RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. 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 whether chemotherapy is more effective with or without rituximab for relapsed non-Hodgkin's lymphoma.

PURPOSE: This randomized phase III trial is studying combination chemotherapy and rituximab to see how well they work compared to combination chemotherapy alone in treating patients with relapsed non-Hodgkin's lymphoma.

OBJECTIVES:

• Compare the response rate and quality of remission in patients with relapsed follicular non-Hodgkin's lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or without rituximab.
• Compare the event-free survival and overall survival of patients treated with these regimens.
• Determine the effect of rituximab as maintenance therapy on progression-free survival of these patients.

OUTLINE: This is a randomized, multicenter study.

• Induction: Patients are randomized to one of two treatment arms. Patients are stratified according to participating center, prior treatment with purine analogues, age, number of prior induction treatments and best response obtained (complete vs partial remission vs no change/progressive disease), time since diagnosis (less than 2 years vs more than 2 years), and bulky disease (less than 10 cm vs greater than 10 cm).

  • Arm I (closed as of 12/20/04): Patients receive induction chemotherapy comprising cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1 and oral prednisone on days 1-5 (CHOP chemotherapy). Treatment repeats every 3 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
  • Arm II: Patients receive CHOP chemotherapy as in arm I. Rituximab IV is administered 1 hour after prednisone and before the IV drugs.

• Maintenance: Patients who achieve partial or complete remission are then randomized to one of two treatment arms. Patients are stratified according to rituximab administration during induction (yes vs no), quality of the response (complete vs partial remission vs no change/progressive disease), and participating center.

  • Arm I: Patients receive no further therapy.
  • Arm II: Beginning 8 weeks after the last CHOP course, patients receive rituximab IV once every 3 months for up to 2 years in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 2 years and then every 4 months thereafter.

PROJECTED ACCRUAL: A total of 752 patients will be accrued for this study within 6 years.

DISEASE CHARACTERISTICS:

• Histologically or cytologically proven stage III or IV follicular non-Hodgkin's lymphoma (NHL)

  • Relapsed after or no response (no change/progressive disease) to no more than 2 adequate non-anthracycline-containing systemic chemotherapy regimens
  • At least 2 months of single-agent therapy (e.g., chlorambucil) AND/OR
  • At least 2 consecutive courses of polychemotherapy (e.g., cyclophosphamide, vincristine, and prednisone) or purine analogues

• Complete or partial remission or no change for at least 4 weeks after completion of prior therapy OR progression during one of a maximum of 2 prior therapy regimens

• CD20 positive

• At least 1 bidimensionally measurable mass

• No greater than 10,000,000/mL circulating tumor cells

• IgG levels at least 3 g/L

• No low-grade NHL transformed into intermediate- or high-grade NHL

• No symptomatic CNS lymphoma

• No bone marrow involvement only 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:

• WHO 0-2

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Bilirubin less than 2.5 times upper limit of normal (ULN)
• Alkaline phosphatase less than 2.5 times ULN

Renal:

• Creatinine less than 2.5 times ULN
• BUN less than 2.5 times ULN

Cardiovascular:

• No severe cardiac disease (i.e., severe heart failure requiring symptomatic treatment)

Pulmonary:

• No severe pulmonary disease

Other:

• No severe neurologic or psychiatric disease
• No severe metabolic disease
• Not pregnant
• Fertile patients must use effective contraception
• No prior malignancy within the past 5 years except nonmelanomatous skin cancer, carcinoma in situ of the cervix, or other cancer curatively treated with surgical therapy
• HIV negative
• No uncontrolled asthma or allergy requiring steroids
• No known hypersensitivity or prior anaphylactic reaction to murine proteins or any component of study drug

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior rituximab
• No prior allogeneic or autologous peripheral blood stem cell transplantation
• Concurrent filgrastim (G-CSF) for stem cell mobilization allowed

Chemotherapy:

• See Disease Characteristics
• No prior anthracyclines or mitoxantrone
• No concurrent chemotherapy for stem cell mobilization

Endocrine therapy:

• Not specified

Radiotherapy:

• Not specified

Surgery:

• Not specified