Pharmacokinetics and Immunogenicity of the First Doses of Peg-Asparaginase -an Alltogether Pilot Study

Background and aim PEG-asparaginase is an indispensable part of the multiagent treatment of acute lymphoblastic leukemia (ALL). However, PEG-asparaginase treatment comes with substantial toxicity leading to discontinuation of therapy, which increases the risk of relapse. The most common toxicity is hypersensitivity, defined as either clinical allergy (13-15%) or silent inactivation (4-10%) both associated with increased clearance and inactivation of PEG-asparaginase. Asparaginase enzyme activity (AEA) measurements are widely used as Therapeutic Drug Monitoring (TDM).

TDM is commonly used to distinguish true allergy associated with inactivation of asparaginase from allergy like reactions where PEG-asparaginase treatment can be continued. TDM is included in most contemporary protocols. Pharmacokinetic (PK) analyses are essential in detecting inactivation of PEG-asparaginase and optimizing PEG-asparaginase treatment. However, TDM evaluated in PK analyses has never been shown reliable to predict hypersensitivity.

Therefore, we aimed to investigate the possibility to identify PK parameters to predict hypersensitivity before the allergic reaction occurred.

Methods Patients with ALL aged 1-45 years treated according to the ALLTogether Pilot Protocol from December2018 to December 2021 in the Nordic and Baltic countries were eligible. A total of 2,228 AEA samples from 219 pediatric and 43 adult patients were analyzed real-time for AEA.

A transit compartment model to characterize the PK of PEG-asparaginase was developed, representing increased clearance over time. AEA was represented by the sum of all compartments.

Results Inactivation of PEG-asparaginase was identified in 44 of 256 patients (17.2%); 9 patients with silent inactivation (20.5%), 12 patients with mild allergy (27.3%) and 23 patients with severe allergy (52.3%). Hypersensitivity mainly occurred after 4^th (n=22 (50%)) or 5^th (n=6 (13.6%)) dose.

A 10-compartmental transit model that allowed an exponential increase in clearance over time described the AEA-time profile best. The model divided patients into stable or exponentially increasing clearance over time. All patients with inactivation of PEG-asparaginase demonstrated an increased clearance over time. Patients with clinical symptoms demonstrated the most prominent increase.

Conclusions PK analysis of AEA enables early identification of increased clearance, which opens new possibilities to predict inactivation of PEG-asparaginase and provides ability to intervene before inactivation of PEG-asparaginase occurs. PK analysis of AEA in addition holds the possibility to reduce the dose of PEG-asparaginase in order to minimize the risk of toxicity while continuously maintaining AEA in the therapeutic range.

Friberg:Pharmetheus AB: Consultancy, Current holder of stock options in a privately-held company. Karlsson:Servier, Roche, Bayer, Merck: Research Funding. Heyman:Amgen: Consultancy, Research Funding; Servier: Research Funding; Pfizer: Research Funding; NovaLab: Research Funding; Swedish Childhood Cancer FundFoundation: Current Employment, Research Funding. Griskevicius:Miltenyi Biomedicine: Membership on an entity's Board of Directors or advisory committees. Schmiegelow:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Research Funding; Amgen: Speakers Bureau; Medscape: Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Illumina: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Albertsen:Jazz: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Erytech Pharma: Membership on an entity's Board of Directors or advisory committees, Other: Financial support to investigator initiated Phase II study.