Chemotherapy in Treating Children With Down Syndrome and Myeloproliferative Disorder, Acute Myelogenous Leukemia, or Myelodysplastic Syndrome

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. PURPOSE: Phase III trial to study the effectiveness of combination chemotherapy in treating children who have Down syndrome and myeloproliferative disorder, acute myelogenous leukemia, or myelodysplastic syndrome.

Detailed Description
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OBJECTIVES: Evaluate the efficacy of reduced-dose induction and intensification chemotherapy, in terms of remission rate, disease-free survival rate, and acute morbidity and mortality, in children with Down syndrome and acute myelogenous leukemia or myelodysplastic syndromes. Define the understanding of the natural history of transient myeloproliferative disorder (TMD) in children with Down syndrome. Determine whether there is a reduction of sequelae in long-term survivors after treatment with this regimen. Determine the incidence of subsequent leukemia in patients with transient myeloproliferative disorder treated with this regimen. Determine the predictive risk factors for developing subsequent leukemia in patients with transient myeloproliferative disorder treated with this regimen. OUTLINE: This is a multicenter study. Group I: Patients are observed if their transient myeloproliferative disorder (TMD) does not require intervention. Patients who require therapy for TMD undergo leukapheresis or exchange transfusion for up to 3 consecutive days. If the TMD does not resolve or there is significant organ involvement, patients receive low-dose cytarabine IV continuously on days 0-4. Treatment repeats at least every 2 weeks for up to 4 courses. Patients who experience a recurrence of TMD at least 8 weeks after resolution or have refractory disease may proceed to group II for further treatment. Group II (closed to accrual as of 6/24/04 except for patients first enrolled in group I): Patients receive induction therapy comprising cytarabine IV continuously, daunorubicin IV continuously, and oral thioguanine twice daily on days 0-3. Treatment repeats every 28 days for 4 courses. Patients with no CNS disease at diagnosis receive cytarabine intrathecally (IT) on day 0. Patients with CNS disease at diagnosis receive cytarabine IT on days 0, 5, and 7. If CNS disease persists on day 7, patients receive up to 6 courses of cytarabine IT, hydrocortisone IT, and methotrexate IT, twice weekly beginning on day 10. Patients who achieve remission after induction therapy receive 2 courses of intensification therapy, for approximately 4 months. During the first course, patients receive cytarabine IV over 3 hours twice daily on days 0, 1, 7, and 8. Patients also receive asparaginase intramuscularly on days 1 and 8. The second course of therapy comprises CNS prophylaxis. Patients with no CNS disease at diagnosis or whose CNS disease resolved by day 7 of induction therapy receive cytarabine IT on days 0, 7, and 14. Patients with persistent CNS disease on day 7 of induction therapy receive cytarabine IT, hydrocortisone IT, and methotrexate IT on days 0, 7, and 14. Patients are followed monthly for 18 months, every 3 months for 1 year, every 6 months for 2.5 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 70 patients with acute myeloid leukemia or myelodysplastic syndromes will be accrued for this study within 3.2 years. A total of 88 patients with transient myeloproliferative disorder who enter remission will be accrued for this study within 5 years.

Official Title
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Treatment of Children With Down Syndrome (DS) and Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), and Transient Myeloproliferative Disorder (TMD): A Phase III Group-Wide Study

Conditions
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Leukemia, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms

Intervention / Treatment
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* Drug: asparaginase
* Drug: cytarabine
* Drug: daunorubicin hydrochloride
* Drug: methotrexate
* Drug: therapeutic hydrocortisone
* Drug: thioguanine


