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

This study is ongoing, but not recruiting participants.
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group Identifier:
First received: August 24, 2006
Last updated: March 16, 2016
Last verified: March 2016
This phase III trial is studying how well combination chemotherapy works in treating young patients with Down syndrome and acute myeloid leukemia or myelodysplastic syndromes. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

Condition Intervention Phase
Childhood Acute Basophilic Leukemia
Childhood Acute Eosinophilic Leukemia
Childhood Acute Erythroleukemia (M6)
Childhood Acute Megakaryocytic Leukemia (M7)
Childhood Acute Minimally Differentiated Myeloid Leukemia (M0)
Childhood Acute Monoblastic Leukemia (M5a)
Childhood Acute Monocytic Leukemia (M5b)
Childhood Acute Myeloblastic Leukemia With Maturation (M2)
Childhood Acute Myeloblastic Leukemia Without Maturation (M1)
Childhood Acute Myelomonocytic Leukemia (M4)
Childhood Myelodysplastic Syndromes
de Novo Myelodysplastic Syndromes
Secondary Acute Myeloid Leukemia
Secondary Myelodysplastic Syndromes
Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies
Drug: asparaginase
Drug: daunorubicin hydrochloride
Drug: cytarabine
Drug: thioguanine
Drug: etoposide
Other: laboratory biomarker analysis
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: The Treatment of Down Syndrome Children With Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) Under the Age of 4 Years

Resource links provided by NLM:

Further study details as provided by Children's Oncology Group:

Primary Outcome Measures:
  • Event-free Survival (EFS) at 3 Years [ Time Frame: Time from study entry to induction failure, relapse, or death assessed at 3 years. ] [ Designated as safety issue: No ]
  • Overall Survival (OS) at 3 Years [ Time Frame: Time from study entry to death, assessed at 3 years. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Induction Remission Rate [ Time Frame: End of induction therapy ] [ Designated as safety issue: No ]
  • Percentage of Patients Experiencing Grade 3 or 4 Toxicity Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 [ Time Frame: From the beginning of induction therapy to the end of intensification therapy ] [ Designated as safety issue: Yes ]
  • Prevalence of Leukemia Phenotype of DS Patients < 4 Years of Age at Diagnosis by Flow Cytometry [ Time Frame: At baseline and at the end of therapy (intensification) or disease relapse ] [ Designated as safety issue: No ]
    The prevalence of megakaryoblastic subtype (AMkL) phenotype will be estimated as the proportion of patients with phenotype data available determined to have the AMkL phenotype. EFS will be estimated for those with and without AMkL using the approach of Kaplan and Meier. Differences in these estimates will be tested for significance using the log-rank statistic test.

  • Prevalence of of GATA1 Mutations of DS Patients < 4 Years of Age at Diagnosis [ Time Frame: At baseline and at the end of therapy (intensification) or disease relapse ] [ Designated as safety issue: No ]
    The prevalence of GATA1 mutations will be estimated as the proportion of patients with phenotype data available determined to have the GATA1 mutations.

  • Proportions of Patients in Morphologic Remission With Positive MRD by Flow Cytometry [ Time Frame: After completion of induction therapy (I, IV) and after completion of intensification therapy ] [ Designated as safety issue: No ]
    Differences in the cumulative incidence of relapse for those with and without MRD will be tested using Gray's test.

  • Cytarabine Drug Sensitivity by R-Strip (MicroMath) Curve Fitting Program. [ Time Frame: Days 1, 2, 8, and 9 of induction II ] [ Designated as safety issue: No ]
    Descriptive statistics will be used to summarize pharmacokinetic parameters, such as peak plasma concentration, area under the concentration time curve, and half-life of elimination

  • Gene Expression Profiles by Microarrays [ Time Frame: At baseline and at the time of relapse (if available) ] [ Designated as safety issue: No ]
    A hierarchical clustering algorithm is used to assemble the genes into a dendrogram or tree structure with branches containing genes with similar patterns of expression. This ordered representation can be graphically displayed with colors that reflect the qualitative and quantitative relationships of the expressed genes.

Enrollment: 205
Study Start Date: March 2007
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (combination chemotherapy)

INDUCTION THERAPY COURSE I: Patients receive cytarabine IT on day 1 and cytarabine IV continuously over 96 hours, daunorubicin hydrochloride IV continuously, and oral thioguanine BID on days 1-4. COURSE II: Patients receive high-dose cytarabine IV over 3 hours BID on days 1, 2, 8, and 9 and asparaginase (IM) on days 2 and 9.

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

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.

Drug: asparaginase
Given IM
Other Names:
  • ASNase
  • Colaspase
  • Crasnitin
  • Elspar
  • L-ASP
Drug: daunorubicin hydrochloride
Given IV
Other Names:
  • Cerubidin
  • Cerubidine
  • daunomycin hydrochloride
  • daunorubicin
  • RP-13057
Drug: cytarabine
Given IV or IT
Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
Drug: thioguanine
Given orally
Other Name: 6-TG
Drug: etoposide
Given IV
Other Names:
  • EPEG
  • VP-16
  • VP-16-213
Other: laboratory biomarker analysis
Correlative studies

  Show Detailed Description


Ages Eligible for Study:   up to 4 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00369317

  Show 97 Study Locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Principal Investigator: Jeffrey Taub, MD Children's Oncology Group
  More Information

Responsible Party: Children's Oncology Group Identifier: NCT00369317     History of Changes
Other Study ID Numbers: AAML0431  NCI-2009-00318  CDR0000492776  COG-AAML0431  AAML0431  U10CA098543 
Study First Received: August 24, 2006
Results First Received: January 6, 2015
Last Updated: March 16, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Down Syndrome
Hypereosinophilic Syndrome
Leukemia, Basophilic, Acute
Leukemia, Eosinophilic, Acute
Leukemia, Erythroblastic, Acute
Leukemia, Megakaryoblastic, Acute
Leukemia, Monocytic, Acute
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Myelodysplastic Syndromes
Neoplasm Metastasis
Abnormalities, Multiple
Bone Marrow Diseases
Chromosome Disorders
Congenital Abnormalities
Genetic Diseases, Inborn
Hematologic Diseases
Intellectual Disability
Leukocyte Disorders
Myelodysplastic-Myeloproliferative Diseases
Myeloproliferative Disorders
Neoplasms by Histologic Type processed this record on May 23, 2016