ACUTE LYMPHOBLASTIC-LEUKEMIA - A GUIDE TO ASPARAGINASE AND PEGASPARGASE THERAPY

The cure rate for children with acute lymphoblastic leukaemia (ALL) ha s increased to approximately 70%, in part related to the use of the pr otein synthesis inhibitor drug asparaginase in multiagent chemotherapy regimens. Its lack of haematological toxicity allows its incorporatio n into phases of therapy in which myelosuppression would be expected e ither from the disease itself (induction therapy) or secondary to othe r chemotherapeutic agents (consolidation, intensification or reinducti on phases of therapy). Its antileukaemic effect is related to the degr ee and duration of asparagine depletion. The 2 native forms of L-aspar aginase are derived from Escherichia coli and Erwinia chrysanthemi. Th e half-lives (t(1/2)) of these forms are approximately 1.2 and 0.6 day s, respectively. In order to increase the biological t(1/2), pegasparg ase was synthesised by the covalent attachment of monomethoxypolyethyl ene glycol (PEG) to native E. coli L-asparaginase: it has a t(1/2) Of approximately 5.7 days. The duration of asparagine depletion, the subs trate amino acid of the drug, is directly related to asparaginase t(1/ 2). Asparaginase is associated with several unique toxicities, includi ng hyperglycaemia, hypolipoproteinaemia, hypoalbuminaemia, coagulation factor deficiencies, hepatotoxicity and pancreatitis. Since asparagin ase is a protein, it may induce hypersensitivity reactions. The incide nce of these reactions increases with use. In addition, silent hyperse nsitivity, i.e. the development of Ige antibodies without clinical rea ctions, results in a decreased t(1/2) of asparaginase, shortened durat ion of asparagine depletion, and probably decreased efficacy. The use of pegaspargase allows continued treatment with asparaginase in patien ts with clinical hypersensitivity reactions. In addition, its use in p atients with silent hypersensitivity may maintain the efficacy of aspa raginase. So far, the optimal use of the 3 forms of asparaginase has n ot been determined in children with ALL, partly due to the lack of app ropriate pharmacokinetic monitoring methods. As the technology has bec ome 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 meth ods (intravenous or intramuscular) and schedules for each form of aspa raginase, based upon pharmacokinetic parameters. The incidence and tim e 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 availabl e as a research tool. These will allow further investigation to determ ine if failure to maintain asparagine depletion is a remediable cause of treatment failure.