Prolonged first-line PEG-asparaginase treatment in pediatric acute lymphoblastic leukemia in the NOPHO ALL2008 protocol-Pharmacokinetics and antibody formation

Background: As pegylated asparaginase is becoming the preferred first-line asparaginase preparation in the chemotherapy regimens of childhood acute lymphoblastic leukemia (ALL), there is a need to evaluate this treatment. Methods: The aim of this study was to evaluate the pharmacokinetics of prolonged upfront biweekly PEG-asparaginase (where PEG is polyethylene glycol) treatment by measuring serum l-asparaginase activity and formation of anti-PEG-asparaginase antibodies. A total of 97 evaluable patients (1-17 years), diagnosed with ALL, and treated according to the NOPHO ALL2008 protocol (where NOPHO is Nordic Society of Paediatric Haematology and Oncology) were included. In the NOPHO ALL2008 protocol, patients are randomized to 8 or 15 doses of intramuscular PEG-asparaginase (Oncaspar (R)) 1,000 IU/m(2)/dose, at 2-week or 6-week intervals with a total of 30-week treatment (Clinical trials.gov. no.: NCT00819351). Results: The pharmacological target of treatment (l-asparaginase activity above 100 IU/l) was reached in 612 of 652 (94%) samples obtained 142 days after PEG-asparaginase administration. Mean l-asparaginase activity was 338 IU/l. Six patients had l-asparaginase activity below 50 IU/l in all samples. A total of 25 patients (26%) developed Immunoglobulin G (IgG) anti-PEG-asparaginase antibodies, but there was no correlation between anti-PEG-asparaginase antibodies and low levels of asparaginase activity. Conclusion: We conclude that prolonged first-line biweekly PEG-asparaginase therapy, 1,000 IU/m(2)/dose was above the pharmacological target in the vast majority of patients. Presence of anti-PEG-asparaginase antibodies was not a predictor of l-asparaginase activity.