RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell or bone marrow transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells.

PURPOSE: Randomized phase III trial to compare the effectiveness of combination chemotherapy followed by bone marrow or peripheral stem cell transplantation in treating patients with acute myelogenous leukemia.

Condition	Treatment or Intervention	Phase
adult acute myelomonocytic leukemia (M4) untreated adult acute myeloid leukemia adult acute differentiated monocytic leukemia (M5b) adult acute myeloblastic leukemia without maturation (M1) adult acute myeloblastic leukemia with maturation (M2) secondary acute myeloid leukemia adult acute poorly differentiated monocytic leukemia (M5a) adult acute megakaryocytic leukemia (M7) adult acute erythroleukemia (M6)	Drug: busulfan  Drug: cyclophosphamide  Drug: cytarabine  Drug: daunorubicin  Drug: etoposide  Drug: filgrastim  Drug: idarubicin  Drug: mesna  Drug: mitoxantrone	Phase III

Further Study Details: 

OBJECTIVES: I. Determine the complete remission (CR) rate following 1 or 2 courses of ICE (idarubicin/cytarabine/etoposide) vs. MICE (mitoxantrone/cytarabine/etoposide) vs. DCE (daunorubicin/cytarabine/etoposide) in patients with newly diagnosed acute myeloid leukemia.

II. Compare disease-free survival and overall survival achieved with each anthracycline on the above induction regimens and with intermediate-dose cytarabine (IDIA vs. NOVIA vs. DIA) as consolidation therapy.

III. Compare disease-free survival, relapse rate, death in first CR, and overall survival in patients who receive peripheral blood stem cells (PBSC) vs. autologous bone marrow transplant (AuBMT) vs. allogeneic bone marrow transplant (AlBMT) as rescue from myeloablative therapy following remission consolidation.

IV. Assess the time to recovery of normal or acceptable polymorphonuclear leukocyte and platelet counts following each treatment step.

V. Determine the incidence and type of grade 4 toxicity and treatment-related mortality.

VI. Evaluate the quality of life during each step of treatment using self-administered questionnaires.

VII. Compare stem cell mobilization after IDIA vs. NOVIA vs. DIA, each using granulocyte colony-stimulating factor as the mobilizing growth factor.

VIII. Assess the rate of completion of stem cell transplantation using PBSC vs. AlBMT vs. AuBMT as the last step of therapy.

IX. Compare the costs of treatment (e.g., antibiotics and transfusion requirements) and hospitalization duration between the AuBMT vs. PBSC.

PROTOCOL OUTLINE: Randomized study. All patients are randomized to Arms I, II, and III for Induction/Consolidation. Patients in CR following Consolidation who have an HLA-identical sibling, are less than 45 or 55 years of age (depending on center policy), and have adequate organ function are nonrandomly assigned to AlBMT on Regimen A; those in CR who are without an available sibling donor and who have adequate organ function proceed to Regimen B, then are randomized to Arms IV and V.

The following acronyms are used: AlBMT Allogeneic Bone Marrow Transplant ARA-C Cytarabine, NSC-63878 AuBMT Autologous Bone Marrow Transplant BU Busulfan, NSC-750 CTX Cyclophosphamide, NSC-26271 DCE DNR/ARA-C/VP-16 DHAD Mitoxantrone, NSC-301739 DIA DNR/ID ARA-C DNR Daunorubicin, NSC-82151 G-CSF Granulocyte Colony-Stimulating Factor (Rhone-Poulenc-Rorer) ICE IDA/ARA-C/VP-16 IDA Idarubicin, NSC-256439 ID Intermediate Dose IDIA IDA/ID ARA-C Mesna Mercaptoethane sulfonate, NSC-113891 MICE DHAD/ARA-C/VP-16 NOVIA DHAD/ID ARA-C PBSC Peripheral Blood Stem Cells TBI Total-Body Irradiation VP-16 Etoposide, NSC-141540

INDUCTION/CONSOLIDATION: Arm I: 3-Drug Combination Chemotherapy followed by 2-Drug Combination Chemotherapy. ICE; followed by IDIA.

Arm II: 3-Drug Combination Chemotherapy followed by 2-Drug Combination Chemotherapy. MICE; followed by NOVIA.

Arm III: 3-Drug Combination Chemotherapy followed by 2-Drug Combination Chemotherapy. DCE; followed by DIA.

