Pharmacokinetics of Asparaginase and Antibody Formation in Interfant-06
Condition: Leukemia
Study type: Observational

Summary: 
      Asparaginase is an important drug in the treatment of childhood leukemia including in infant
      (<1 year). The prognosis for infants is bad.

      Information about drug metabolism in neonates and infants is scarce as well as the reactions
      of an immature immune system to foreign proteins. The aims of this study is to describe the
      metabolism (pharmacokinetics) of asparaginase after administration intramuscularly and to
      evaluate the formation of antibodies against the drug (enzyme) during treatment in order to
      optimize the asparaginase treatment in infants in the future.
    

Detailed description: 
      Combination chemotherapy for acute lymphoblastic leukaemia (ALL) usually includes a bacterial
      L-asparaginase enzyme derived from Escherichia coli or Erwinia species. Several studies have
      described the pharmacokinetics in children above 1 year of age of asparaginase given
      intramuscularly as well as intravenously. The development of anti-asparaginase antibodies to
      these foreign proteins has also been described.

      Chemotherapy for infant ALL also includes L-asparaginase. However, the pharmacokinetics of
      asparaginase and antibody formation in infants is needed to be described to optimize therapy
      for this group of patients who have a doubtful prognosis.

      Background In general the information about drug metabolism in neonates and infants is scarce
      as well as the reactions of an immature immune system to foreign proteins. Several
      pharmacokinetic studies have been performed in children above one year of age, but no data is
      available about pharmacokinetics and antibody formation during treatment with any
      asparaginase preparation in infants.

      Pharmacokinetics:

      Asparaginase is used in the treatment of childhood ALL since it depletes the blood of
      asparagines, which can be synthesized by normal cells but not by leukemic lymphoblasts. It
      has been shown that serum activities above 100 IU/l ensure depletion of asparagine in serum
      and CNS. In many cases even values considerably lower than 100 IU/l will deplete asparagine
      from the serum1-5.

      In the Interfant-06 protocol the doses of asparaginase are adopted from childhood
      ALL-protocols without scientific foundation. Infants may metabolise asparaginase differently
      and thus may not achieve amino acid depletion.

      Antibody formation:

      Asparaginase is a foreign protein for the human body, so patients may develop antibodies
      against it, resulting in allergic reactions (probably mediated by IgE-antibodies) or silent
      antibodies (IgG antibodies, blocking the effect of the enzyme). In the first case treatment
      most often is stopped and in the second case treatment is insufficient6-7, and thus giving
      the patient a poorer prognosis in both cases.

      In Interfant-06 patients are treated with native E.coli asparaginase for a period followed by
      PEG-asparaginase later during their treatment. Studies in older children have shown that
      approximately 1/3 of the patients develop IgG-antibodies against native E.coli after 5-6
      doses7. Other studies have shown that IgG-antibodies against native E.coli asparaginase
      cross-react with PEG-asparaginase, resulting in a faster clearance of the enzyme8. Allergic
      reactions (any grade) to native E.coli asparaginase are encountered in approximately 30 % of
      children11-12. There is no knowledge about the frequency of antibody formation during
      asparaginase therapy in infants.

      Aim

      The study has the purposes:

        -  to describe the pharmacokinetics of intramuscular native E.coli and PEG-asparaginase in
           children below 1 year at diagnosis

        -  to evaluate antibody formation during asparaginase treatment with E.coli followed by
           PEG-asparaginase in infants
    

Observational model: Case-Only
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Infants (children < 1 year) with ALL treated according to Interfant-06 at one of the
        Pediatric Oncology Centers in the Nordic Countries
      
Biospecimen description: 
      Serum is retained for measurement of enzyme activities and antibodies
    
Keywords: Interfant-06; Infant ALL; Asparaginase; Pharmacokinetics of asparaginase; Antibody formation