Rituximab and Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With B-Cell Non-Hodgkin's Lymphoma

OBJECTIVES:

Primary

• Compare the time to treatment failure in patients with previously untreated, low-risk, aggressive, B-cell non-Hodgkin's lymphoma treated with 2 different schedules of immunochemotherapy comprising rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone with vs without radiotherapy.

Secondary

• Compare the time to progression in patients treated with these regimens.
• Compare the overall and disease-free/relapse-free survival of patients treated with these regimens.
• Compare the complete response rate in patients treated with these regimens.
• Compare the tumor control in patients treated with these regimens.
• Compare the safety of these regimens in these patients.
• Compare the pharmacoeconomics of these regimens.
• Compare patient adherence to these regimens.

OUTLINE: This is an open-label, randomized, multicenter study. Patients are stratified according to study center, serum lactic dehydrogenase level (≤ upper limit of normal [ULN] vs > ULN), disease stage (I or II vs III or IV), ECOG performance status (0-1 vs 2-3), bulky disease, and extranodal involvement. Patients with initial bulky disease and/or qualifying extranodal involvement are randomized to 1 of 4 treatment arms. Patients with non-bulky disease are randomized to treatment arms I or III.

All patients will be given the option of receiving a 1-week course of pretreatment therapy comprising vincristine IV once on day -6 and oral prednisone once daily on days -6 to 0.

• Arm I (R-CHOP-21): Patients receive R-CHOP immunochemotherapy comprising rituximab IV, cyclophosphamide IV over 15 minutes, doxorubicin IV, and vincristine IV on day 1 and oral prednisone once daily on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
• Arm II (R-CHOP-21 and radiotherapy): Patients receive R-CHOP as in arm I. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Beginning 2-6 weeks after the last course of R-CHOP, patients who achieve a complete remission (CR) undergo radiotherapy 5 days a week for approximately 5½ weeks.
• Arm III (R-CHOP-14): Patients receive R-CHOP as in arm I. Patients also receive filgrastim (G-CSF) subcutaneously once daily on days 4-13 or until blood counts recover. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
• Arm IV (R-CHOP-14 and radiotherapy): Patients receive R-CHOP as in arm I. Patients also receive G-CSF an in arm III. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Beginning 2-6 weeks after the last course of R-CHOP, patients who achieve CR undergo radiotherapy as in arm II.

Patients in all arms undergo restaging of their disease after courses 3 and 6 of R-CHOP. Patients with stable disease after 6 courses or disease progression after courses 3 or 6 proceed to salvage chemotherapy off study. Patients achieving a partial remission or an unconfirmed CR after 6 courses undergo additional restaging 4 weeks later. Patients with disease progression proceed to salvage chemotherapy off study. Patients who achieve CR after 6 courses of R-CHOP or have a confirmed CR after the additional restaging undergo radiotherapy according to randomization (as above).

After completion of study treatment, patients are followed periodically for 5 years and then annually thereafter.

PROJECTED ACCRUAL: A total of 1,072 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed aggressive B-cell non-Hodgkin's lymphoma, including the following subtypes:

• Grade 3 follicular lymphoma
• Diffuse B-cell lymphoma, including diffuse large cell lymphoma with the following variants:

• Centroblastic
• Immunoblastic
• Plasmablastic
• Anaplastic large cell
• T-cell-rich B-cell lymphoma
• Primary effusion lymphoma
• Intravascular B-cell lymphoma
• Primary mediastinal B-cell lymphoma
• Burkitt's or Burkitt-like lymphoma
• Mantle cell lymphoma (blastoid)
• Aggressive marginal zone lymphoma (monocytoid)
• Previously untreated disease
• CD20-positive disease
• International prognostic index (IPI) score 0 or 1 (age-adjusted)

• Only patients with bulky disease, as defined by largest single or conglomerate tumor ≥ 7.5 cm in diameter, are allowed to have an IPI score of 0
• No mucosa-associated lymphoid tissue (MALT) lymphoma
• No CNS involvement of lymphoma (intracerebral, meningeal, or intraspinal)

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Platelet count ≥ 100,000/mm³
• WBC ≥ 2,500/mm³
• No known hypersensitivity to the study medications
• No known HIV-positivity
• No active hepatitis infection
• Not pregnant or lactating
• Negative pregnancy test
• No other malignancy within the past 5 years except carcinoma in situ or basal cell skin cancer
• No impaired left ventricular function
• No severe cardiac arrhythmias
• No other impaired organ function
• No other serious disorder

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy or radiotherapy
• No prior immunosuppressive treatment with cytostatics
• No concurrent participation in other treatment studies