Response-Based Chemotherapy in Treating Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome in Younger Patients With Down Syndrome

PRIMARY OBJECTIVES:

I. To determine the 2-year event-free-survival (EFS) for children with standard risk Down
syndrome (DS) acute myeloid leukemia (AML) (minimal residual disease [MRD]-negative after one
cycle of induction therapy) after elimination of high dose (HD) Ara-C (cytarabine) from the
treatment regimen.

II. To determine the 2-year EFS for children with high risk DS AML (MRD-positive after one
cycle of induction therapy) after intensification of treatment equivalent to that used for
high risk AML in children without DS.

EXPLORATORY OBJECTIVES:

I. To compare the feasibility and analytical characteristics of flow cytometry, polymerase
chain reaction (PCR) and targeted error-corrected sequencing of GATA binding protein 1
(globin transcription factor 1) (GATA1) mutations as methods to detect MRD in DS AML.

II. To establish a DS AML cell bank of viably frozen bone marrow samples collected at the end
of induction and corresponding non-tumor deoxyribonucleic acid (DNA) samples collected at end
of Induction 1.

OUTLINE:

INDUCTION I: Patients receive cytarabine intrathecally (IT) on day 1 and intravenously (IV)
continuously over 96 hours, daunorubicin hydrochloride IV over 1-15 minutes, and thioguanine
orally (PO) twice daily (BID) on days 1-4. Induction I continues for a minimum of 28 days.

Patients are assigned to 1 of 2 treatment arms based on their MRD status after completion of
Induction I.

ARM A (STANDARD RISK) (Closed to accrual and treatment with amendment #4A 01/07/2019):

INDUCTION II: Patients receive cytarabine IV continuously over 96 hours, daunorubicin
hydrochloride IV over 1-15 minutes, and thioguanine PO BID on days 1-4. Induction II
continues for a minimum of 28 days.

INDUCTION III: Patients receive cytarabine, daunorubicin hydrochloride, and thioguanine as in
Induction II. Induction III continues for a minimum of 28 days.

INTENSIFICATION I: Patients receive cytarabine IV continuously over 168 hours on days 1-7 and
etoposide IV over 60-120 minutes on days 1-3. Intensification I continues for a minimum of 28
days.

INTENSIFICATION II: Patients receive cytarabine and etoposide as in Intensification I.
Intensification II continues for a minimum of 28 days.

ARM B (HIGH RISK):

INDUCTION II: Patients receive high dose cytarabine IV over 1-3 hours every 12 (Q12) hours on
days 1-4 and mitoxantrone hydrochloride IV over 15-30 minutes on days 3-6. Induction II
continues for a minimum of 28 days.

INTENSIFICATION I: Patients receive high dose cytarabine IV over 1-3 hours Q12 hours and
etoposide IV over 90-120 minutes on days 1-5. Intensification I continues for a minimum of 28
days.

INTENSIFICATION II: Patients receive high dose cytarabine IV over 3 hours Q12 hours on days
1, 2, 8, and 9. Patients also receive asparaginase or asparaginase Erwinia chrysanthemi (E.
carotovora) intramuscularly (IM) or IV over 30 minutes on days 2 and 9. Intensification II
continues for a minimum of 28 days.

After completion of study treatment, patients are followed up at 1 month, monthly for 12
months, every 3 months for 12 months, every 6 months for 3 years, annually for 10 years, and
then at relapse.

Inclusion Criteria:

- Patients must have constitutional trisomy 21 (Down syndrome) or trisomy 21 mosaicism
(by karyotype or fluorescence in situ hybridization [FISH])

- Patient has one of the following:

- Patients has previously untreated de novo AML and meets the criteria for AML with
>= 20% bone marrow blasts as set out in the World Health Organization (WHO)
Myeloid Neoplasm classification

- Attempts to obtain bone marrow either by aspirate or biopsy must be made
unless clinically prohibitive; in cases where it is clinically prohibitive,
peripheral blood with an excess of 20% blasts and in which adequate flow
cytometric and cytogenetics/FISH testing is feasible can be substituted for
the marrow exam at diagnosis

- Patients has cytopenias and/or bone marrow blasts but does not meet the criteria
for the diagnosis of AML (WHO Myeloid Neoplasm classification) because of < 20%
marrow blasts and meets the criteria for a diagnosis of myelodysplastic syndrome
(MDS)

- Patients has a history of transient myeloproliferative disorder (which may or may
not have required chemotherapy intervention), who:

- Are > 8 weeks since resolution of transient myeloproliferative disease (TMD) with
>= 5% blasts, OR

- Patients who have an increasing blast count (>= 5%) in serial bone marrow
aspirates performed at least 4 weeks apart

- Children who have previously received chemotherapy, radiation therapy or any
anti-leukemic therapy are not eligible for this protocol, with the exception of
cytarabine for the treatment of TMD

- There are no minimal organ function requirements for enrollment on this study

- Note: Previous cardiac repair with sufficient cardiac function is not an
exclusion criteria

- Each patient?s parents or legal guardians must sign a written informed consent

- All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human subjects research must be met

Exclusion Criteria:

- Patients with promyelocytic leukemia (French-American-British [FAB] M3)

- Prior therapy

- Patients =< 30 days from the last dose of cytarabine used for treatment of TMD