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

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: The Treatment of Down Syndrome Children With Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) Under the Age of 4 Years

Brief Summary: 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.

Detailed Summary:

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.

  • Event-free Survival (EFS) at 3 Years [ Time Frame: Time from study entry to induction failure, relapse, or death assessed at 3 years. ]
  • Overall Survival (OS) at 3 Years [ Time Frame: Time from study entry to death, assessed at 3 years. ]


    • Original Primary Outcome:

    Current Secondary Outcome:

    • Induction Remission Rate [ Time Frame: End of induction therapy ]
    • 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 ]
    • 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 ]
      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 ]
      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 ]
      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 ]
      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) ]
      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.


    Original Secondary Outcome:

    Information By: Children's Oncology Group

    Dates:
    Date Received: August 24, 2006
    Date Started: March 2007
    Date Completion:
    Last Updated: February 7, 2017
    Last Verified: February 2017