POSTCONSOLIDATION THERAPY: Regimen A: Single-Agent Chemoablation plus Radioablation or 2-Drug Chemoablation followed by Hematopoietic Rescue. CTX; plus TBI (equipment unspecified); or CTX/BU; followed by AlBMT. Entry on EORTC study comparing CI IDA with standard CTX/TBI or CTX/BU encouraged.

Regimen B: Stem cell Mobilization and Harvest. G-CSF or CTX/G-CSF.

Arm IV: Single-Agent Chemoablation plus Radioablation or 2-Drug Chemoablation followed by Hematopoietic Rescue. CTX/TBI or CTX/BU; followed by PBSC.

Arm V: Single-Agent Chemoablation plus Radioablation or 2-Drug Chemoablation followed by Hematopoietic Rescue. CTX/TBI or CTX/BU; followed by AuBMT.

PROJECTED ACCRUAL: 1,520 patients will be randomized for Induction/Consolidation over about 5 years; if excessive deaths are found at interim analyses, the inferior arm will close. It is expected that 744 patients will be randomized for Postconsolidation therapy, with 345 patients followed until relapse/death.

Ages Eligible for Study:  15 Years   -   60 Years

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Newly diagnosed acute myeloid leukemia (AML) of any FAB histology (M1-M7) except M3; At least 30% blast cells in bone marrow smears
• Secondary leukemias eligible, as follows: Following cured malignancies, including Hodgkin's disease; Following exposure to alkylating agents or radiotherapy for other reasons
• The following leukemias are excluded: Blast crisis of chronic myeloid leukemia; Leukemia secondary to other myeloproliferative disease; Leukemia secondary to myelodysplastic syndrome of more than 6 months duration
• No other progressive malignant disease

--Prior/Concurrent Therapy--

• No prior therapy for AML (chemotherapy, radiotherapy, or more than 7 days of corticosteroids)

--Patient Characteristics--

• Age: 15 to 60
• Performance status: Not specified
• Hematopoietic: Not applicable
• Hepatic: Bilirubin no greater than 1.5 x ULN
• Renal: Creatinine no greater than 1.5 x ULN
• Cardiovascular: No severe heart failure requiring diuretics or with an LVEF less than 50%
• Other: No severe concomitant neurologic disease; No severe concomitant psychologic disease

