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



Status:Recruiting
Conditions:Cancer, Other Indications, Blood Cancer, Blood Cancer, Blood Cancer, Blood Cancer, Hematology
Therapuetic Areas:Hematology, Oncology, Other
Healthy:No
Age Range:Any - 3
Updated:3/17/2019
Start Date:November 23, 2015

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Risk-Stratified Therapy for Acute Myeloid Leukemia in Down Syndrome

This phase III trial studies response-based chemotherapy in treating newly diagnosed acute
myeloid leukemia or myelodysplastic syndrome in younger patients with Down syndrome. Drugs
used in chemotherapy work in different ways to stop the growth of cancer cells, either by
killing the cells, by stopping them from dividing, or by stopping them from spreading.
Response-based chemotherapy separates patients into different risk groups and treats them
according to how they respond to the first course of treatment (Induction I). Response-based
treatment may be effective in treating acute myeloid leukemia or myelodysplastic syndrome in
younger patients with Down syndrome while reducing the side effects.

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
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