title: A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study.
abstract: For this study, 118 children with standard-risk acute lymphoblastic leukemia (ALL) were given randomized assignments to receive native or pegylated Escherichia coli asparaginase as part of induction and 2 delayed intensification phases. Patients treated with pegaspargase had more rapid clearance of lymphoblasts from day 7 and day 14 bone marrow aspirates and more prolonged asparaginase activity than those treated with native asparaginase. In the first delayed intensification phase, 26% of native asparaginase patients had high-titer antibodies, whereas 2% of pegaspargase patients had those levels. High-titer antibodies were associated with low asparaginase activity in the native arm, but not in the pegaspargase arm. Adverse events, infections, and hospitalization were similar between arms. Event-free survival at 3 years was 82%. A population pharmacodynamic model using the nonlinear mixed effects model (NONMEM) program was developed that closely fit the measured enzyme activity and asparagine concentrations. Half-lives of asparaginase were 5.5 days and 26 hours for pegaspargase and native asparaginase, respectively. There was correlation between asparaginase enzymatic activity and depletion of asparagine or glutamine in serum. In cerebrospinal fluid asparagine, depletion was similar with both enzyme preparations. Intensive pegaspargase for newly diagnosed ALL should be tested further in a larger population.
authors.affiliation: Children's Hospital, Los Angeles, CA, USA. vavramis@chla.usc.edu
authors.forename: Vassilios I
authors.initials: VI
authors.lastname: Avramis
authors.forename: Susan
authors.initials: S
authors.lastname: Sencer
authors.forename: Antonia P
authors.initials: AP
authors.lastname: Periclou
authors.forename: Harland
authors.initials: H
authors.lastname: Sather
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Bostrom
authors.forename: Lewis J
authors.initials: LJ
authors.lastname: Cohen
authors.forename: Alice G
authors.initials: AG
authors.lastname: Ettinger
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Ettinger
authors.forename: Janet
authors.initials: J
authors.lastname: Franklin
authors.forename: Paul S
authors.initials: PS
authors.lastname: Gaynon
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Hilden
authors.forename: Beverly
authors.initials: B
authors.lastname: Lange
authors.forename: Fataneh
authors.initials: F
authors.lastname: Majlessipour
authors.forename: Pracad
authors.initials: P
authors.lastname: Mathew
authors.forename: Michael
authors.initials: M
authors.lastname: Needle
authors.forename: Joseph
authors.initials: J
authors.lastname: Neglia
authors.forename: Gregory
authors.initials: G
authors.lastname: Reaman
authors.forename: John S
authors.initials: JS
authors.lastname: Holcenberg
authors.forename: Linda
authors.initials: L
authors.lastname: Stork
mesh_terms: D000596:Amino Acids / Q000097:blood; D000906:Antibodies / Q000097:blood; D001215:Asparaginase / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics*; D001711:Biotransformation; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004926:Escherichia coli / Q000201:enzymology; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000188:drug therapy*; D012449:Safety; D013810:Therapeutic Equivalency; D016896:Treatment Outcome
chemical_list: D000596:Amino Acids; D000906:Antibodies; D011092:Polyethylene Glycols; C042705:pegaspargase; D001215:Asparaginase