RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with radiation therapy may kill more tumor cells. Bone marrow transplantation can replace immune cells that were destroyed by chemotherapy.

PURPOSE: Randomizedphase III trial to study the effectiveness of chemotherapy compared with or without bone marrow transplantation in treating patients with acute lymphoblastic leukemia.

Condition	Treatment or Intervention	Phase
untreated adult acute lymphoblastic leukemia stage I adult lymphoblastic lymphoma stage III adult lymphoblastic lymphoma stage IV adult lymphoblastic lymphoma contiguous stage II adult lymphoblastic lymphoma noncontiguous stage II adult lymphoblastic lymphoma	Drug: asparaginase  Drug: cyclophosphamide  Drug: cytarabine  Drug: daunorubicin  Drug: dexamethasone  Drug: doxorubicin  Drug: hydrocortisone  Drug: leucovorin calcium  Drug: mercaptopurine  Drug: methotrexate  Drug: mitoxantrone  Drug: prednisolone  Drug: prednisone  Drug: vincristine  Procedure: allogeneic bone marrow transplantation  Procedure: autologous 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 remission induction, toxicity, and duration of remission in patients with newly diagnosed acute lymphoblastic leukemia or lymphoblastic lymphoma treated with prednisone vs dexamethasone plus cyclophosphamide, daunorubicin, and vincristine as induction.
• Compare the survival and disease-free survival of patients treated with autologous bone marrow transplantation (BMT) followed by low- or high-intensity maintenance chemotherapy with cranial irradiation after consolidation.
• Determine the relative and disease-free survival of patients treated with autologous or allogeneic BMT after identical induction, consolidation, and conditioning regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to center and risk group (high vs standard).

Induction

• Patients are randomized to 1 of 2 treatment arms.
• Arm I:Patients receive daunorubicin IV on days 1-3 and 15 and 16; cyclophosphamide (CTX) IV on days 1 and 8; vincristine (VCR) IV on days 1, 8, 15, and 22; and prednisone IV or orally every 8 hours on days 1-7 and 15-21.
• Arm II: Patients receive daunorubicin, CTX, and VCR as in arm I and dexamethasone IV or orally on days 1-8 and 15-22.
• Patients on both arms without CNS disease at presentation receive CNS prophylaxis comprising methotrexate (MTX) intrathecally (IT) on days 1, 8, 15, and 22. Patients on both arms with CNS disease at presentation receive CNS therapy comprising hydrocortisone (HC) IT and MTX IT alternating with cytarabine (ARA-C) IT twice a week until CSF clears. After induction, patients on both arms proceed to consolidation, regardless of response.

Consolidation

• Patients receive ARA-C IV over 2 hours every 12 hours on days 29-34 and mitoxantrone IV on days 33-35. Patients without CNS disease at presentation receive CNS prophylaxis comprising MTX IT on day 29. Patients with CNS disease at presentation receive CNS therapy comprising HC IT and MTX IT alternating with ARA-C weekly for 6 weeks. Patients who achieve complete response (CR) at day 55-60 receive MTX IV on days 64 and 79, leucovorin calcium IV or orally every 6 hours on days 65-67 and 80-82, and asparaginase IV over 1 hour or intramuscularly on days 65 and 80.
• Standard-risk patients who are under age 20 and achieve CR after day 80 are assigned to arm IV of group A. Patients who achieve CR after day 80 and have a genotypically or phenotypically HLA-matched family donor, a family donor mismatched at only 1 locus (A, B, or DR), or an HLA-matched unrelated donor proceed to group B. Patients who achieve CR after day 80 and are eligible for autologous bone marrow transplantation (BMT) proceed to group A. Patients found to be at extremely high risk are taken off study.

Group A

• Patients are randomized to 1 of 2 treatment arms.
• Arm III: Autologous bone marrow is harvested. Patients receive bone marrow ablation comprising CTX IV over 1 hour on days -4 and -3 and total body irradiation on day -1. Autologous bone marrow is reinfused on day 0. Beginning at month 8 (4 months after BMT), patients receive first maintenance comprising VCR IV, doxorubicin IV, and dexamethasone IV (VAD) or VCR IV, doxorubicin IV, and prednisolone IV (VAP) on days 1-4 and 29-32. Patients receive second maintenance comprising oral mercaptopurine daily and oral MTX daily beginning at month 10 and continuing through year 3. Patients without CNS disease at presentation receive CNS prophylaxis comprising MTX IT on days 1 and 29. Patients with CNS disease at presentation receive CNS therapy comprising ARA-C IT, MTX IT, and HC IT beginning at 1 month after BMT and continuing monthly for 1 year and then every 3 months through year 3.
• Arm IV: Patients receive CTX IV and ARA-C IV continuously on day 1, oral mercaptopurine on days 8-28, and oral MTX on days 8, 15, and 22 during months 4, 7, 11, 13, 17, 21, 25, and 29. Patients receive MTX IV over 30 minutes on day 1, leucovorin calcium IV or orally every 6 hours on days 2-4, asparaginase IV over 1 hour or intramuscularly on day 2, oral mercaptopurine on days 8-28, and oral MTX on days 8, 15, and 22 during months 6, 10, 12, 15, 19, 23, and 27. Patients receive VAD or VAP as in arm III beginning at month 8. Patients without CNS disease at presentation receive CNS prophylaxis comprising whole brain radiotherapy and MTX IT on day 1 of radiotherapy during month 5. Patients with CNS disease at presentation receive CNS therapy as in arm III.

