This phase II trial is studying how well giving combination chemotherapy together with rituximab and bevacizumab works in treating older patients with stage II, stage III, or stage IV diffuse large B-cell lymphoma. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. Monoclonal antibodies, such as rituximab and bevacizumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Bevacizumab may also stop the growth of cancer cells by blocking blood flow to the cancer. Giving combination chemotherapy together with monoclonal antibodies may kill more cancer cells.

PRIMARY OBJECTIVES:

I. To estimate the 1-year progression-free survival rate in patients with advanced stage diffuse large B-cell NHL treated with CHOP - rituximab - bevacizumab.

II. To estimate the response rate (complete, complete unconfirmed, and partial) and 2-year progression-free survival of this regimen in patients with advanced stage diffuse large B-cell NHL.

III. To evaluate the toxicities associated with this regimen. IV. To correlate angiogenic biomarkers with patient outcome.

OUTLINE: This is a multicenter study.

Patients receive rituximab IV, bevacizumab IV over 30-90 minutes, cyclophosphamide IV over 15 minutes, doxorubicin IV, and vincristine IV on day 1. Patients also receive oral prednisone on days 1-5. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed at least every 6 months for 2 years and then annually for 3 years.

Inclusion Criteria:

• All patients must have previously untreated Stage III, IV, or bulky Stage II diffuse large B-cell non-Hodgkin's lymphoma which is positive for CD20; a report providing confirmation of CD20 expression must be submitted

• Pathology Review: Adequate sections from the original diagnostic specimen must be available for submission for review by the SWOG Lymphoma Pathology Laboratory; an adequate biopsy requires sufficient tissue to establish the architecture and a REAL or WHO histologic subtype with certainty; thus, core biopsies, especially multiple core biopsies may be adequate; whereas, needle aspirations or cytologies are not adequate

• Specimens for analysis of angiogenic markers must be submitted to the University of Arizona

• All patients must have bidimensionally measurable disease documented within 28 days prior to registration; patients with non-measurable disease in addition to measurable disease must have all nonmeasurable disease assessed within 42 days prior to registration

• Patients must have a unilateral or bilateral bone marrow aspirate and biopsy performed within 42 days prior to registration

• Patients must have a CT scan of the chest/abdomen and pelvis performed within 28 days prior to registration

• Patients must not have clinical evidence of central nervous system involvement by lymphoma; any laboratory or radiographic tests performed to assess CNS involvement must be negative within 42 days of registration

• Patients may not have a previous diagnosis of indolent lymphoma (histologic transformation or mixed histologies with an indolent or nodular component are ineligible)

• Patients must not have received prior chemotherapy, radiation, or antibody-based therapy for lymphoma

• Patients must have a Zubrod performance status of 0 - 2

• Serum LDH must be measured within 28 days prior to registration

• Patients must have a cardiac ejection fraction >= 45% by MUGA scan or a 2-d ECHO with no significant abnormalities within 42 days prior to registration

• Absolute neutrophil count > 1,000/mcL obtained within 28 days prior to registration

• Platelet count > 100,000/mcL obtained within 28 days prior to registration

• Serum creatinine < 2 x the institutional upper limit of normal within 28 days prior to registration

• Patients must have urine proteinuria screened by dipstick or urine analysis within 28 days prior to registration; in patients with proteinuria >= +1 or urine protein:creatinine ratio >= 1.0, a 24 hour urine protein should be obtained and the level < 1gm/24 hours to be eligible

• Patients must not have a history of hypersensitivity reaction to products containing Polysorbate 20 (Tween 20), Chinese hamster ovary cell products, or recombinant human antibodies

• Patients known to be HIV-positive, or who have a history of solid organ transplantation are ineligible due to the concern over immunosuppression associated with B-cell depletion; patients at high risk of Hepatitis B virus infection should be screened before initiation of rituximab

• Patients must not have uncontrolled hypertension

• Patients with a history of prior myocardial infarction, unstable angina, stroke, or arterial thrombosis within 6 months are ineligible

• Patients with clinically significant peripheral vascular disease, a serious or non-healing wound, ulcer, or bone fracture, or a bleeding diathesis/coagulopathy are ineligible

• Patients with a history of venous thrombosis requiring full-dose anticoagulation or currently receiving anticoagulation therapy may be eligible provided that the following criteria are met:

  • The patient must have an in-range INR (usually between 2 and 3) on a stable dose of warfarin or on a stable dose of LMW heparin
  • The patient must not have bleeding or pathological conditions that carry a high risk of bleeding (e.g. tumor involving major vessels, known varices)

• Patients who have had a major surgical procedure or traumatic injury within 28 days prior to registration or anticipation of major surgical procedure during the course of therapy are ineligible

• Patients with a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months are ineligible

• Patients requiring continuous supplemental oxygen therapy are ineligible

• No prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer for which the patient has been disease-free for five years

• Pregnant or nursing women may not participate in this study due to the potential for congenital abnormalities, and of harm to nursing infants due to this treatment regimen; women or men of reproductive potential may not participate unless they have agreed to use an effective contraceptive method during the study period and for at least 6 months after the completion of therapy

• If Day 28 or 42 falls on a weekend or holiday, the limit may be extended to the next working day

• Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines

• At the time of patient registration, the treating institution's name and ID number must be provided to the Data Operations Center in Seattle in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered into the data base