Asparaginase pharmacokinetics after intensive polyethylene glycol-conjugated L-asparaginase therapy for children with relapsed acute lymphoblastic leukemia.

Abstract

PURPOSE:

Asparaginase therapy is an important component in the treatment of children with acute lymphoblastic leukemia. Polyethylene glycol-conjugated asparaginase (PEG-ASNase) has significant pharmacological advantages over native Escherichia coli asparaginase. We investigated the pharmacokinetics of PEG-ASNase, presence of antibodies to PEG-ASNase, and concentrations of asparagine in serum and cerebrospinal fluid (CSF) in combination chemotherapy for relapsed pediatric acute lymphoblastic leukemia.

EXPERIMENTAL DESIGN:

Twenty-eight pediatric patients with relapsed medullary (n = 16) and extramedullary (n = 11) acute lymphoblastic leukemia were enrolled at three pediatric institutions and had at least two serum and CSF samples obtained for analysis. Patients received induction therapy (including PEG-ASNase 2500 IU/m2 intramuscularly weekly on days 2, 9, 16, and 23) and intensification therapy (including PEG-ASNase 2500 IU/m2 intramuscularly once on day 7). Serum samples were obtained weekly during induction and intensification. CSF samples were obtained during therapeutic lumbar punctures during induction and intensification.

RESULTS:

Weekly PEG-ASNase therapy resulted in PEG-ASNase activity of >0.1 IU/ml in 91-100% of patients throughout induction. During intensification, PEG-ASNase on day 7 resulted in PEG-ASNase activity >0.1 IU/ml in 94% and 80% of patients on days 14 and 21, respectively. Serum and CSF asparagine depletion was observed and maintained during induction and intensification in the majority of samples. PEG-ASNase antibody was observed in only 3 patients.

CONCLUSIONS:

Intensive PEG-ASNase therapy in the treatment of relapsed acute lymphoblastic leukemia reliably results in high-level serum PEG-ASNase activity, and asparagine depletion in serum and CSF is usually achieved. Incorporation of intensive PEG-ASNase in future trials for recurrent acute lymphoblastic leukemia is warranted.

• Authors: Douglas S Hawkins, Julie R Park, Blythe G Thomson, Judy L Felgenhauer, John S Holcenberg, Eduard H Panosyan, Vassilios I Avramis
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 16 Pg. 5335-41 (Aug 15 2004) ISSN: 1078-0432 [Print] United States
• PMID: 15328169 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Delayed-Action Preparations
• Glutamine
• Polyethylene Glycols
• Asparagine
• pegaspargase
• Asparaginase

Topics

• Adolescent
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Asparaginase (pharmacokinetics, therapeutic use, toxicity)
• Asparagine (blood, cerebrospinal fluid)
• Child
• Child, Preschool
• Delayed-Action Preparations
• Female
• Glutamine (blood)
• Humans
• Immunophenotyping
• Male
• Polyethylene Glycols (pharmacokinetics, therapeutic use, toxicity)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy)
• Recurrence