Combination Chemotherapy in Treating Young Patients With Down Syndrome and Acute Myeloid Leukemia or Myelodysplastic Syndromes

PRIMARY OBJECTIVES:

I. Determine the event-free survival (EFS) and overall survival rates in pediatric patients
with Down syndrome (DS) and acute myeloid leukemia AML or myelodysplastic syndromes MDS
treated with induction therapy comprising cytarabine, daunorubicin hydrochloride,
thioguanine, and asparaginase followed by intensification therapy comprising cytarabine and
etoposide.

II. Determine if the EFS rate in these patients can be increased with an intensified course
of cytarabine therapy during induction therapy, compared to the EFS rate of patients in
protocol COG-A2971.

III. Determine if the number of intrathecal chemotherapy treatments can be reduced in these
patients.

IV. Determine if the total cumulative anthracycline dose can be reduced in these patients.

SECONDARY OBJECTIVES:

I. Determine the type and degree of treatment-related toxicity in these patients.

II. Determine the prevalence of leukemia phenotype and globin transcription factor 1 (GATA1)
mutations of DS patients < 4 years of age at diagnosis.

III. Determine the relationship of GATA1 mutations with leukemia phenotype and EFS rates of
DS patients < 4 years of age at diagnosis.

IV. Determine the relationship of minimal residual disease monitored by flow cytometry and
remission status during and after completion of therapy based on bone marrow morphology.

V. Examine parameters of in vitro drug sensitivity and in vivo Ara-C pharmacokinetics.

VI. Examine gene expression profiles by microarrays and the relationship to leukemia
phenotype and outcome.

VII. Examine the relationship of functional polymorphisms in phase I and phase II
detoxification genes and DNA repair pathways that may modify susceptibility to leukemia and
outcome of therapy in DS children.

VIII. Assess the effect of karyotypic abnormalities on survival. IX. Establish a DS leukemia
cell bank for future biological studies.

OUTLINE: This is a nonrandomized, multicenter study.

INDUCTION THERAPY: Patients undergo 4 courses of induction therapy. Each course is 28 days.

COURSE I: Patients receive intrathecal (IT) cytarabine on day 1* and cytarabine IV
continuously over 96 hours, daunorubicin hydrochloride IV continuously over 96 hours, and
oral thioguanine twice daily on days 1-4.

NOTE: *Patients with Central Nervous System (CNS) disease receive cytarabine IT twice weekly
for up to 6 doses; patients with persistent CNS leukemia after 6 doses of IT cytarabine are
removed from the study.

COURSE II: Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1, 2,
8, and 9 and asparaginase intramuscularly (IM) on days 2 and 9.

COURSE III: Patients receive treatment as in course 1.

COURSE IV: Patients receive cytarabine IV, daunorubicin hydrochloride IV, and oral
thioguanine as in course 1.

Induction therapy continues in the absence of disease progression or unacceptable toxicity.
Patients with partial response, relapsed, or refractory disease after completion of course 4
are taken off study. Patients achieving complete response proceed to intensification
therapy.

INTENSIFICATION THERAPY: Patients receive cytarabine IV continuously over 168 hours on days
1-7 and etoposide IV over 1 hour on days 1-3. Treatment repeats every 28 days for 2 courses
in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for 5 years and
then annually thereafter.

Inclusion Criteria:

- Diagnosis DS or DS mosaicism by karyotype or chromosomal analysis

- Diagnosis of myelodysplastic syndromes (MDS) with < 30% blasts or acute myeloid
leukemia (AML)

- Newly diagnosed disease

- Patients with a history of transient myeloproliferative disorder (TMD) are eligible
provided the patient is diagnosed with AML or MDS at > 90 days of age AND meets
either of the following criteria:

- At least 30% blasts in the bone marrow regardless of time since resolution of
TMD

- More than 8 weeks since resolution of TMD with ≥ 5% blasts in the bone marrow

- Immunophenotype required for study entry

- No promyelocytic leukemia

- Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by
radionuclide angiogram

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST or ALT < 2.5 times ULN

- Creatinine adjusted according to age as follows:

- No greater than 0.4 mg/dL (≤ 5 months)

- No greater than 0.5 mg/dL (6 months -11 months)

- No greater than 0.6 mg/dL (1 year-23 months)

- No greater than 0.8 mg/dL (2 years-5 years)

- No greater than 1.0 mg/dL (6 years-9 years)

- No greater than 1.2 mg/dL (10 years-12 years)

- No greater than 1.4 mg/dL (13 years and over [female])

- No greater than 1.5 mg/dL (13 years to 15 years [male])

- No greater than 1.7 mg/dL (16 years and over [male])

- Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min

- No evidence of dyspnea at rest

- No exercise intolerance

- Pulse oximetry > 94%

- No prior chemotherapy, radiotherapy, or any antileukemic therapy

- Intrathecal cytarabine therapy given at diagnosis allowed

- Prior therapy for TMD allowed