Increase in peg-asparaginase clearance as a predictor for inactivation in patients with acute lymphoblastic leukemia

Abstract

Asparaginase is an essential component of acute lymphoblastic leukemia (ALL) therapy, yet its associated toxicities often lead to treatment discontinuation, increasing the risk of relapse. Hypersensitivity reactions include clinical allergies, silent inactivation, or allergy-like responses. We hypothesized that even moderate increases in asparaginase clearance are related to later inactivation. We therefore explored mandatory monitoring of asparaginase enzyme activity (AEA) in patients with ALL aged 1-45 years treated according to the ALLTogether pilot protocol in the Nordic and Baltic countries to relate mean AEA to inactivation, to build a pharmacokinetic model to better characterize the pharmacokinetics of peg-asparaginase and assess whether an increased clearance relates to subsequent inactivation. The study analyzed 1631 real-time AEA samples from 253 patients, identifying inactivation in 18.2% of the patients. This inactivation presented as mild allergy (28.3%), severe allergy (50.0%), or silent inactivation (21.7%). A pharmacokinetic transit compartment model was used to describe AEA-time profiles, revealing that 93% of patients with inactivation exhibited prior increased clearance, whereas 86% of patients without hypersensitivity maintained stable clearance throughout asparaginase treatment. These findings enable prediction of inactivation and options for either dose increments or a shift to alternative asparaginase formulations to optimize ALL treatment strategies.

Fig. 1. Flowchart illustrating inclusion and exclusion.

Ph+ = Philadelphia chromosome positive acute lymphoblastic leukemia. * Patients with one sample or only samples outside the defined timeslot 14 +/− 2 days from previous dose. One patient had plasmapheresis and samples were not reliable.

Fig. 2. AEA measurements and 95% CI over time in the groups; IM administration, IV administration,

AEA measurements day 1,4,7 and 11 after first dose and AEA C_trough after every dose of peg-asparaginase. Patients with inactivation are illustrated as the blue line (including one patient with IM administered PEG-asparaginase and three patients ≥16 years) and patients in the non-inactivation group as the red, black and green line according to route of administration and age group.

Fig. 3. AEA measurements and 95% CI over time in the groups; Allergic reaction on 3^rd dose, 4^th dose, and 5^th dose compared to no inactivation.

AEA measurements day 1,4,7 and 11 after first dose and AEA C_trough after every dose of peg-asparaginase for patients <16 years (IV administration). Patients without inactivation are shown in red, those experiencing allergic reactions on the 3^rd dose in blue, on the 4^th dose in green, and on the 5^th dose in black.

Fig. 4. Risk of inactivation of peg-asparaginase.

Logistic regression model with AEA seven days after first dose.