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Acute Lymphoblastic Leukaemia

A Guide to Asparaginase and Pegaspargase Therapy

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Summary

The cure rate for children with acute lymphoblastic leukaemia (ALL) has increased to approximately 70%, in part related to the use of the protein synthesis inhibitor drug asparaginase in multiagent chemotherapy regimens. Its lack of haematological toxicity allows its incorporation into phases of therapy in which myelosuppression would be expected either from the disease itself (induction therapy) or secondary to other chemotherapeutic agents (consolidation, intensification or reinduction phases of therapy). Its antileukaemic effect is related to the degree and duration of asparagine depletion.

The 2 native forms of L-asparaginase are derived from Escherichia coli and Ewinia chrysantherni. The half-lives (t½) of these forms are approximately 1.2 and 0.6 days, respectively. In order to increase the biological t½, pegaspargase was synthesised by the covalent attachment of monomethoxypolyethylene glycol (PEG) to native E. coli L-asparaginase: it has a t½, of approximately 5.7 days. The duration of asparagine depletion, the substrate amino acid of the drug, is directly related to asparaginase t½.

Asparaginase is associated with several unique toxicities, including hyperglycaemia, hypolipoproteinaemia, hypoalbuminaemia, coagulation factor deficiencies, hepatotoxicity and pancreatitis. Since asparaginase is a protein, it may induce hypersensitivity reactions. The incidence of these reactions increases with use. In addition, silent hypersensitivity, i.e. the development of IgG antibodies without clinical reactions, results in a decreased t½ of asparaginase, shortened duration of asparagine depletion, and probably decreased efficacy. The use of pegaspargase allows continued treatment with asparaginase in patients with clinical hypersensitivity reactions. In addition, its use in patients with silent hypersensitivity may maintain the efficacy of asparaginase.

So far, the optimal use of the 3 forms of asparaginase has not been determined in children with ALL, partly due to the lack of appropriate pharmacokinetic monitoring methods. As the technology has become available, it has been demonstrated that there is little rationale for the dosage and administration schedules presently in use. Studies are required to determine appropriate dosages and administration methods (intravenous or intramuscular) and schedules for each form of asparaginase, based upon pharmacokinetic parameters. The incidence and time to onset of hypersensitivity (clinical or silent) reactions and the appropriate means of continuing asparaginase therapy with therapeutic effect needs to be evaluated. Pharmacokinetic studies are now available as a research tool. These will allow further investigation to determine if failure to maintain asparagine depletion is a remediable cause of treatment failure.

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Authors and Affiliations

  1. Division of Paediatric Hematology-Oncology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, The Institute for Children with Cancer and Blood Disorders, The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, New Jersey, 08901, USA

    Lawrence J. Ettinger & Alice G. Ettinger

  2. Division of Hematology-Oncology, Childrens Hospital Los Angeles, Los Angeles, California, USA

    Wassilios I. Avramis

  3. Department of Paediatrics, University of Wisconsin Medical Center, Madison, Wisconsin, USA

    Paul S. Gaynon

  4. Children’s Cancer Group, University of Southern California School of Medicine, Arcadia, California, USA

    Lawrence J. Ettinger, Alice G. Ettinger, Wassilios I. Avramis & Paul S. Gaynon

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  1. Lawrence J. Ettinger
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  2. Alice G. Ettinger
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  3. Wassilios I. Avramis
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  4. Paul S. Gaynon
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Correspondence to Lawrence J. Ettinger.

Additional information

1 A review from the Children’s Cancer Group Asparaginase Task Force.

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Ettinger, L.J., Ettinger, A.G., Avramis, W.I. et al. Acute Lymphoblastic Leukaemia. BioDrugs 7, 30–39 (1997). https://doi.org/10.2165/00063030-199707010-00005

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