PEG-Asparaginase (PEG-ASNase) is a key component in the treatment of pediatric Acute Lymphoblastic Leukemia (ALL). Hypersensitivity reactions and silent inactivation remain relevant challenges. Historically, premedication has been avoided due to concerns about masking allergic reactions, but recent studies suggest it may reduce clinical hypersensitivity and the need to switch formulations.

To evaluate the impact of premedication on PEG-ASNase activity, hypersensitivity reactions and inactivation in children with de novo ALL.

Prospective, multicenter, randomised trial including patients under 18-years of age with ALL and treated with PEG- ASNase between February 2021 and September 2024 at nine Brazilian hospitals. Patients were randomized into two groups: Group 1 received premedication (corticosteroid and antihistamine) before each PEG-ASNase infusion and Group 2 received PEG-ASNase without premedication (control group). Asparaginase Enzyme Activity (AEA) was assessed at 7±2 days and 14±2 days after each dose.

441 patients were included: 216 (49%) in the premedication group and 225 (51%) in the control group. Groups were comparable in terms of age, gender, risk stratification and ALL subtype. Clinical hypersensitivity occurred in 43 (10%) patients and silent inactivation in 58 (13%) patients (AEA < 0.1 IU/mL). Premedication did not affect the rate of hypersensitivity (p = 0.525), inactivation (p = 1.000) or AEA levels (p=0.627). Inactivation was significantly associated with hypersensitivity (p < 0.001) and AEA levels were lower in patients with clinical allergy on days 7±2 and 14±2 (p = 0.003). The incidence of silent inactivation was 8% (95% CI 6.7% to 13.1%; p < 0.0001).

This multicenter, prospective and randomized study provides robust evidence that premedication does not reduce clinical hypersensitivity or silent inactivation of PEG-asparaginase in pediatric ALL. Given the absence of benefit and the potential for increased costs and masking of reactions, the routine use of premedication in this context should be reconsidered. Our findings support a shift in clinical practice toward more judicious use of premedication, reserving it for selected cases rather than as a standard approach.