Efficacy and safety of recombinant asparaginase in infants ( < 1 year) with previously untreated acute lymphoblastic leukemia, a phase II clinical trial

Acute Lymphoblastic Leukemia (ALL) is a clonal disease resulting from genetic
mutations and transformations of a single early progenitor lymphoid cell.
Uncontrolled expansion of leukemic blasts in the bone marrow leads to
suppression of normal haematopoieses as well as disseminated infiltration of
organs and release of blasts into the peripheral blood.

ALL is the most common malignancy in childhood accounting for 30% of all
cancers and 80% of all leukemias in this age group. Four % of the patients are
diagnosed int the first year of their life.

The treatment of of ALL depends on the use of intensive multiagent chemotherapy
given for 2 years. In selected patients stem cell transplantation is used.
Patients with ALL are usually treated within a study protocol. In the
Netherlands, infants with newly diagnosed ALL are treated according to the
international Interfant-06 protocol.

ASNase is an essential component of treatment of children with newly diagnosed
ALL. Several recently published data have clearly demonstrated that this drug
contributes to the total treatment outcome of children with ALL by at least
10-20%. It is not known if this percentage is the same in infants. But, allergy
against asparaginase is an important clinical problem, as this may lead to
early interruption of asparaginase therapy, resulting in lower cumulative
asparaginase dose which worsens prognosis.

Recombinant Asparaginase (rASNase) has similar enzymatic , pharmacokinetic and
pharmacodynamic properties as E-coli ASNase but is a much purer preparation.
This new ASNase may therefore cause less hypersensitivity reactions than the
currently approved drugs. In a recent pilot study at ErasmusMC Sophia it was
shown that this drug has similar safety profile as regular native E-coli
derived ASNase, and leads to similar asparagine depletion. Currently a larger
national study is conducted to compare the efficacy and safety of rASNase and
E-coli ASNase in a larger number of children (1-18 yr) with newly diagnosed
ALL. The current study aims the efficacy and safety of recombinant ASNase in
infants (children < 1 yr) with newly diagnosed ALL.

This non-controlled multicentric phase II study is designed to assess the
safety and to describe (in relation to children of higher age) the
pharmacodynamics of recombinant ASNase for first-line treatment of infants (< 1
year of age at diagnosis) with de novo ALL treated according to the
Interfant-06 protocol.

a non-controlled, multicentric phase II clinical trial to evaluate the efficacy
and safety of repeated infusions with recombinant ASNase during induction
treatment of infants with ALL.

Treatment consists of recombinant asparaignase (6 doses) in induction therapy.

The risk and burden of participation are similar to a standard infant ALL
therapy. A potential benefit may arise if we can prove that patients with
recombinant asparaginase indeed have fewer allergic reactions to asparaginase,
which may increase the cumulative asparaginase dose and leads to a better
prognosis for these children. Potential risk factors are associated with the
blood sampling - although this is always combined with regular blood sampling
time points according to the Interfant-06 protocol. All patients will have a
central venous line. New side-effects may occur, although based on chemical, PK
and PD properties of the drug this will be unlikely.