RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. It is not yet known which combination chemotherapy regimen is more effective for non-Hodgkin's lymphoma.

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

OBJECTIVES:

• Compare the overall survival rate, progression free survival rate, clinical and molecular remission rates, and time to treatment failure in patients with newly diagnosed stage III or IV follicular non-Hodgkin's lymphoma treated with chlorambucil, mitoxantrone, and dexamethasone versus fludarabine, mitoxantrone, and dexamethasone.
• Compare the efficacy and tolerability of these regimens in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to International Prognostic Index score [low risk (score 1) vs intermediate low risk (score 2) vs intermediate high risk (score 3) vs high risk (score 4 or 5)]. Patients are randomized to one of two treatment arms.

• Arm I: Patients receive mitoxantrone IV on day 1, oral chlorambucil on days 1-10, and oral dexamethasone on days 1-5.
• Arm II: Patients receive mitoxantrone and dexamethasone as in arm I and fludarabine IV on days 1-3.

Treatment continues every 4 weeks for 4-8 courses.

Patients are followed at 3, 6, and 12 months, every 6 months for 1 year, and then annually thereafter until clinical relapse.

PROJECTED ACCRUAL: A total of 500 patients (250 per arm) will be accrued for this study within 4 years.

DISEASE CHARACTERISTICS:

• Histologically proven newly diagnosed stage III or IV follicular non-Hodgkin's lymphoma

  • REAL classification grade I, II, or III

• Treatment necessity indicated by presence of the following:

  • B symptoms
  • Bone marrow failure
  • Bulky or progressive disease
  • Compression syndromes

• No CNS involvement

PATIENT CHARACTERISTICS:

Age:

• 18 to 70

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• No autoimmune hemolytic anemia or active hemolysis
• Direct Coombs' negative

Hepatic:

• Alkaline phosphatase no greater than 2.5 times upper limit of normal (ULN)*
• Bilirubin no greater than 2.5 times ULN* NOTE: *Unless attributable to lymphoma

Renal:

• Creatinine no greater than 2.5 times ULN (unless attributable to lymphoma)

Cardiovascular:

• No severe cardiac failure
• Ejection fraction at least 45%

Other:

• Not pregnant or nursing
• Fertile patients must use effective contraception during and for at least 6 months after study
• HIV negative
• No prior malignancy except carcinoma in situ of the cervix or squamous cell skin cancer
• No other serious medical disease that would limit lifespan or ability to tolerate chemotherapy

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• Not specified

Endocrine therapy:

• No concurrent systemic corticosteroids

Radiotherapy:

• Not specified

Surgery:

• Not specified

Other:

• No prior therapy