RATIONALE: Monoclonal antibodies, such as rituximab, 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. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Lenalidomide may also stop the growth of non-Hodgkin's lymphoma by blocking blood flow to the cancer. Giving rituximab together with lenalidomide may kill more cancer cells.

PURPOSE: This randomized phase II trial is studying how well rituximab and/or lenalidomide works in treating patients with follicular non-Hodgkin's lymphoma that has relapsed after previous rituximab-based combination therapy.

OBJECTIVES:

Primary

• Compare the overall and complete response rate in patients with follicular non-Hodgkin's lymphoma that has relapsed after prior rituximab-based combination therapy treated with rituximab and/or lenalidomide.
• Compare time to progression (TTP) in patients treated with these regimens.

Secondary

• Compare TTP after prior rituximab-based combination therapy vs TTP in patients treated with these regimens.
• Determine the toxicity profile in patients treated with these regimens.
• Correlate Fc-receptor-polymorphism profiling with response in patients treated with these.
• Correlate changes in natural killer (NK) cells, activated NK cells, activated T-cells, and several plasma cytokines after exposure to lenalidomide therapy, followed by rituximab, with objective response rate in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to time to disease progression after prior rituximab-based combination therapy (≥ 6 months and < 12 months vs ≥ 12 months and < 24 months vs ≥ 24 months). Patients are randomized to 1 of 3 treatment arms.

• Arm I: Patients receive rituximab IV on days 1, 8, 15, and 22.
• Arm II: Patients receive oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
• Arm III: Patients receive lenalidomide as in arm II. Treatment with lenalidomide repeats every 28 for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients also receive rituximab IV on days 8, 15, and 22 of course 1 and day 1 of course 2.

After completion of study treatment, patients are followed for up to 10 years from study entry.

PROJECTED ACCRUAL: A total of 180 patients (90 for arm I, 45 each for arms II and III) will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically* confirmed follicular non-Hodgkin's lymphoma
• Grade 1, 2, or 3a disease (> 15 centroblasts per high-power field with centrocytes present) NOTE: *Bone marrow biopsy as the sole means of diagnosis is not acceptable; fine-needle aspirates are not acceptable
• Confirmed CD20 antigen expression by flow cytometry or immunohistochemistry
• Measurable disease > 1 cm
• No non-measurable disease only, including any of the following:
• Bone lesions
• Ascites
• Pleural/pericardial effusion
• Lymphangitis cutis/pulmonis
• Bone marrow involvement
• Must have been treated with and achieved a complete or partial response or stable disease after prior rituximab-based combination therapy (e.g., rituximab and chemotherapy given either concurrently or within 30 days of each other)
• Time to disease progression ≥ 6 months after first rituximab dose in prior rituximab-based combination therapy
• No known CNS involvement

PATIENT CHARACTERISTICS:

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,000/μL
• Platelet count ≥ 75,000/µL

Hepatic

• Bilirubin ≤ 2 times upper limit of normal (ULN) (unless due to Gilbert's disease or lymphoma)

Renal

• Creatinine ≤ 2 times ULN (unless due to lymphoma)

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No known HIV positivity
• No "currently active" secondary malignancy (e.g., Waldenstrom's macroglobulinemia) except nonmelanoma skin cancer
• Patients are not considered to have a "currently active" second malignancy if they have completed anticancer therapy and deemed to have < 30% risk of relapse by their physician

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Disease Characteristics
• See Radiotherapy

Chemotherapy

• See Disease Characteristics
• No concurrent chemotherapy

Endocrine therapy

• More than 2 weeks since prior corticosteroids except for maintenance therapy (at a dose ≤ 20 mg/day) for a nonmalignant disease
• No concurrent hormonal therapy except for the following:
• Steroids for adrenal failure
• Hormones for non-disease-related conditions (e.g., insulin or diabetes)
• No concurrent dexamethasone or other steroids for antiemetics
• Concurrent dexamethasone for infusion reactions allowed

Radiotherapy

• No prior radioimmunotherapy

Other

• No other concurrent investigational or commercial agents or therapies for lymphoma