Group B

• Allogeneic bone marrow is harvested. Patients receive bone marrow ablation as in arm III beginning on day 100. Allogeneic bone marrow is infused over 15-30 minutes on day 0.
• Patients in groups A and B with CNS disease at presentation undergo radiotherapy to focal infiltration at entry or concurrently with total body irradiation, or whole brain radiotherapy during maintenance (if no prior CNS irradiation). At any time during the study, patients who develop marrow relapse (more than 5% leukemic blasts in bone marrow on 2 occasions), CNS relapse (blasts in CSF, cranial nerve palsy, or CNS mass), or testis or other extramedullary relapse are taken off study.

PROJECTED ACCRUAL: A total of 392 patients will be accrued for this study within approximately 6 years.

Ages Eligible for Study:  15 Years   -   60 Years,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Newly diagnosed acute lymphoblastic leukemia or lymphoblastic lymphoma with more than 30% blasts in bone marrow

PATIENT CHARACTERISTICS: Age:

• 15 to 60

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics

Hepatic:

• Bilirubin less than 2 mg/dL (unless elevation due to leukemic involvement of liver)

Renal:

• Creatinine less than 2 mg/dL (unless elevation due to leukemic involvement of kidneys)

Cardiovascular:

• No severe cardiac disease

Pulmonary:

• No severe pulmonary disease

Other:

• No severe neurologic or metabolic disease
• HIV negative (if tested)
• No other prior malignancy except nonmelanomatous skin cancer, stage I cervical carcinoma, or other curatively treated malignancy

PRIOR CONCURRENT THERAPY: Biologic therapy:

• No prior biologic therapy

Chemotherapy:

• No prior chemotherapy

Endocrine therapy:

• No prior endocrine therapy

Radiotherapy:

• No prior radiotherapy

Surgery:

• No prior surgery

Belgium
      A.Z. St. Jan, Brugge,  8000,  Belgium
      Algemeen Ziekenhuis Middelheim, Antwerpen,  B-2020,  Belgium
      C.H.U. Saint-Pierre, Brussels,  1000,  Belgium
      Centre Hospitalier Peltzer-La Tourelle, Verviers,  B-4800,  Belgium
      CHU Sart-Tilman, LIEGE,  B-4000,  Belgium
      Hopital Universitaire Erasme, Brussels,  1070,  Belgium
      Universitair Ziekenhuis Antwerpen, Edegem,  B-2650,  Belgium
Croatia
      Medical School/University of Zagreb, Zagreb (Agram),  10000,  Croatia
      University Hospital Rebro, Zagreb,  10000,  Croatia
Czech Republic
      University Hospital - Olomouc, Olomouc,  775 20,  Czech Republic
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
Germany
      Kreiskrankenhaus Meissen, Meissen,  D-01662,  Germany
Italy
      A. Perrino Hospital, Brindisi,  72100,  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 Civile Alessandria, Alessandria,  I-15100,  Italy
      Ospedale Civile Avellino, Avellino,  Italy
      Ospedale Di Montefiascone, Montefiascone,  I-01027,  Italy
      Ospedale Ferrarotto, Catania,  95124,  Italy
      Ospedale Gen. Provinciale Santa Maria Goretti, Latina,  04100,  Italy
      Ospedale Maggiore Lodi, Lodi,  I-20075,  Italy
      Ospedale Molinette, Turin (Torino),  10126,  Italy
      Ospedale Regionale A. Pugliese, Catanzaro,  88100,  Italy
      Ospedale S. Antonio Abate, Gallarate Varese,  21013,  Italy
      Ospedale S. Gennaro ASL NA1, Naples (Napoli),  80136,  Italy
      Ospedale San Carlo, Potenza,  85100,  Italy
      Ospedale Santa Croce, Cuneo,  12100,  Italy
      Ospedali Riuniti Foggia, Foggia,  71100,  Italy
      Policlinico - Cattedra di Ematologia, Palermo,  90100,  Italy
      Policlinico di Careggi, Firenze (Florence),  50134,  Italy
      Policlinico Monteluce, Perugia,  06122,  Italy
      Universita Degli Studi di Bari Policlinico, Bari,  70124,  Italy
Netherlands
      Groot Ziekengasthuis 's-Hertogenbosch, 's-Hertogenbosch,  5211 NL,  Netherlands
      Leiden University Medical Center, Leiden,  2300 CA,  Netherlands
      Maxima Medisch Centrum - locatie Eindhoven, Eindhoven,  5631 BM,  Netherlands
      Onze Lieve Vrouwe Gasthuis, Amsterdam,  1091 HA,  Netherlands
      University Medical Center Nijmegen, Nijmegen,  NL-6500 HB,  Netherlands
Portugal
      Hospital Escolar San Joao, Porto,  4200,  Portugal
Slovakia
      Institute of Hematology & Transfusiology, University Hospital, Bratislava,  85107,  Slovakia
Turkey
      Ibn-i Sina Hospital, Ankara,  06100,  Turkey

Study chairs or principal investigators

Roel Willemze, MD, PhD,  Study Chair,  Leiden University Medical Center   
Denis Fiere, MD,  Study Chair,  Leucemies Aigues et Lymphomes de l'Adulte   

Study ID Numbers:  CDR0000064498; EORTC-06951; FRE-LALA-94
Record last reviewed:  May 2004
Last Updated:  October 13, 2004
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00002700
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2005-04-08