Austria
      Universitaetsklinik, Innsbruck,  A-6020,  Austria
Belgium
      A.Z. St. Jan, Brugge,  8000,  Belgium
      Algemeen Ziekenhuis Middelheim, Antwerp,  2020,  Belgium
      CHU Sart-Tilman, LIEGE,  B-4000,  Belgium
      Hopital Universitaire Erasme, Brussels,  1070,  Belgium
      Institut Jules Bordet, Brussels (Bruxelles),  1000,  Belgium
      Universitair Ziekenhuis Antwerpen, Edegem,  B-2650,  Belgium
Croatia
      Medical School/University of Zagreb, Zagreb (Agram),  41000,  Croatia
      University Hospital Rebro, Zagreb,  41000,  Croatia
Czech Republic
      Institute of Hematology and Blood Transfusion, Prague,  128 20,  Czech Republic
      University Hospital - Olomouc, Olomouc,  775 20,  Czech Republic
France
      Centre Antoine Lacassagne, Nice,  06189,  France
      Centre Medico-Chirurgical Foch, Suresnes,  92151,  France
      Hopital Cochin, Paris,  75674,  France
      Hopital Edouard Herriot, Lyon,  69437,  France
      Hopital Necker, Paris,  75743,  France
      Hotel Dieu de Paris, Paris,  75181,  France
      Institut Gustave Roussy, Villejuif,  F-94805,  France
Germany
      Klinikum Grosshadern, Munich (Muenchen),  D-81377,  Germany
      Staedtische Kliniken Duisburg, Duisburg,  D-47055,  Germany
Hungary
      County Hospital, Kecskemet,  H-6000,  Hungary
Italy
      Arcispedale S. Maria Nuova, Reggio Emilia,  42100,  Italy
      Azienda Ospedale S. Luigi - Universita Di Torino, Orbassano, (Torino),  10043,  Italy
      Azienda Ospedaliera "A. Cardarelli", Naples (Napoli),  80127,  Italy
      Azienda Ospedaliera Di Parma, Parma,  43100,  Italy
      Azienda Ospedaliera Ospedale E. Mortelli, Sondalo (SO),  23037,  Italy
      Azienda Policlinico Umberto Primo, Rome,  00161,  Italy
      Centro Trapianti di Midollo Osseo, Cremona,  26100,  Italy
      Federico II University Medical School, Naples (Napoli),  80131,  Italy
      Instituto Scientifico H.S. Raffaele, Milano (Milan),  20132,  Italy
      Istituto di Ematologia Universita - University di Sassari, Sassari,  07100,  Italy
      Ospedal SS Annunziata, Taranto,  74100,  Italy
      Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo,  71013,  Italy
      Ospedale Cervello, Palermo,  90146,  Italy
      Ospedale Civile Alessandria, Alessandria,  I-15100,  Italy
      Ospedale Civile Avellino, Avellino,  Italy
      Ospedale Civile Pescara, Pescara,  65100,  Italy
      Ospedale Ferrarotto, Catania,  95124,  Italy
      Ospedale Gen. Provinciale Santa Maria Goretti, Latina,  04100,  Italy
      Ospedale Maggiore, Novara,  28100,  Italy
      Ospedale Maggiore Ca Granda, Milano (Milan),  20162,  Italy
      Ospedale Maggiore Lodi, Lodi,  I-20075,  Italy
      Ospedale Molinette, Turin (Torino),  10126,  Italy
      Ospedale Nuovo Pellegrini, Naples (Napoli),  80144,  Italy
      Ospedale Oncologico A. Businco, Cagliari,  09124,  Italy
      Ospedale Regionale A. Di Summa, Brindisi,  I-72100,  Italy
      Ospedale Regionale A. Pugliese, Catanzaro,  88100,  Italy
      Ospedale S. Antonio Abate, Gallarate Varese,  21013,  Italy
      Ospedale S. Gennora USL 42, Naples (Napoli),  80136,  Italy
      Ospedale San Carlo, Potenza,  85100,  Italy
      Ospedale San Eugenio, Rome,  00144,  Italy
      Ospedale San Francesco, Nuoro,  08100,  Italy
      Ospedale San Martino/Cliniche Universitarie Convenzionale, Genoa (Genova),  16132,  Italy
      Ospedale San Salvatore, Pesaro,  I-61100,  Italy
      Ospedale Santa Croce, Cuneo,  12100,  Italy
      Ospedale Torrette University Ancona, Ancona,  60020,  Italy
      Ospedali Riuniti, Reggio Calabria,  89100,  Italy
      Ospedali Riuniti Foggia, Foggia,  71100,  Italy
      Policlinico - Cattedra di Ematologia, Palermo,  90100,  Italy
      Policlinico A. Gemelli - Universita Cattolica del Sacro Cuore, Rome,  00168,  Italy
      Policlinico Monteluce, Perugia,  06122,  Italy
      Policlinico P. Giaccone - Universita Di Palermo, Palermo,  90127,  Italy
      Universita Degli Studi di Bari Policlinico, Bari,  70124,  Italy
      Universita Degli Studi di Firenze - Policlin. di Careggi, Firenze (Florence),  1 (50-134),  Italy
      Universita di Modena, Modena,  41100,  Italy
      University and I.R.C.C.S. Policlinico San Matteo, Pavia,  27100,  Italy
Netherlands
      Groot Ziekengasthuis 's-Hertogenbosch, 's-Hertogenbosch,  5211 NL,  Netherlands
      Leiden University Medical Center, Leiden,  2300 ZA,  Netherlands
      Medisch Spectrum Twente, ENSCHEDE,  7500 KA,  Netherlands
      Onze Lieve Vrouwe Gasthuis, Amsterdam,  1091 HA,  Netherlands
      Sint Joseph Ziekenhuis, Veldhoven,  5500 MB DB,  Netherlands
      University Medical Center Nijmegen, Nijmegen,  NL-6252 HB,  Netherlands
Portugal
      Hospitais da Universidade de Coimbra (HUC), Coimbra,  3049,  Portugal
      Hospital Escolar San Joao, Porto,  4200,  Portugal
Turkey
      Ibn-i Sina Hospital, Ankara Univeristy, Ankara,  06100,  Turkey

Study chairs or principal investigators

Robert A. Zittoun,  Study Chair,  EORTC Leukemia Cooperative Group   

Study ID Numbers:  CDR0000063311; EORTC-06931
Record last reviewed:  July 2004
Last Updated:  October 13, 2004
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00002549
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2005-04-08