Study of Blood Samples From Newborns With Down Syndrome

PRIMARY OBJECTIVES:

I. To further our biological understanding of the natural history of transient
myeloproliferative disorder (TMD) and its relationship to subsequent leukemia by facilitating
the development of a TMD cell and protein bank, and repository of DNA/RNA from
megakaryoblasts for future biological studies.

II. To investigate the biology of TMD molecular changes associated with resolution of TMD or
its conversion to acute myeloid leukemia within each mortality-risk group by conducting GATA1
mutational analyses, hematopoiesis clonality studies, assessment of RAS mutations, and
genomic instability studies using glycophorin A assays.

III. To determine if high-resolution microarray genomic analysis of TMD blasts (using
Affymetrix SNP Genechip technology to assess gene expression, copy number variation, and loss
of heterozygosity) can predict the development of subsequent leukemia.

IV. To determine the relationship of minimal residual disease (monitored by peripheral blood
flow cytometry and GATA1 mutational studies) to clinical remission status and development of
subsequent leukemia within each mortality-risk group of TMD patients.

V. To evaluate the relationship between karyotype (including FISH analysis) and subsequent
leukemia in TMD patients.

VI. To examine pharmacogenetics and in vitro drug sensitivity to cytarabine (MTT assay) in
blasts from TMD patients.

VII. To examine the relationship of functional polymorphisms in Phase I and Phase II drug
detoxification genes, DNA repair, and DNA synthesis pathways that may modify susceptibility
to leukemia and outcome in TMD patients.

VIII. To determine the relationship between fibrosis-associated serum factors (e.g.,
platelet-derived growth factor, transforming growth factor beta, N-terminal peptide of III
procollagen, type IV collagen, and hyaluronic acid) and event-free survival.

OUTLINE: This is a multicenter study.

Patients undergo peripheral blood collection periodically for biomarker analysis. Samples are
analyzed for GATA1 mutations by real-time PCR, polymorphisms, cytogenetics, and K-RAS
mutations, gene expression, drug sensitivity patterns, and minimal residual disease by flow
cytometry.

Patients are followed up periodically for 5 years.

Inclusion Criteria:

- Diagnosis of transient myeloproliferative disorder (TMD) at < 90 days of age and
meeting 1 of the following criteria:

- A diagnosis of Down syndrome or Down syndrome mosaicism AND non-erythroid and
non-lymphoid blasts (any amount) in the peripheral blood verified with a second
sample

- Patients with typical physical characteristics of Down syndrome are allowed
before cytogenetic or FISH confirmation of the diagnosis

- Trisomy 21-positive leukemic blasts documented by biopsy of any organ (including
> 5% non-erythroid/non-lymphoid blasts documented by bone marrow aspirate or
biopsy)

- Infants with isolated trisomy 21 positivity identified only in the leukemic
blasts are allowed

- Institutional immunophenotype characterization is required for study enrollment