Protocol ALL-11:Treatment study protocol of the Dutch Childhood Oncology Group for children and adolescents (1-19 year) with newly diagnosed acute lymphoblastic leukemia

Treatment study protocol of the Dutch Childhood Oncology Group for children and
adolescents (1-19 year) with newly diagnosed acute lymphoblastic leukemia.

Since 1999, infants with ALL diagnosed <1 year of age are treated on specific
protocols of the Interfant collaborative group. Patients with the Philadelphia
chromosome positive ALL chromosomes are treated on specific protocols of the
EsPhALL group since 2004. All other ALL patients were treated according to the
ALL-10 protocol that started in 2004. This treatment protocol included 3
different stratification arms (standard risk, medium risk and high risk) which
are very different in their intensity. The factors used for risk group
stratification in the ALL-10 protocol were the presence of t[4;11], a poor
response to initial therapy, as measured in the peripheral blood by response to
prednisone and one intrathecal dose of methotrexate (MTX) after one week of
therapy (so-called prednisone response), induction failure after 33 days of
combination chemotherapy and the minimal residual disease measured by PCR at
day 33 and day 79. The ALL-10 protocol was the first DCOG protocol where
therapy stratification was done by analysis of MRD. MRD was used for this
purpose because an earlier study showed that MRD had a very strong prognostic
value: patients with very low levels of MRD (standard risk group) had an
excellent outcome, patients with high levels of MRD (high risk group) a poor
outcome and patients with intermediate levels (medium risk group) had an
intermediate outcome.

The ALL-10 protocol is - based upon its very good outome - used as basis for
the ALL-11 protocol.

1. To improve the overall outcome as compared to the previous protocols of the
DCOG, especially ALL-9 and ALL-10.
This is aimed for by decreasing therapy for part of the patients (TEL/AML1,
Down syndrome, PPR only), increasing therapy for IKZF1 mutated cases,
decreasing the cumulative dose of anthracyclines, omitting cranial irradiation
and total body irradiation and individualizing asparaginase therapy for all
patients.

2. Does a continuous schedule of Asparaginase lead to less allergic
reaction/inactivation of Asparaginase than the standard non continuous schedule
of Asparaginase?
Patients are randomized to receive noncontinuous PEGasparaginase in IA
(induction) and intensification of the Medium Risk group (standard arm A) or to
receive continuous PEGasparaginase in IA, IB, M and intensification,
(continuous arm B) with the same cumulative number of doses of PEGasparaginase.

3. Does prophylactic administration of intravenous immunoglobulins reduce the
number of infections during the intensive treatment phases?
Patients are randomized in the induction and MR treatment group to receive or
not receive prophylactic immunoglobulins

4. Individualize the dose schedule of asparaginase by therapeutic drug
monitoring in order to detect silent inactivation of asparaginase, to prevent
allergic/anaphylactic reactions, to switch Asparaginase preparation in time and
to prevent too high levels with possible toxicity.

National multicenter open-label randomized clinical trial (Phase III)

1) Stratificatie into risk groups, based upon riskfactors
Standard risk (SR) group:
* MRD-negativity at TP1 (day 33) and at TP2 (day 79 before start of Protocol M)
AND
* no CNS involvement or testis involvement at diagnosis AND
* no prednisone poor response at day 8 AND
* absence of any HR criterion
Medium risk (MR) group
* inconclusive/missing MRD results or MRD-positivity at TP1 (day 33) and/or at
TP2 (day 79 before the start of protocol M), but MRD level at day 79 < 10*3
AND
* absence of any HR criterion
High Risk (HR) group:
* MRD level > 10-3 or unknown at TP1 and MRD level of * 10*3 at TP2, OR
* presence of the t(4;11)(q11;q23) translocation or the corresponding fusion
gene MLL/AF4, OR
* no complete remission at day 33
* Note: children with Down syndrome that fulfill the HR criteria are assigned
to the MR group

2) Randomisations:
A. Does a continuous schedule of Asparaginase lead to less allergic
reaction/inactivation of Asparaginase than the standard non continuous schedule
of Asparaginase?
Patients are randomized to receive noncontinuous PEGasparaginase in IA
(induction) and intensification of the Medium Risk group (standard arm A) or to
receive continuous PEGasparaginase in IA, IB, M and intensification,
(continuous arm B) with the same cumulative number of doses of PEGasparaginase.

B. Does prophylactic administration of intravenous immunoglobulins reduce the
number of infections during the intensive treatment phases?
Patients are randomized in the induction and MR treatment group to receive or
not receive prophylactic immunoglobulins

Randomisations:

A. Does a continuous schedule of Asparaginase lead to less allergic
reaction/inactivation of Asparaginase than the standard non continuous schedule
of Asparaginase?
Patients are randomized to receive noncontinuous PEGasparaginase in IA
(induction) and intensification of the Medium Risk group (standard arm A) or to
receive continuous PEGasparaginase in IA, IB, M and intensification,
(continuous arm B) with the same cumulative number of doses of PEGasparaginase.

B. Does prophylactic administration of intravenous immunoglobulins reduce the
number of infections during the intensive treatment phases?
Patients are randomized in the induction and MR treatment group to receive or
not receive prophylactic immunoglobulins.

Patients may suffer from additional burden and risk due to the IVIg
administrations. However, this study aims at reducing the risk of serious
infections, and therefore we feel that the additional burden an drisks may be
justified.