RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining peripheral stem cell transplantation with more than one drug regimen may kill more tumor cells. It is not known whether receiving standard combination chemotherapy alone is more effective than receiving multiple combination chemotherapy plus peripheral stem cell transplantation for aggressive non-Hodgkin's lymphoma.

PURPOSE: This randomized phase III trial is comparing giving different combination chemotherapy regimens together with peripheral stem cell transplantation to see how well they work in treating patients with newly diagnosed aggressive non-Hodgkin's lymphoma.

Condition	Treatment or Intervention	Phase
adult diffuse large cell lymphoma adult diffuse mixed cell lymphoma adult immunoblastic large cell lymphoma anaplastic large cell lymphoma	Drug: cyclophosphamide  Drug: cytarabine  Drug: doxorubicin  Drug: etoposide  Drug: filgrastim  Drug: hydrocortisone  Drug: leucovorin calcium  Drug: melphalan  Drug: methotrexate  Drug: methylprednisolone  Drug: mitoxantrone  Drug: prednisone  Drug: vincristine  Procedure: biological response modifier therapy  Procedure: bone marrow ablation with stem cell support  Procedure: chemotherapy  Procedure: colony-stimulating factor therapy  Procedure: cytokine therapy  Procedure: high-dose chemotherapy  Procedure: peripheral blood stem cell transplantation  Procedure: radiation therapy	Phase III

Further Study Details: 

OBJECTIVES:

• Compare the efficacy of sequential high-dose chemotherapy and autologous peripheral blood stem cell transplantation with standard chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with newly diagnosed aggressive non-Hodgkin's lymphoma and poor prognostic factors.
• Compare the toxic effects of these 2 regimens in these patients.
• Compare the response rates and overall survival of patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are randomized to one of two treatment arms.

• Arm I: Patients receive standard chemotherapy comprising cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Patients receive cyclophosphamide IV over 30 minutes, doxorubicin IV, and vincristine IV on day 1. Patients receive oral prednisone daily on days 1-5. Treatment repeats every 21 days for 6-8 courses. Patients with bulky disease at diagnosis or residual disease after chemotherapy receive radiotherapy 30-60 days after initiation of the last course of CHOP.
• Patients receive 5 regimens of chemotherapy administered in sequence.
• Regimen A : Patients receive CHOP as in Arm I.
• Regimen B: Three weeks after starting regimen A, patients receive high-dose cyclophosphamide IV over 24 hours on day 1. Patients without initial bone marrow involvement receive filgrastim (G-CSF) subcutaneously (SC) daily beginning on day 3 and continuing until autologous peripheral blood stem cells (PBSC) are harvested. PBSC are harvested on days 13-15 or when blood counts recover. Patients with initial bone marrow involvement do not undergo harvest of PBSC at this time, but receive G-CSF SC daily.
• Regimen C: Two to three weeks after high-dose cyclophosphamide, patients receive vincristine IV and high-dose methotrexate IV over 6 hours on day 2. Patients receive leucovorin calcium IV every 6 hours on days 3-5 beginning 24 hours after initiation of the methotrexate infusion.
• Regimen D: Within 1-2 weeks after the administration of methotrexate in regimen C, patients receive methylprednisolone IV followed 6 hours later by high-dose etoposide IV over 10 hours on day 1. Patients receive methylprednisolone IV on day 2. Patients without initial bone marrow involvement receive G-CSF SC daily beginning on day 3 and continuing until blood counts recover. Patients with initial bone marrow involvement receive G-CSF SC daily until autologous PBSC are harvested. PBSC are harvested on days 10-14 or when blood counts recover.
• Regimen E: Myeloablative therapy and autologous PBSC transplantation begin 16-40 days after the administration of etoposide. Patients receive mitoxantrone IV over 1 hour every 2 hours for 3 doses on day 2 and melphalan IV over 30 minutes on day 5. PBSC are reinfused on day 6 beginning at least 24 hours after the administration of melphalan. Patients receive G-CSF SC or by continuous infusion beginning on day 7. Patients with bulky disease at diagnosis or residual disease after chemotherapy receive radiotherapy 30-100 days after PBSC transplantation.

Patients at high risk of developing CNS disease receive prophylactic intrathecal chemotherapy. Patients may receive cytarabine, methotrexate, and hydrocortisone or methotrexate and hydrocortisone every 1-2 weeks for 6 courses.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: Approximately 400 patients will be accrued for this study within 4-5 years.

Ages Eligible for Study:  18 Years   -   60 Years,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed aggressive non-Hodgkin's lymphoma (NHL)
• Diffuse large B-cell lymphoma
• Primary mediastinal large B-cell lymphoma
• Anaplastic large cell lymphoma (B-cell, T-cell, or null-cell type)
• At least two of the following risk factors:
• Stage III or IV
• LDH greater than upper limit of normal (ULN)
• ECOG 2, 3, or 4
• No CNS involvement

PATIENT CHARACTERISTICS: Age:

• 18 to 60

Performance status:

• See Disease Characteristics
• ECOG 0-4

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• No hepatitis B or C
• AST or ALT no greater than 2 times ULN*
• Bilirubin no greater than 2.34 mg/dL* NOTE: *Unless due to tumor involvement

Renal:

• Creatinine clearance at least 60 mL/min (unless due to tumor involvement)

Cardiovascular:

• No significant heart failure
• LVEF normal
• No active angina pectoris
• No myocardial infarction within the past 6 months
• No major ventricular arrhythmia

Pulmonary:

• No significant lung disorder

Other:

• HIV negative
• No severe active acute or chronic infection
• No severe psychoses
• No prior or concurrent malignancy except adequately treated carcinoma in situ of the cervix or nonmelanomatous skin cancer
• Not pregnant or nursing
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY: Biologic therapy:

• Not specified

Chemotherapy:

• No prior chemotherapy for NHL (except emergency therapy, but no more than 1 course of standard chemotherapy)

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy for NHL (except emergency therapy of no greater than 600 cGy radiation)
• No concurrent prophylactic radiotherapy to the brain

Surgery:

• Not specified

Austria
      Allgemeines Krankenhaus der Stadt Wien, Vienna,  A-1090,  Austria
Germany
      Dr. Horst-Schmidt-Kliniken, Wiesbaden,  D-65199,  Germany
Greece
      Saint Savvas Cancer Hospital of Athens, Athens,  11522,  Greece
Italy
      European Institute of Oncology, Milano,  20141,  Italy
Switzerland
      Centre Hospitalier Universitaire Vaudois, Lausanne,  1011,  Switzerland
      Hopital Cantonal Universitaire de Geneve, Collonge-Bellerive,  CH-1245,  Switzerland
      Inselspital, Bern, Bern,  CH-3010,  Switzerland
      Kantonsspital - St. Gallen, St. Gallen,  CH-9007,  Switzerland
      Klinik Hirslanden, Zurich,  CH-8008,  Switzerland
      Oncology Institute of Southern Switzerland, Bellinzona,  CH-6500,  Switzerland
      Ratisches Kantons und Regionalspital, Chur,  CH-7000,  Switzerland
      Universitatsspital-Basel, Basel,  CH-4031,  Switzerland

Study chairs or principal investigators

Daniel C. Betticher, MD,  Study Chair,  Inselspital, Bern   

Study ID Numbers:  CDR0000066075; SWS-SAKK-38/97; EU-97037; NCT00003215
Record last reviewed:  March 2005
Last Updated:  March 10, 2005
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00003215
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08