RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Bone marrow transplantation may be able to replace immune cells that were destroyed by chemotherapy to kill tumor cells. It is not yet known which regimen of combination chemotherapy with or without bone marrow transplantation is more effective in treating promyelocytic leukemia PURPOSE: Randomized phase III trial to compare the effectiveness of different combination chemotherapy regimens with or without bone marrow transplantation in treating patients who have promyelocytic leukemia.

Condition	Treatment or Intervention	Phase
untreated adult acute myeloid leukemia adult acute promyelocytic leukemia (M3)	Procedure: chemotherapy  Procedure: biological response modifier therapy  Procedure: radiation therapy  Procedure: autologous bone marrow transplantation  Procedure: allogeneic bone marrow transplantation  Procedure: bone marrow transplantation  Procedure: differentiation therapy  Drug: bone marrow ablation with stem cell support  Drug: busulfan  Drug: cyclophosphamide  Drug: cytarabine  Drug: etoposide  Drug: idarubicin  Drug: mercaptopurine  Drug: methotrexate  Drug: mitoxantrone  Drug: thioguanine  Drug: tretinoin	Phase III

Further Study Details: 

OBJECTIVES: I. Determine the complete remission (CR) rate in patients with acute promyelocytic leukemia treated with induction comprising tretinoin (ATRA) and idarubicin (IDA). II. Determine the presence of the promyelocyte-retinoic acid receptor alpha (PML-RARa) transcript using polymerase chain reaction (PCR) in patients with CR after 3 sequential consolidation regimens comprising cytarabine (ARA-C) plus IDA, followed by mitoxantrone plus etoposide, and then IDA, ARA-C, and thioguanine. III. Determine the percentage of patients who complete the protocol, including PML-RARa-positive patients treated with post-consolidation bone marrow transplantation (BMT) and PML-RARa-negative patients treated with maintenance comprising mercaptopurine (MP) plus methotrexate (MTX) vs ATRA only vs MP plus MTX alternating with ATRA vs observation only. IV. Compare the disease-free survival (DFS) and overall survival of these patients treated with these regimens. V. Determine the rate and type of grade 4 toxicity, treatment-related mortality, and time to granulocyte and platelet recovery associated with each phase of treatment in these patients. VI. Determine the DFS and overall survival of PML-RARa-positive patients who are ineligible for BMT and are treated with maintenance comprising MP plus MTX alternating with ATRA. VII. Compare the quality of life of patients treated with these regimens.

PROTOCOL OUTLINE: This is a randomized, multicenter study. Induction: Patients receive oral tretinoin (ATRA) twice daily beginning on day 1 and continuing for 30-90 days and idarubicin (IDA) IV over 15 minutes on days 2, 4, and 8. ATRA is discontinued before day 90 in the presence of complete remission (CR) at day 30 or 60, unacceptable toxicity, or disease progression or in the absence of at least a partial remission at day 60. Patients who achieve CR during induction proceed to consolidation. First consolidation: Within 2 weeks after achieving CR, patients receive cytarabine (ARA-C) IV over 6 hours followed 3 hours later by IDA IV over 15 minutes on days 1-4. Second consolidation: Within 4-6 weeks after initiation of first consolidation, patients receive mitoxantrone IV over 30 minutes and etoposide IV over 1 hour (beginning 12 hours after initiation of mitoxantrone infusion) on days 1-5. Third consolidation: Within 4-6 weeks after initiation of second consolidation, patients receive ARA-C subcutaneously every 8 hours and oral thioguanine every 8 hours on days 1-5 and IDA IV over 15 minutes on day 1. Patients proceed to group A if they are promyelocyte-retinoic acid receptor alpha (PML-RARa)-negative after recovery from third consolidation. Patients proceed to allogeneic bone marrow transplantation (BMT) on group B if they are PML-RARa-positive, achieve CR, are under age 55, and have an HLA-A, -B, and -DR identical, chronic myelomonocytic leukemia nonreactive, family donor after recovery from third consolidation. Patients proceed to autologous BMT on group B if they are PML-RARa-positive, achieve CR, and have no identical family donor or are age 55 and over after recovery from third consolidation. Patients proceed to arm III of group A if they are PML-RARa-positive and ineligible for BMT after recovery from third consolidation. Group A (maintenance): Patients are stratified according to participating center and initial white blood cell count. Patients are randomized to 1 of 4 treatment arms. Arm I: Patients receive oral mercaptopurine (MP) daily and oral methotrexate (MTX) weekly. Arm II: Beginning 3 months after recovery from third consolidation, patients receive oral ATRA on days 1-15. Treatment on arms I and II continues every 3 months for 2 years in the absence of disease progression or unacceptable toxicity. Arm III: Patients receive 1 course of arm I treatment, alternated by 1 course of arm II treatment. Alternating treatment continues every 3 months for 2 years in the absence of disease progression or unacceptable toxicity. Arm IV: Patients undergo observation only. Group B: Eligible patients receive conditioning comprising cyclophosphamide (CTX) IV for 2 days followed by total body irradiation or oral busulfan on days -9 to -6 and CTX on days -5 to -2. Autologous or allogeneic bone marrow is infused on day 0 (within 4 months after initiation of third consolidation). Quality of life is assessed at baseline, after induction, after each consolidation regimen, and then every 3 months beginning after treatment on group A or B. Patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 750 patients will be accrued for this study within 7.5 years.

