肠杆菌 asparaginase）pegaspargase 的 1 剂。Pegcristantaspase 是一种重组 PEG 化的欧文氏菌 asparaginase，具有改善的药代动力学特性，是为对 pegaspargase 过敏的患者开发的。在这里，我们报告了一系列在儿科 2 期 pegcrisantaspase 试验中接受治疗的患者系列。
对 ALL 或淋巴母细胞淋巴瘤且对 pegaspargase 过敏的儿科患者在儿童肿瘤学组试验 AALL1421（Jazz 13-011）上注册，并接受静脉注射 pegcrisantaspase。在给药前后监测血清 asparaginase 活性 (SAA)；进行抗 asparaginase 和抗-PEG 抗体免疫原性检测，并评估补体激活情况。
接受治疗的 4 名患者中有 3 名发生了对 pegcrisantaspase 的过敏反应，表现为临床过敏反应或 SAA 的快速清除。免疫原性检测表明，所有 3 名过敏患者均存在抗-PEG 免疫球蛋白 G 抗体，表明存在 PEG 介导的免疫反应。
尽管这一系列患者数量较少，但提供了数据，表明对 pegaspargase 的 PEG 部分存在预先存在的免疫原性，并提出了 PEG 化是否可能是优化欧文氏菌 asparaginase 给药的有效策略的问题。需要进一步研究更大的队列以确定针对 PEG 介导的 pegaspargase 过敏反应的预先存在抗体的发生率。
