Response-Based Chemotherapy in Treating Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome in Younger Patients with Down Syndrome
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: * Patient 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 * Patient 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) * For patients who do not meet criteria for AML or MDS as outlined above; patient has a history of transient myeloproliferative disorder (which may or may not have required chemotherapy intervention and: ** Is > 8 weeks since resolution of transient myeloproliferative disease (TMD) with >= 5% blasts, OR ** Has 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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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 in case of relapse.
Trial Phase Phase III
Trial Type Treatment
Lead Organization
Children's Oncology Group
Principal Investigator
Jason Noah Berman
- Primary ID AAML1531
- Secondary IDs NCI-2015-00324, s16-01673
- Clinicaltrials.gov ID NCT02521493