Rituximab and Combination Chemotherapy in Treating Older Patients With Previously Untreated B-Cell Lymphoma

OBJECTIVES:

Primary

• Determine a pharmacokinetic profile for pharmacokinetics-based or rituximab within a CHOP-14 regimen comprising cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone in elderly patients with previously untreated aggressive B-cell lymphoma.
• To determine whether increased single-doses of rituximab for males can compensate their lower serum levels.
• Evaluate the safety and toxicity profile of this regimen in male patients.

Secondary

• Determine the rate of complete responses, primary progressions under therapy, event-free survival, progression-free survival, and overall survival in patients treated with this regimen.
• Determine the rate of primary progression in patients treated with this regimen.

OUTLINE: This is a multicenter study. All patients undergo the following treatment.

• Prephase treatment: Patients receive vincristine subcutaneously on day -6 and oral prednisone on days -6 to 0.
• Immunochemotherapy and radiotherapy: Patients receive CHOP chemotherapy comprising cyclophosphamide IV over 15 minutes, doxorubicin hydrochloride IV, and vincristine IV on day 1 and oral prednisone once daily on days 1-5. Patients also receive pegfilgrastim subcutaneously on days 4, 18, 32, 46, 60, and 74. Treatment with CHOP chemotherapy repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who show no response after course 4 of CHOP chemotherapy proceed to salvage chemotherapy off study.

Patients are evaluated 2-4 weeks after completion of CHOP. Patients with initial bulky disease (i.e., diameter ≥ 7.5 cm) or extranodal involvement AND achieving complete remission (CR), unconfirmed CR (CRu), or partial remission undergo radiotherapy 5 days a week for 4 weeks. Patients who do not achieve CR or CRu 2 months after completion of radiotherapy proceed to salvage chemotherapy off study.

Patients are then stratified according to center, International Prognostic Index (1-2 vs 3-5), disease involvement (bulky vs extranodal vs bulky and/or extranodal), age (61-70 years old vs 71-80 years old), and gender. Patients are randomized to 1 of 2 treatment arms.

• Arm I (2-weekly rituximab): Patients receive rituximab IV 375 mg/m^2 (females) and 500 mg/m^2 (males) over 4 hours on days 0, 14, 28, 42, 56, 70, 84, and 98. Patients also receive pegfilgrastim subcutaneously on day 4 of each course.
• Arm II (pharmacokinetic-based dose-dense rituximab): Patients receive rituximab IV 375 mg/m^2 (females) and 500 mg/m^2 (males) over 4 hours on days -1, 0, 3, 7, 14, 21, 28, and 42. Patients also receive pegfilgrastim subcutaneously on day 4 of each course.

Some patients undergo blood sample collection periodically during and after treatment for pharmacokinetic studies.

After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then once a year therafter.

DISEASE CHARACTERISTICS:

• Histological diagnosis of aggressive B-cell lymphoma

• Previously untreated disease
• Stage I-IV disease
• CD20-positive disease
• Any International Prognostic Index (IPI) score
• No secondary lymphoma after prior chemotherapy or radiotherapy
• No primary CNS lymphoma
• No primary gastrointestinal (MALT) lymphoma

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Life expectancy ≥ 3 months
• AST and ALT ≤ 3 times normal unless related to lymphoma
• Bilirubin ≤ 2 mg/dL unless related to lymphoma
• Creatinine ≤ 2 times normal unless related to lymphoma
• Fertile patients must use effective contraception
• No known allergic reactions against foreign proteins
• No active infections requiring systemically administered antibiotics or antiviral medications
• No noncompensated heart failure
• No dilatative cardiomyopathy
• No coronary heart disease with ST-segment depression in ECG
• No myocardial infarction during the past 6 months
• No chronic lung disease with hypoxemia
• No severe noncompensated hypertension
• No severe noncompensated diabetes mellitus
• No clinical signs of cerebral dysfunction
• No severe psychiatric disease
• No known HIV infection
• No active chronic hepatitis B or C infection
• No other concurrent diseases that exclude the administration of therapy as outlined by the study protocol

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• More than 12 weeks since prior clinical trial participation
• No prior participation in this study
• No prior therapy, including murine antibody, for this cancer
• No prior organ transplantation
• No concurrent response-adapted radiotherapy ("iceberg radiotherapy")
• No other concurrent anticancer chemotherapy or other study medication