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.

Condition	Treatment or Intervention	Phase
Myeloid Leukemia Myelodysplastic Syndromes Refractory Anemia	Drug: cytarabine  Drug: daunorubicin  Drug: dexamethasone  Drug: etoposide  Drug: idarubicin  Drug: mitoxantrone  Drug: thioguanine  Procedure: allogeneic bone marrow transplantation  Procedure: biological response modifier therapy  Procedure: bone marrow ablation with stem cell support  Procedure: bone marrow transplantation  Procedure: chemotherapy  Procedure: radiation therapy	Phase III

Further Study Details: 

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).

• 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.
• 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.
• 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.

Ages Eligible for Study:  up to  14 Years,  Genders Eligible for Study:  Both

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

Belgium
      U.Z. Gasthuisberg, Leuven,  B-3000,  Belgium
      Universitair Ziekenhuis Gent, Ghent,  B-9000,  Belgium
      Academisch Ziekenhuis der Vrije Universiteit Brussel, Brussels,  1090,  Belgium
      Clinique de l'Esperance, Montegnee,  4420,  Belgium
      Centre Hospitalier Regional de la Citadelle, LIEGE,  4000,  Belgium
      Algemeen Ziekenhuis Middelheim, Antwerp,  2020,  Belgium
      Hopital Universitaire Des Enfants Reine Fabiola, Brussels,  1020,  Belgium
France
      Hopital Americain, Reims,  51092,  France
      Hopital Robert Debre, Paris,  75019,  France
      Institut Curie - Section Medicale, Paris,  75248,  France
      Centre Hospitalier Regional de Lille, Lille,  59037,  France
      Centre Antoine Lacassagne, Nice,  06189,  France
      Hopital Jean Bernard, Poitiers,  86021,  France
      CHR de Grenoble - La Tronche, Grenoble,  38043,  France
      CHR Hotel Dieu, Nantes,  44093,  France
      CHU de Caen, Caen,  14033,  France
      CHR de Besancon - Hopital Saint-Jacques, Besancon,  25030,  France
      Centre Hospitalier Regional et Universitaire d'Angers, Angers,  49033,  France
      Hopital Debrousse, Lyon,  69322,  France
      Hopital Arnaud de Villeneuve, Montpellier,  34295,  France
      Hopital Universitaire Hautepierre, Strasbourg,  67098,  France
      Hopital des Enfants (Purpan Enfants), Toulouse,  31026,  France
Portugal
      Hospital Escolar San Joao, Porto,  4200,  Portugal

Study chairs or principal investigators

Catherine Behar, MD,  Study Chair,  Hopital Americain   

Study ID Numbers:  CDR0000078212; EORTC-58921
Record last reviewed:  February 2003
Last Updated:  October 13, 2004
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00002517
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2005-04-08