RATIONALE: Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. 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. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin, vincristine, and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving lenalidomide together with rituximab and combination chemotherapy may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of lenalidomide when given together with rituximab and combination chemotherapy and to see how well they work in treating patients with newly diagnosed stage II, stage III, or stage IV diffuse large cell or follicular B-cell lymphoma.

OBJECTIVES:

Primary

• To determine the maximum tolerated dose of lenalidomide when given in combination with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone in patients with newly diagnosed stage II-IV diffuse large cell or grade 3 follicular B-cell lymphoma. (Phase I)
• To assess the efficacy of this regimen, in terms of event-free survival and response rate, in these patients. (Phase II)
• To assess the safety of this regimen in these patients. (Phase II)

Secondary

• To assess the host immune function at baseline and after treatment and correlate these parameters with tumor response and event-free survival.

OUTLINE: This is a multicenter, phase I dose-escalation study of lenalidomide followed by a phase II study.

• Phase I: Patients receive rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine IV on day 1, oral prednisone on days 1-5, and oral lenalidomide on days 1-10. Patients also receive pegfilgrastim subcutaneously on day 2. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
• Phase II: Patients receive lenalidomide at the maximum tolerated dose determined in phase I and rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, prednisone, and pegfilgrastim as in phase I.

Blood is collected at baseline, before course 3, and after completion of study treatment for translational research studies. Research studies include immune function and cytokine analysis, T- and B- quantitative lymphocyte analysis, and single nucleotide polymorphism analysis.

After completion of study therapy, patients are followed every 3 months for 1 year, every 4 months for 1 year, and then every 6 months for 3 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed diffuse large cell or grade 3A/B follicular lymphoma

  • Newly diagnosed disease
  • Stage II, III, or IV disease

• Measurable disease, defined as ≥ 1 lesion ≥ 1.5 cm in one diameter, as detected by CT scan or PET-CT scan (PET/CT fusion)

• CD20-positive disease

• No post-transplant lymphoproliferative disorder (PTLD)

• No CNS lymphoma or cerebrospinal fluid involvement with malignant lymphoma cells

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2

• ANC ≥ 1,500/mm³

• Platelet count ≥ 100,000/mm³

• Total bilirubin ≤ 1.5 times upper limit of normal (ULN) OR direct bilirubin normal

• Alkaline phosphatase ≤ 3 times ULN (5 times ULN if direct liver involvement by lymphoma)

• AST ≤ 3 times ULN (5 times ULN if direct liver involvement by lymphoma)

• Creatinine ≤ 2 times ULN

• Not pregnant or nursing

• Negative pregnancy test

• Fertile female patients must use effective double-method contraception for ≥ 28 days before, during, and for ≥ 28 days after completion of study therapy

• Fertile male patients must use effective contraception during and for ≥ 28 days after completion of study therapy, even if they have had a successful vasectomy

• No blood, sperm, or semen donation during and for ≥ 28 days after completion of study therapy

• Willing to return to enrolling institution for follow-up

• Willing to provide blood samples for translational research purposes

• No comorbid systemic illness or other severe concurrent disease that, in the judgment of the investigator, would preclude study entry or significantly interfere with the proper assessment of safety and toxicity of the prescribed study regimen

• No known HIV positivity

• Not immunocompromised

• No concurrent uncontrolled illness including, but not limited to, any of the following:

  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness/social situation that would preclude compliance with study requirements

• No other active malignancy, except localized nonmelanotic skin cancer or any cancer that, in the judgment of the investigator, has been treated with curative intent and will not interfere with the study treatment plan and response assessment

• No myocardial infarction within the past 6 months

• No congestive heart failure requiring ongoing maintenance therapy for life-threatening ventricular arrhythmias

• Ejection fraction ≥ 45% by MUGA or ECHO

• No history of life threatening or recurrent thrombosis/embolism (unless on anticoagulation therapy during study treatment)

PRIOR CONCURRENT THERAPY:

• No prior radiotherapy to ