Low-Dose Cytarabine in Treating Infants With Down Syndrome and Transient Myeloproliferative Disorder

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as cytarabine, work in different ways to stop the growth of abnormal cells, either by killing the cells or by stopping them from dividing. Giving low-doses of cytarabine may be an effective treatment for Down syndrome and transient myeloproliferative disorder. Sometimes the disease may not need treatment until it progresses. In this case, observation may be sufficient. PURPOSE: This phase III trial is studying low-dose cytarabine to see how well it works in treating infants with Down syndrome and transient myeloproliferative disorder.

Detailed Description
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OBJECTIVES: Primary Determine whether very low-dose cytarabine can improve event-free survival (EFS) rates in infants with high-risk transient myeloproliferative disorder (TMD), using high-risk TMD patients from clinical trial COG-A2971 for historic comparison, and in infants with intermediate-risk TMD, using intermediate-risk TMD patients from clinical trial COG-A2971 for historic comparison. Maintain the current high overall EFS rate in low-risk TMD patients. Secondary Assess the toxicity of this regimen in these patients. OUTLINE: This is a nonrandomized, multicenter, crossover study. Patients are stratified according to disease risk (high or intermediate vs low). Group I (patients with high- or intermediate-risk transient myeloproliferative disorder [TMD]): Patients receive very low-dose cytarabine subcutaneously twice daily on days 1-7. Treatment repeats every 14 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease or complete or hepatic clinical remission undergo observation. Group II (patients with low-risk TMD): Patients are observed. If symptoms of intermediate- or high-risk disease develop, patients may crossover to group I. After completion of study treatment, patients are followed periodically for 10 years. PROJECTED ACCRUAL: A total of 180 patients will be accrued for this study.

Official Title
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Treatment of Transient Myeloproliferative Disorder (TMD) in Children With Down Syndrome (DS)

Conditions
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Leukemia

Intervention / Treatment
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* Drug: cytarabine
* Procedure: observation


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of transient myeloproliferative disorder (TMD) Diagnosis of Down syndrome or Down syndrome mosaicism (confirmed by karyotype analysis within the past 3 weeks) AND 1 of the following: Nonerythroid and nonlymphoid blasts (any amount) in the peripheral blood with verification of a second sample Trisomy 21-positive leukemic blasts documented by biopsy of any organ (including > 5% nonerythroid/nonlymphoid blasts documented by bone marrow aspirate or biopsy) Immunophenotype characterization required High-, intermediate-, or low-risk TMD, as defined by the following: High-risk TMD, meeting 1 of the following criteria: Life-threatening cardio-respiratory compromise due to complications of TMD (e.g., organomegaly or effusions) Life-threatening cardio-respiratory compromise is defined as cardiovascular grade 4 edema, grade 4 pericardial effusions, or grade 4 pleural effusions Hyperleukocytosis, defined as a WBC > 100,000/mm³ Any degree of hepatomegaly (palpable on physical exam) combined with life-threatening hepatic dysfunction Life-threatening hepatic dysfunction is defined as grade 4 disseminated intravascular coagulation, grade 4 ascites, grade 4 bilirubin (> 10.0 times upper limit of normal [ULN]), or grade 4 AST or ALT (> 20.0 times ULN) Intermediate-risk TMD, meeting all of the following criteria: Hepatomegaly (palpable on physical exam) combined with non life-threatening hepatic dysfunction (i.e., grade 1-3 hepatic dysfunction [AST or ALT ≤ 2.5 times ULN] and/or a total or direct bilirubin ≤ 1.5 times ULN) No evidence of life-threatening cardiovascular, respiratory, or hepatic compromise due to complications of TMD Low-risk TMD, meeting all of the following criteria: No palpable hepatomegaly on physical exam OR hepatomegaly is present without hepatic dysfunction (i.e., grade 0 hepatic dysfunction) No evidence of life-threatening cardiovascular, respiratory, or hepatic compromise due to complications of TMD PATIENT CHARACTERISTICS: See Disease Characteristics No biliary atresia by hepatic ultrasound for patients with bilirubin 3.0-10.0 times ULN PRIOR CONCURRENT THERAPY: No prior antileukemic therapy (except for leukapheresis or exchange transfusion)
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I<br>Patients receive very low-dose cytarabine subcutaneously twice daily on days 1-7. Treatment repeats every 14 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease or complete or hepatic clinical remission undergo observation. | Drug: cytarabine<br>* Given subcutaneously<br>|
| Other: Group II<br>Patients are observed. If symptoms of intermediate- or high-risk disease develop, patients may crossover to group I. | Procedure: observation<br>* No intervention<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  |  | 
| Disease-related mortality |  |  | 
| Percentage of patients experiencing grade 3-4 toxicity |  |  | 
| Incidence of subsequent leukemia in patients for whom transient myeloproliferative disorder is resolved |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute myeloid leukemia/transient myeloproliferative disorder