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. Monoclonal antibodies such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. It is not yet known which regimen of combination chemotherapy, with or without rituximab, is more effective for non-Hodgkin's lymphoma.

PURPOSE: Randomized phase III trial to compare the effectiveness of two regimens of combination chemotherapy followed by rituximab or observation in treating patients who have stage III or stage IV low-grade non-Hodgkin's lymphoma.

OBJECTIVES:

• Compare response rate, time to progression, time to treatment failure, and survival of patients with low grade non-Hodgkin's lymphoma treated with a cyclophosphamide and fludarabine regimen (closed as of 9/2000) or standard treatment with cyclophosphamide, vincristine, and prednisone.
• Determine the effect of maintenance with rituximab (IDEC-C2B8 monoclonal antibody) on time to progression, times to treatment failure, and survival, as well as its effects on lymphocyte number, subsets, and quantitative immunoglobulin levels over time in these patients.

OUTLINE: This a two step, stratified, randomized study.

Patients are stratified for arms I and II (step 1) by age (under 60 vs 60 and over), tumor burden (high vs low), histology (follicular vs other), and B symptoms (present vs absent). After arms I and II have been completed, patients are stratified in arms III and IV (step 2) by extent of residual disease (minimal vs gross), histology (follicular vs other), and initial tumor burden.

• Arm I (closed as of 9/2000): Patients receive cyclophosphamide IV over 30-45 minutes on day 1 and fludarabine IV over 10-20 minutes on days 1-5. Treatment repeats every 28 days in the absence of disease progression for a minimum of 4 courses and a maximum of 6 courses.
• Arm II: Patients receive cyclophosphamide IV over 30-45 minutes and vincristine IV on day 1, and oral prednisone on days 1-5. Treatment repeats every 21 days in the absence of disease progression for a minimum of 6 courses and a maximum of 8 courses.

After completion of therapy on arm I or II, patients are randomized into step 2 of this study comprising arms III and IV.

• Arm III: Patients receive maintenance therapy with rituximab (IDEC-C2B8 monoclonal antibody) IV weekly for 4 weeks. Courses repeat every 6 months for 2 years. Maintenance therapy begins 4 weeks after the last chemotherapy.
• Arm IV: Patients undergo no maintenance therapy and are observed. Patients are followed every 3 months for 2 years, every 6 months for the next 3 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 515 patients will be accrued for this study.

• Biological: rituximab
• Drug: cyclophosphamide
• Drug: prednisone
• Drug: vincristine sulfate

DISEASE CHARACTERISTICS:

• Histologically confirmed stage III-IV low grade non-Hodgkin's lymphoma

  • Small lymphocytic
  • Follicular small cleaved cell
  • Follicular mixed cleaved cell
  • Follicular large cell

• Measurable disease by at least one of the following:

  • Radiographic findings must provide clear-cut measurements
  • Bidimensionally measurable, clearly defined defect or mass measuring at least 2 cm in diameter on a radionuclide or CT scan
  • An enlarged spleen extending at least 2 cm below the costal margin, provided that no explanation other than lymphomatous involvement is likely
  • An enlarged liver with proof of lymphoma in the liver by biopsy

• May have low or high tumor burden

  • High tumor burden defined as:

    • Nodal or extranodal mass at least 7 cm
    • 3 or more nodal masses greater than 3 cm
    • Systemic symptoms or B symptoms
    • Risk of extrinsic compression of vital organ
    • Leukemia phase with lymphocyte count of greater than 5,000/mm3
    • Absolute neutrophil count less than 1,500/mm3
    • Hemoglobin less than 10 g/dL
    • Platelet count less than 100,000/mm3
• Patients with both diffuse and follicular architectural elements are eligible if histology is predominantly follicular (at least 50% of the cross-sectional area)
• If diagnosis of low grade non-Hodgkin's lymphoma had been made over 1 year ago, diagnostic confirmation using either fine needle aspiration or nodal biopsy is required NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-1

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics
• WBC greater than 3,000/mm^3 (unless documented bone marrow involvement)
• Platelet count greater than 100,000/mm^3 (unless documented bone marrow involvement)

Hepatic:

• Bilirubin less than 2.0 mg/dL
• SGOT no greater than 5 times upper limit of normal (ULN)
• Alkaline phosphatase no greater than 5 times ULN

Renal:

• Creatinine no greater than 1.5 mg/dL

Other:

• No other malignancy within the past 5 years except treated carcinoma in situ of the cervix or basal or squamous cell carcinoma of the skin
• No active, uncontrolled infections
• Adequate contraception required of all fertile patients

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior immunotherapy

Chemotherapy:

• No prior chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy

Surgery:

• Not specified

• National Cancer Institute (NCI)
• Cancer and Leukemia Group B