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Blood, 15 March 2002, Vol. 99, No. 6, pp. 1986-1994
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
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
Vassilios I. Avramis,
Susan Sencer,
Antonia P. Periclou,
Harland Sather,
Bruce C. Bostrom,
Lewis J. Cohen,
Alice G. Ettinger,
Lawrence J. Ettinger,
Janet Franklin,
Paul S. Gaynon,
Joanne M. Hilden,
Beverly Lange,
Fataneh Majlessipour,
Pracad Mathew,
Michael Needle,
Joseph Neglia,
Gregory Reaman, and
John S. Holcenberg
From Children's Hospital Los Angeles, CA; Children's
Hospitals and Clinics and the University of Minnesota, Minneapolis, MN;
Children's Cancer Group, Arcadia, CA; Rhone-Poulenc Rorer Inc,
Collegeville, PA; Saint Peter's University Hospital, New Brunswick,
NJ; Children's Hospital and Clinics, St Paul, MN; University of New
Mexico, Albuquerque; Children's Hospital of Philadelphia, PA;
Children's National Medical Center, Washington, DC; and Children's
Hospital Medical Center, Seattle, WA.
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.
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