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/m 2 intramuscularly weekly on days 2, 9, 16, and 23) and intensification therapy (including PEG-ASNase 2500 IU/m 2 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 PEGASNase 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.

Pharmacodynamics and safety of intravenous pegaspargase during remission induction in adults aged 55 years or younger with newly diagnosed acute lymphoblastic leukemia

“…32 In addition, a single injection of pegaspargase can be given instead of the inconvenient administration of multiple doses of native asparaginase. Pegaspargase has shown antileukemic activity similar to that of E coli asparaginase in children with recurring ALL 39,[42][43][44] who have already been exposed to the native form, as well as in newly diagnosed patients. 19,35 In contrast to children, pharmacokinetic and toxicity data on pegaspargase in adults is very limited.…”

Comparison between Two Erwinia carotovora L-Asparaginase II Constructions: cloning, Heterologous Expression, Purification, and Kinetic Characterization

“…(Hawkins et al, 2004), since the toxicity of the enzyme is partially attributable to the L-glutaminase activity (Howard and Carpenter, 1972). The k cat /K m ratio is an apparent second-order rate constant that determines the specificity for competing substrates (Fersht, 1999).…”

“…This is particularly important, since the glutaminase activity of therapeutic preparations of L-asparaginases II has been implicated in causing side effects such as serious liver disorders, acute pancreatitis, hyperglycemia and immunosuppression (Hawkins et al, 2004;Krasotkina et al, 2004). Interestingly, no report using the sequence of E. carotovora L-asparaginase II mature protein and recombinant DNA technology for its heterologous expression aiming at commercial production are available.…”

The eighth international childhood acute lymphoblastic leukemia workshop (‘Ponte di Legno meeting’) report: Vienna, Austria, April 27–28, 2005

“…In ALL, the modal chromosome number peaks around 47, with a smaller peak at 56-57 chromosomes. The most common chromosomal gain was of X, followed by the trisomies typically found in non-DS ALL (chromosomes 4,6,10,14,17,18,21). Recurrent abnormalities included the ETV6-RUNX1 fusion (n ¼ 12, accounting for 8% overall or 13% of cases diagnosed after 1995), and t(8;14)(q11;q32) (n ¼ 4, or 3%).…”

“…There is an increasing trend towards using the pegylated preparation upfront because of its longer half-life, which permits less frequent injections, and because of its lower immunogenicity, as compared to the native product. [16][17][18] The native E. coli asparaginase has never been considered a viable option in patients who develop allergy to pegylated E. coli asparaginase. Before it was removed from the market in 2002, Erwinase (Erwinia chrysanthemi asparaginase) was the best option for patients who developed allergic reactions to either E. coli preparation.…”