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Cytogenetically proven Down Syndrome (constitutional trisomy 21) with transient myeloproliferative disorder (TMD), myelodysplastic syndromes (MDS), or acute myelogenous leukemia (AML) Must be confirmed by bone marrow aspirate, cerebrospinal fluid exam, or blood test Trisomy 21 mosaicism allowed Group I: Diagnosis of TMD in patients no older than 90 days at initial presentation Must have nonerythroid blasts (any amount) in the peripheral blood and one of the following: Verification with a second sample More than 5% bone marrow blasts Hepatomegaly and/or splenomegaly Lymphadenopathy Cardiac or pleural effusions OR Histologically or cytologically proven TMD with blasts in an affected organ or in fluid (pericardial, pleural, or peritoneal) Bone marrow aspirate is required Group II (closed to accrual as of 6/24/04): Diagnosis of MDS or AML (except M3 subtype) in patients older than 90 days with more than 29% blasts in bone marrow (with or without history of TMD), or any of the following histologies: Refractory anemia (RA) RA with excess blasts (RAEB) RAEB in transformation RA with ringed sideroblasts (RARS) Primary cytopenia (later confirmed by bone marrow aspirate as due to marrow hypoplasia) defined by one or more of the following: Absolute neutrophil count less than 500/mm^3 Untransfused platelet count less than 30,000/mm^3 Untransfused hemoglobin less than 8 g/dL The following diagnoses will be observed only: RA with mild cytopenias* RARS with mild cytopenias* Mild primary cytopenias (one or more) without dysplasia (confirmed by hypoplastic bone marrow exam) NOTE: * Platelet count 30-150,000/mm3, absolute neutrophil count 500-1,499/mm3, and hemoglobin greater than 8 g/dL Granulocytic sarcoma (chloroma), with or without bone marrow involvement, allowed PATIENT CHARACTERISTICS: Age: See Disease Characteristics 21 and under Performance status: Not specified Life expectancy: Not specified Hematopoietic: See Disease Characteristics Hepatic: See Disease Characteristics Renal: Not specified Cardiovascular: Shortening fraction greater than 27% by echocardiogram* OR Ejection fraction greater than 47% by radionuclide angiogram* NOTE: *For patients with MDS and AML (as of 2/24/04, previously diagnosed MDS or AML closed to accrual; MDS or AML that develops (secondary to TMD) after study enrollment or MDS that requires initial observation [with or without subsequent treatment] allowed) PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: Prior chemotherapy for TMD allowed No prior chemotherapy for malignancy Endocrine therapy: Concurrent topical or inhaled steroids for other conditions allowed Radiotherapy: No prior radiotherapy for malignancy Surgery: Not specified Other: No prior antileukemic therapy Prior enrollment on this study for TMD allowed

Ages Eligible for Study
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Maximum Age: 21 Years

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: Arm A: TMD patients only<br>Patients are observed if their transient myeloproliferative disorder (TMD) does not require intervention. Patients who require therapy for TMD undergo leukapheresis or exchange transfusion for up to 3 consecutive days. If the TMD does not resolve or there is significant organ involvement, patients receive low-dose cytarabine IV continuously on days 0-4. Treatment repeats at least every 2 weeks for up to 4 courses. Patients who experience a recurrence of TMD at least 8 weeks after resolution or have refractory disease may proceed to group II for further treatment. patients will continue to be followed for remission induction, EFS, DFS and OS regardless of the type of leukemia that develops. | Drug: cytarabine<br>* Given IT<br>* Other names: NSC #063878;|
| Experimental: Arm B: AML/MDS patients only<br>(closed to accrual as of 6/24/04 except for patients first enrolled in group I): Patients receive induction therapy comprising cytarabine IV continuously, daunorubicin hydrochloride IV continuously, and oral thioguanine twice daily on days 0-3. Treatment repeats every 28 days for 4 courses. Patients with no CNS disease at diagnosis receive cytarabine intrathecally (IT) on day 0. Patients with CNS disease at diagnosis receive cytarabine IT on days 0, 5, and 7. If CNS disease persists on day 7, patients receive up to 6 courses of cytarabine IT, therapeutic hydrocortisone IT, and methotrexate IT, twice weekly beginning on day 10. Asparaginase during Intensification 1 day 1 hour 18. | Drug: asparaginase<br>* Given IV<br>* Other names: NSC #109229;Drug: cytarabine<br>* Given IT<br>* Other names: NSC #063878;Drug: daunorubicin hydrochloride<br>* Given IV<br>* Other names: NSC #82151;Drug: methotrexate<br>* Given IV<br>* Other names: NSC #000740;Drug: therapeutic hydrocortisone<br>* Given IT<br>* Other names: NSC #010483;Drug: thioguanine<br>* Given IV<br>* Other names: NSC # 000752;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Free Survival |  | Length of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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childhood acute monocytic leukemia (M5b), childhood acute monoblastic leukemia (M5a), myelodysplastic/myeloproliferative neoplasm, unclassifiable, juvenile myelomonocytic leukemia, secondary myelodysplastic syndromes, childhood myelodysplastic syndromes, untreated childhood acute myeloid leukemia and other myeloid malignancies, childhood acute myeloblastic leukemia without maturation (M1), childhood acute myeloblastic leukemia with maturation (M2), childhood acute myelomonocytic leukemia (M4), childhood acute erythroleukemia (M6), childhood acute megakaryocytic leukemia (M7), refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, de novo myelodysplastic syndromes, childhood acute minimally differentiated myeloid leukemia (M0), chronic myelomonocytic leukemia