Combination Chemotherapy in Treating Children With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug may kill more cancer cells. It is not yet known which regimen of combination chemotherapy is more effective for acute myeloid leukemia or myelodysplastic syndrome. PURPOSE: Randomized phase III trial to compare the effectiveness of different combination chemotherapy regimens in treating children who have newly diagnosed acute myeloid leukemia or myelodysplastic syndrome.

Detailed Description
-----------------
OBJECTIVES: Compare the efficacy of idarubicin vs mitoxantrone in induction and first intensification in terms of achieving and maintaining complete remissions in children with acute myeloid leukemia or myelodysplastic syndrome. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to center and disease type (de novo acute myeloid leukemia (AML) vs AML secondary to myelodysplastic syndrome (MDS) vs MDS). Induction: Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive cytarabine (ARA-C) IV continuously on days 1 and 2 and then IV over 30 minutes every 12 hours on days 3-8, mitoxantrone IV on days 3-5, etoposide (VP-16) IV over 1 hour on days 6-8, and ARA-C intrathecally (IT) on days 1 and 8. Arm II: Patients receive ARA-C and VP-16 as in arm I and idarubicin IV on days 3-5. Patients on both arms with CNS disease at presentation receive ARA-C IT every 3 days until the CSF clears and then weekly until the first intensification. After induction, patients on both arms proceed to first intensification, regardless of response. First intensification: When blood counts recover and within 40 days after initiating induction, patients are randomized to 1 of 2 treatment arms. Arm III: Patients receive high-dose ARA-C IV over 3 hours every 12 hours on days 1-3 (if allogeneic bone marrow transplantation (BMT) is planned) or days 1-4 (if allogeneic BMT is not planned) and mitoxantrone IV on days 7-9. Arm IV: Patients receive high-dose ARA-C as in arm III and idarubicin IV on days 7-9. Patients who achieve complete remission (CR) after first intensification and have an HLA-identical, chronic myelomonocytic leukemia-nonreactive, sibling donor undergo allogeneic BMT. Patients who achieve CR after intensification and have no suitable donor receive intensive chemotherapy as defined below. All patients with chloroma at presentation undergo local radiotherapy beginning after final intensification. Second intensification: When blood counts recover, patients receive daunorubicin IV continuously, ARA-C IV continuously, VP-16 IV continuously, oral thioguanine, and oral dexamethasone on days 1-4 and 11-14 and ARA-C IT on days 1, 4, 11, and 14. Third intensification: When blood counts recover, patients receive high-dose ARA-C IV over 3 hours every 12 hours on days 1-3 and VP-16 IV over 1 hour on days 2-5. When blood counts recover, autologous bone marrow is harvested in the event of subsequent relapse. Maintenance: When blood counts recover, patients receive oral thioguanine daily and ARA-C subcutaneously 4 days a month for 1 year. PROJECTED ACCRUAL: A total of 310 patients will be accrued for this study within 5 years.

Official Title
-----------------
IDA VS MTZ IN INDUCTION AND INTENSIFICATION TREATMENT OF AML OR MDS IN CHILDREN, A PHASE III RANDOMIZED STUDY

Conditions
-----------------
Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
-----------------
* Drug: cytarabine
* Drug: daunorubicin hydrochloride
* Drug: dexamethasone
* Drug: etoposide
* Drug: idarubicin
* Drug: mitoxantrone hydrochloride
* Drug: thioguanine
* Procedure: allogeneic bone marrow transplantation
* Radiation: radiation therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Newly diagnosed acute myeloid leukemia (AML) based on the cytological, cytochemical, and immunological criteria of the FAB classification Must meet 1 of the following criteria: More than 30% blasts in marrow (calculation based on the total number of nucleated cells except lymphocytes and plasmocytes) Presence of granulocytic sarcoma (chloroma) Disease must be associated with at least 1 of the following: More than 3% myeloperoxidase- or Sudan black-positive blasts More than 3% platelet peroxidase-positive blasts More than 20% esterase-positive blasts Immunological markers compatible with a myeloid differentiation, including 1 of the following criteria: Blasts positive for myeloid-associated antigen and negative for B- or T-lymphocyte antigens Blasts positive for at least 2 myeloid antigens (except CD3 and CD8) A cytogenetic abnormality associated with AML OR Newly diagnosed myelodysplastic syndrome (MDS) based on the cytological and cytochemical criteria of the FAB classification Eligible subtypes: Refractory anemia with excess blasts (RAEB) RAEB in transformation Chronic myelomonocytic leukemia No promyelocytic leukemia (M3 or M3v) treated with tretinoin (protocol EORTC-06915) No AML secondary to hematologic or malignant disease other than MDS Registration must occur within 48 hours of diagnosis PATIENT CHARACTERISTICS: Age: Under 15 Performance status: Not specified Life expectancy: Not specified Hematopoietic: See Disease Characteristics No uncontrolled bleeding disorder Hepatic: Not specified Renal: No renal failure Cardiovascular: No congenital heart disease Other: No encephalopathy No genetic disorders No uncontrolled infection PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: Not specified Endocrine therapy: Not specified Radiotherapy: Not specified Surgery: Not specified Other: No prior antileukemic therapy

Ages Eligible for Study
-----------------
Maximum Age: 14 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: cytarabine|nan|
|Drug: daunorubicin hydrochloride|nan|
|Drug: dexamethasone|nan|
|Drug: etoposide|nan|
|Drug: idarubicin|nan|
|Drug: mitoxantrone hydrochloride|nan|
|Drug: thioguanine|nan|
|Procedure: allogeneic bone marrow transplantation|nan|
|Radiation: radiation therapy|nan|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
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 monoblastic leukemia (M5a), childhood acute monocytic leukemia (M5b), childhood acute erythroleukemia (M6), childhood acute megakaryocytic leukemia (M7), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, chronic myelomonocytic leukemia, de novo myelodysplastic syndromes, childhood acute minimally differentiated myeloid leukemia (M0)