Ages Eligible for Study:  16 Years   -   74 Years

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Newly diagnosed acute promyelocytic leukemia
• Must have promyelocyte-retinoic acid receptor alpha transcript at disease presentation

--Prior/Concurrent Therapy--

• Biologic therapy: Not specified
• Chemotherapy: No concurrent cytotoxic chemotherapy
• Endocrine therapy: Prior corticosteroids for leukemia allowed
• Radiotherapy: No concurrent radiotherapy
• Surgery: Not specified
• Other: No prior antileukemic therapy

--Patient Characteristics--

Age: 16 to 74

Performance status: Not specified

Life expectancy: Not specified

Hematopoietic: Not specified

Hepatic:

• Bilirubin no greater than 3 times upper limit of normal (ULN)
• AST no greater than 3 times ULN
• Alkaline phosphatase no greater than 3 times ULN

Renal: Creatinine no greater than 2.5 mg/dL

Cardiovascular: No cardiac contraindication to anthracycline chemotherapy

Other:

• No active serious infection not controlled by antibiotics
• No severe concurrent psychiatric disease
• No other malignancy except basal cell carcinoma
• Not pregnant or nursing
• Negative pregnancy test

Austria
      Innsbruck Universitaetsklinik, Innsbruck,  A-6020,  Austria
Belgium
      A.Z. St. Jan, Brugge,  8000,  Belgium
      Algemeen Ziekenhuis Middelheim, Antwerp,  2020,  Belgium
      C.H.U. Saint-Pierre, Brussels (Bruxelles),  1000,  Belgium
      Centre Hospitalier Peltzer-La Tourelle, Verviers,  B-4800,  Belgium
      CHU Sart-Tilman, LIEGE,  B-4000,  Belgium
      Hopital Universitaire Erasme, Brussels,  1070,  Belgium
      Institut Jules Bordet, Brussels (Bruxelles),  1000,  Belgium
      U.Z. Gasthuisberg, Leuven,  B-3000,  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
      Onkologicka Klinka A Onkologicka Lab, Prague,  128 08,  Czech Republic
France
      Centre Antoine Lacassagne, Nice,  06189,  France
      Centre Hospitalier Regional de Lille, Lille,  59037,  France
      Centre Medico-Chirurgical Foch, Suresnes,  92151,  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 Duisburg, Duisburg,  D-47055,  Germany
      Klinikum Grosshadern, Munich (Muenchen),  D-81377,  Germany
Italy
      Azienda Ospedaliera "A. Cardarelli", Naples (Napoli),  80127,  Italy
      Azienda Ospedaliera di Padova, Padova (Padua),  35128,  Italy
      Azienda Ospedaliera Di Parma, Parma,  43100,  Italy
      Azienda Policlinico Umberto Primo, Rome,  00161,  Italy
      Cattedra di Immunologia Clinica, Turin (TO),  10128,  Italy
      Centro Trapianti di Midollo Osseo, Cremona,  26100,  Italy
      Federico II University Medical School, Naples (Napoli),  80131,  Italy
      I.R.C.C.S. Policlinico San Matteo, Pavia,  27100,  Italy
      Istituto di Ematologia Universita - University di Sassari, Sassari,  07100,  Italy
      Istituto Scientifico H.S. Raffaele, Milano,  20132,  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 Di Montefiascone, Montefiascone,  I-01027,  Italy
      Ospedale Ferrarotto, Catania,  95124,  Italy
      Ospedale Gen. Provinciale Santa Maria Goretti, Latina,  04100,  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 Convenzionate, 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 Foggia, Foggia,  71100,  Italy
      Policlinico - Cattedra di Ematologia, Palermo,  90100,  Italy
      Policlinico A. Gemelli - Universita Cattolica del Sacro Cuore, Rome,  00168,  Italy
      Policlinico di Careggi, Firenze (Florence),  50134,  Italy
      Policlinico Monteluce, Perugia,  06122,  Italy
      Universita Degli Studi di Bari Policlinico, Bari,  70124,  Italy
Netherlands
      Academisch Medisch Centrum, Amsterdam,  1105 AZ,  Netherlands
      Academisch Ziekenhuis Groningen, Groningen,  9713 EZ,  Netherlands
      Groot Ziekengasthuis 's-Hertogenbosch, 's-Hertogenbosch,  5211 NL,  Netherlands
      Leiden University Medical Center, Leiden,  2300 CA,  Netherlands
      Leyenburg Ziekenhuis, 's-Gravenhage (Den Haag, The Hague),  2545 CH,  Netherlands
      University Hospital - Rotterdam Dijkzigt, Rotterdam,  3000 CA,  Netherlands
      University Medical Center Nijmegen, Nijmegen,  NL-6500 HB,  Netherlands
Turkey
      Ibn-i Sina Hospital, Ankara University, Ankara,  06100,  Turkey

Study chairs or principal investigators

Petra Muus,  Study Chair,  EORTC Leukemia Cooperative Group   
Franco Mandelli,  Study Chair

Study ID Numbers:  CDR0000064499; EORTC-06952
Record last reviewed:  April 2003
Last Updated:  October 13, 2004
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00002701
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2005-04-08