Combination Chemotherapy in Treating Young Patients With Down Syndrome and Acute Myeloid Leukemia or Myelodysplastic Syndromes
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.
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: daunorubicin hydrochloride
Other: laboratory biomarker analysis
|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|
- Event-free survival (EFS) [ Time Frame: Time from study entry to induction failure, relapse, or death ] [ Designated as safety issue: No ]
The cure model parameters to be used in the one-sample log-rank test^35 will be estimated at the time of the first interim analysis. The Kaplan-Meier method will be used to calculate estimates of EFS.
Corresponding confidence intervals will be calculated using Greenwood's formula.44. The log-rank statistic will be used to test for differences in EFS.
- Induction remission rate [ Time Frame: At baseline, days 14 and 28 of induction therapy ] [ Designated as safety issue: No ]
- Overall survival (OS) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]The Kaplan-Meier method will be used to calculate estimates of OS. Corresponding confidence intervals will be calculated using Greenwood's formula.44 The log-rank statistic will be used to test for differences in OS.
- 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 tehrapy ] [ 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 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.
|Study Start Date:||March 2007|
|Primary Completion Date:||October 2013 (Final data collection date for primary outcome measure)|
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.
Other Names:Drug: daunorubicin hydrochloride
Other Names:Drug: cytarabine
Given IV or IT
Other Names:Drug: thioguanine
Other Name: 6-TGDrug: etoposide
Other Names:Other: laboratory biomarker analysis
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