PEG-Asparaginase (PEG-ASNase) is essential in the treatment of pediatric Acute Lymphoblastic Leukemia (ALL). While mortality has declined, treatment-related toxicities, particularly non-immunogenic ones, remain underreported, especially in multicenter prospective studies.

To characterize the incidence and clinical profile of non-immunogenic toxicities associated with PEG-ASNase in Brazilian children receiving first-line treatment for ALL.

This prospective, multicenter, randomized study enrolled patients < 18-years with ALL treated at nine Brazilian centers between February 2021 and September 2024. Participants were randomised into two groups: one receiving premedication (corticosteroid + antihistamine) before each PEG-ASNase infusion and a control group without premedication. Asparaginase Enzyme Activity (AEA) was monitored in all patients.

A total of 441 patients were included (216 with premedication; 225 without premedication). Groups were comparable regarding age, gender, risk stratification and ALL subtype. The overall incidence of non-immunogenic toxicities was as follows: hypofibrinogenemia (24.3%), hypertriglyceridemia (13.2%), hepatotoxicity (5.0%), thrombosis (4.3%), pancreatitis (3.4%), hyperglycemia (3.4%), nephrotoxicity (1.8%) and hemorrhage (0.7%). Premedication and PEG-ASNase inactivation were not associated with significant differences in toxicity rates (p>0.05). However, Poisson regression revealed a significant association between AEA levels and both pancreatitis and hypertriglyceridemia. Thrombosis was more frequent in older children, while pancreatitis was associated with female sex (p < 0.05).

This is the first prospective, randomized and multicenter Brazilian study to assess non-immunogenic toxicities related to PEG-ASNase in pediatric ALL. Overall, toxicity rates were lower than previously reported. Despite some limitations, the findings offer valuable clinical insights and inform practical recommendations on toxicity suspicion, diagnosis and management.