Transient myeloproliferative disease in children with Down syndrome
Part A: Screening newborns with Down syndrome for TMD
Part B: Treatment and follow-up of children with Down syndrome and TMD

Children with Down syndrome have an increased risk of developing both acute
myeloid leukemia and acute lymphoblastic leukemia. The prognosis of myeloid
leukemia in children with Down syndrome is better than in children without Down
syndrome, which is due to a specific type of myeloid leukemia these children
develop, referred to as *myeloid leukemia of Down syndrome* (ML DS). This
leukemia is characterized by occurrence at a very young age, low diagnostic
white blood cell count (WBC), enhanced chemosensitivity, GATA1 mutations, and
the occurrence of a transient myeloproliferative syndrome (TMD) in newborns.
Due to the enhanced sensitivity to chemotherapy, and to a greater
susceptibility for treatment- related complications, children with ML DS are
usually treated with reduced- intensity treatment protocols. TMD occurs in
approximately 10% of Down syndrome newborns, although this was only studied in
selected populations of hospitalized children. Approximately 15-20% of children
with symptomatic TMD die from their disease, mainly due to liver fibrosis,
effusions, and organomegaly with high WBCs. Furthermore, approximately 20% of
children who survive from TMD subsequently develop ML DS. It is unknown why
only a subgroup of children develops true leukemia at follow-up, and what
drives this progression. It is also unknown if ML-DS can occur without
preceding TMD.

So far, no protocol was available to screen for TMD, and provide uniform
treatment and follow-up guidelines. In this study, we will perform a
population-based screening of DS children in the Netherlands for the occurrence
of TMD, by testing a blood sample that will be drawn within 4 weeks after birth
(part A of the study). As there is a nation-wide registry for children with
Down syndrome, we will be informed about the number of children who will
participate in the screening program. When TMD is diagnosed, children will be
included in the TMD protocol, which provides treatment guidelines for treatment
of symptomatic TMD, and aims at reducing the morbidity and mortality associated
with this disease (part B of the protocol, in collaboration with the AML-BFM
Study Group). The overall aim of part B of the protocol, however, is not only
to reduce the TMD-related morbidity and mortality, but also to reduce the
number of children that subsequently develop ML DS. This is supported by data
from a pilot-study from the AML-BFM SG that showed a reduction in subsequent
ML-DS development when comparing children with symptomatic TMD that had been
treated with children with non-symptomatic TMD that did not receive treatment.
To further study this concept of chemo-prophylaxis, we will also treat TMD
children with persisting residual disease levels, as determined by
flowcytometry or by GATA-1 quantative PCR at week 8 after birth, with low-dose
chemotherapy (cytarabine). The hypothesis is that slow spontaneous clearance of
blasts is a risk-factor for later leukemia development. This study will
therefore also prospectively test whether chemo-prophylaxis of ML DS by
treating the pre-leukemic clone is feasible, and reduces the number of
subsequent leukemias.

Primary aims:
1. To perform a population-based screen to estimate the exact frequency ot
transient leukemia in Dutch newborns with Down syndrome
2. To investigate the realtionship between transient leukemia and the
occurrence of DS ML and ALL at later age.
3. To include children with transient leukemia in the DCOG protocol for
treatment and follow-up of TMD (part B). In this prootcol it is investigated
whether selected children can be saved from the mortality associated with TMD
and whether progression to DS ML can be prevented.

Secondary aims:
1. To indentify novel egnetic aberrations involved in the progression from
transient leukemia to DS ML.
2. To investigate whether ALL in DS children is also preceded by a pre-leukemic
clone detectable in the neonatal blood from DS children.
3. To describe the differences in hematological and clinical parameters between
children with and without transient leukemia.

This is a prospective non-randomzied multicenter study.

All Ducth hospitals with a pediatric ward will be asked for participation in
teh screening part of the protocol. We need to screen 811 evaluabel children
with Down syndrome, which implicates that there is a blood sample available
which allows screening for TMD, and that 3-year follow-up of a particular child
is possible. This means that we have to screen more than 811 children, as some
may be lost to follow-up due to other problems such as cardiac disease, etc.

In case TMD is diagnosed, patients will be referred to a pediatric oncology
center for treament and follow-up of TMD (part B of the study). Children with
TMD may be treated because of disease-related symtoms, or because they do not
sufficiently clear their TMD at the age of 8 weeks. The latter is an new
treatment approach, and is based on preliminary observations from the AML-BFM
SG, who observed that children who were treated showed a lower rate of
progression to DS ML.

To reach the number of children required in part A and B the study will last
around 6 years.

This study includes 2 different types of interventions:

1. chldren included in part A will have to undergo peripheral blood sampling,
in most of the cases in combination with a diagnostic sample, to diagnose
whether transent leukemia is present
- children included in the transient leukemia treatment protocol may be treated
with cytarabine in case of symptomatic transient leukemia or high minimal
residual disease levels. Approximately 30% of children will be treated for this
indication.

The major burden for children without transient leukemia is that they need to
undergo peripheal blood sampling, although this may often be combined with
regular blood sampling needed for clinical care.

Children with TMD will beincluded in the TMD protocol and may be exposed to
cytarabine treatment, in case of clinical symptoms or high minimal residual
disease levels. The latter is a new treatment indication, based on the
assumption that slow clearance of leukemia is associated with later progression
to DS ML. The side-effects of this low-dose chemotherapy are minimal - as
described in the protocol.