Trial Information

Post-marketing Surveillance Study of the Pharmacokinetics of Asparaginase and Antibody Formation in Interfant-06

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