Early prediction of subsequent peg-asparaginase inactivation in acute lymphoblastic leukaemia patients-A NOPHO...

Polyethylene glycol (peg)-asparaginase plays a crucial role in acute lymphoblastic leukaemia (ALL) treatment, yet its associated toxicity often leads to treatment discontinuation, elevating relapse risk. Hypersensitivity with inactivation of asparaginase is common and often associated with severe allergic reactions. This study aims to comprehensively analyse asparaginase enzyme activity (AEA) pharmacokinetics, validate a previously developed pharmacokinetic model based on intravenous administration and evaluate its capability to detect changes in clearance before inactivation in patients treated with intramuscular peg-asparaginase. The study, covering 644 patients aged 1-45 with ALL under the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 Protocol (February 2017-December 2022, in Nordic and Baltic countries), included 3003 AEA samples. Sampling occurred 14 days post peg-asparaginase doses, with additional sampling between doses. The incidence of inactivation was 15.2%. Utilizing the pharmacokinetic model, estimates revealed an 87.8% sensitivity and 65.5% specificity for detecting increased peg-asparaginase clearance over time in patients experiencing inactivation. Identification of increased clearance preceding inactivation in the NOPHO ALL2008 dataset highlights the potential of pharmacokinetic sampling to predict inactivation and enable timely intervention before clinical manifestation, with further refinement and inclusion of additional protocols into a unified model offering the promise of improving clinicians' ability to assess individual patient risk.