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


METHODS
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.
Hawkins
Douglas S
DS
Children's Hospital and Regional Medical Center, Seattle, Washington 98105-0371, USA. doug.hawkins@seattlechildrens.org
Park
Julie R
JR
Thomson
Blythe G
BG
Felgenhauer
Judy L
JL
Holcenberg
John S
JS
Panosyan
Eduard H
EH
Avramis
Vassilios I
VI
D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001215:Asparaginase / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity; D001216:Asparagine / Q000097:blood / Q000134:cerebrospinal fluid; D002648:Child; D002675:Child, Preschool; D003692:Delayed-Action Preparations; D005260:Female; D005973:Glutamine / Q000097:blood; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D011092:Polyethylene Glycols / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D012008:Recurrence
D003692:Delayed-Action Preparations; D005973:Glutamine; D011092:Polyethylene Glycols; D001216:Asparagine; C042705:pegaspargase; D001215:Asparaginase