Combination Chemotherapy With or Without Rituximab in Non-Hodgkin's Lymphoma

OBJECTIVES:

• Compare the time to treatment failure in patients with CD20-positive diffuse large B-cell non-Hodgkin's lymphoma treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like chemotherapy with vs without rituximab.
• Compare the tumor control, progression rate, and complete remission rate in patients treated with these regimens.
• Compare the disease-free and overall survival rate of patients treated with these regimens.
• Compare the toxicity of these regimens in these patients.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to participating center, bulky disease (no vs yes), International Prognostic Index score (0 vs 1), and chemotherapy (CHOP vs CHOEP vs PMitCEBO vs MACOP-B). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive 1 of the following chemotherapy regimens according to participating country:

• CHOP: Patients receive cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1 and oral prednisone or prednisolone on days 1-5. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
• CHOEP-21: Patients receive cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1; etoposide IV on days 1-3; and oral prednisone on days 1-5. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
• PMitCEBO: Patients receive mitoxantrone IV, cyclophosphamide IV, and etoposide IV on day 1; vincristine IV and bleomycin IV on day 8; and oral prednisolone daily during weeks 1-4 and every other day during week 5. Treatment repeats every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity.
• MACOP-B: Patients receive cyclophosphamide IV and doxorubicin IV on days 1, 15, 29, 43, 57, and 71; methotrexate IV and vincristine IV on days 8, 36, and 64; bleomycin IV and vincristine IV on days 22, 50, and 78; and oral or intramuscular prednisone on days 1-84. Treatment continues in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive arm I regimens (according to participating country) and rituximab as follows:

• CHOP and rituximab: Patients receive CHOP as in arm I and rituximab IV on day 1.
• CHOEP-21 and rituximab: Patients receive CHOEP-21 as in arm I and rituximab IV on day 1.
• PMitCEBO and rituximab: Patients receive PMitCEBO as in arm I and rituximab IV on day 1 during courses 1 and 4; on day 8 during courses 2 and 5; and on day 1 at 1 and 4 weeks after completion of the last course of PMitCEBO chemotherapy.
• MACOP-B and rituximab: Patients receive MACOP-B as in arm I and rituximab IV on days 1, 22, 43, 64, 85, and 106.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 820 patients will be accrued for this study within approximately 2 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed diffuse large B-cell non-Hodgkin's lymphoma according to REAL classification

• Diagnosed within the past 6 weeks
• CD20+ disease
• Ann Arbor stage II, III, or IV disease or stage I bulky disease
• International Prognostic Index (IPI) score of 0 or 1

• Score 0 defined by all of the following:

• Stage I or II disease
• ECOG performance status of 0 or 1
• Lactic dehydrogenase (LDH) no greater than upper limit of normal (ULN)
• Score 1 defined by 1 of the following:

• Stage I or II disease; ECOG performance status of 0 or 1; and LDH greater than ULN
• Stage I or II disease; ECOG performance status 2 or 3; and LDH no greater than ULN
• Stage III or IV disease; ECOG performance status 0 or 1; and LDH no greater than ULN
• Previously untreated disease
• Mediastinal B-cell lymphoma allowed
• No secondary lymphoma after prior chemotherapy or radiotherapy for other malignancies
• No transformed lymphoma
• No primary CNS lymphoma
• No primary gastrointestinal (MALT) lymphoma
• No post-transplant lymphoproliferative disorder

PATIENT CHARACTERISTICS:

Age

• 18 to 60

Performance status

• See Disease Characteristics
• ECOG 0-3

Life expectancy

• At least 3 months

Hematopoietic

• Not specified

Hepatic

• Bilirubin no greater than 2.0 mg/dL*
• Transaminases no greater than 3 times normal*
• No active chronic hepatitis B or C infection NOTE: *Unless related to lymphoma

Renal

• Creatinine no greater than 2 times normal* NOTE: *Unless related to lymphoma

Cardiovascular

• No myocardial infarction within the past 6 months
• No uncompensated heart failure
• No dilatative cardiomyopathy
• No coronary heart disease with ST segment depression on ECG
• No severe uncompensated hypertension

Pulmonary

• No chronic lung disease with hypoxemia

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV negative
• No known allergic reactions against foreign proteins
• No other prior malignancy except basal cell skin cancer or carcinoma in situ of the cervix
• No concurrent disease that would preclude study treatment
• No active infections requiring systemic antibiotics or antiviral medications
• No severe uncompensated diabetes mellitus
• No clinical signs of cerebral dysfunction
• No severe psychiatric disease

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior murine antibodies

Chemotherapy

• No other concurrent anticancer chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• No concurrent response-adapted (slow response or unconfirmed complete response) radiotherapy

Surgery

• Not specified

Other

• No prior lymphoma-specific treatment
• More than 12 weeks since prior participation in another clinical trial
• No prior participation in this study
• No other concurrent study medication