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.
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.
Avramis
Vassilios I
VI
Children's Hospital, Los Angeles, CA, USA. vavramis@chla.usc.edu
Sencer
Susan
S
Periclou
Antonia P
AP
Sather
Harland
H
Bostrom
Bruce C
BC
Cohen
Lewis J
LJ
Ettinger
Alice G
AG
Ettinger
Lawrence J
LJ
Franklin
Janet
J
Gaynon
Paul S
PS
Hilden
Joanne M
JM
Lange
Beverly
B
Majlessipour
Fataneh
F
Mathew
Pracad
P
Needle
Michael
M
Neglia
Joseph
J
Reaman
Gregory
G
Holcenberg
John S
JS
Stork
Linda
L
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
D000596:Amino Acids; D000906:Antibodies; D011092:Polyethylene Glycols; C042705:pegaspargase; D001215:Asparaginase