Maese Luke, Loh Mignon L, Choi Mi Rim, Agarwal Shirali, Aoki Etsuko, Liang Yali, Lin Tong, Girgis Suzette, Chen Cuiping, Roller Shane, Chandrasekaran Vijayalakshmi, Iannone Robert, Silverman Lewis B, Raetz Elizabeth A, Rau Rachel E
Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Utah, Huntsman Cancer Institute, Primary Children's Hospital, Salt Lake City, UT.
Department of Pediatrics and the Ben Towne Center for Childhood Cancer Research, Seattle Children's Hospital, University of Washington, Seattle, WA.
Blood Adv. 2025 Jan 14;9(1):66-77. doi: 10.1182/bloodadvances.2024013346.
Children's Oncology Group study AALL1931 investigated the efficacy and safety of recombinant Erwinia asparaginase (JZP458) in patients with acute lymphoblastic leukemia/lymphoblastic lymphoma and hypersensitivity reactions/silent inactivation to Escherichia coli-derived asparaginases. Each pegylated Escherichia coli asparaginase dose remaining in a patient's treatment plan was replaced by intramuscular (IM) or IV JZP458 (6 doses) administered Monday/Wednesday/Friday (MWF). Three IM cohorts (1a [25 mg/m2 MWF], n = 33; 1b [37.5 mg/m2 MWF], n = 83; 1c [25/25/50 mg/m2 MWF], n = 51) and 1 IV cohort (25/25/50 mg/m2 MWF, n = 62) were evaluated. The proportion (95% confidence interval [CI]) of patients maintaining nadir serum asparaginase activity (NSAA) levels of ≥0.1 IU/mL at the last 72 (primary end point) and 48 hours during course 1 was 90% (95% CI, 81-98) and 96% (95% CI, 90-100) in IM cohort 1c, respectively, and 40% (95% CI, 26-54) and 90% (95% CI, 82-98) in the IV cohort. Population pharmacokinetic modeling results were comparable with observed data, predicting the vast majority of patients would maintain therapeutic NSAA levels when JZP458 is administered IM or IV 25 mg/m2 every 48 hours, or IM 25/25/50 mg/m2 MWF, or with mixed IM and IV administration (IV/IV/IM 25/25/50 mg/m2 MWF). Drug discontinuation occurred in 23% and 56% of patients in the IM and IV cohorts, respectively; 13% and 33% because of treatment-related adverse events (mainly allergic reactions and pancreatitis). JZP458 achieves therapeutic NSAA levels via multiple IM and IV dosing schedules based on combined observed and modeled data with a safety profile consistent with other asparaginases. This trial was registered at www.ClinicalTrials.gov as #NCT04145531.
儿童肿瘤研究组AALL1931研究调查了重组欧文氏菌天冬酰胺酶（JZP458）在急性淋巴细胞白血病/淋巴细胞淋巴瘤患者以及对大肠杆菌衍生天冬酰胺酶过敏反应/沉默失活患者中的疗效和安全性。患者治疗计划中剩余的每剂聚乙二醇化大肠杆菌天冬酰胺酶均由周一/周三/周五（MWF）肌肉注射（IM）或静脉注射（IV）的JZP458（6剂）替代。评估了3个IM队列（1a [25mg/m² MWF]，n = 33；1b [37.5mg/m² MWF]，n = 83；1c [25/25/50mg/m² MWF]，n = 51）和1个IV队列（25/25/50mg/m² MWF，n = 62）。在第1疗程的最后72小时（主要终点）和48小时，IM队列1c中维持最低血清天冬酰胺酶活性（NSAA）水平≥0.1 IU/mL的患者比例（95%置信区间[CI]）分别为90%（95%CI，81 - 98）和96%（95%CI，90 - 100），IV队列中分别为40%（95%CI，26 - 54）和90%（95%CI，82 - 98）。群体药代动力学建模结果与观察数据相当，预测当每48小时IM或IV给予JZP458 25mg/m²，或IM给予25/25/50mg/m² MWF，或采用IM和IV混合给药（IV/IV/IM 25/25/50mg/m² MWF）时，绝大多数患者将维持治疗性NSAA水平。IM和IV队列中分别有23%和56%的患者停药；13%和33%是由于治疗相关不良事件（主要是过敏反应和胰腺炎）。基于观察和建模数据的综合结果，JZP458通过多种IM和IV给药方案达到治疗性NSAA水平，其安全性与其他天冬酰胺酶一致。该试验已在www.ClinicalTrials.gov上注册，编号为#NCT04145531。
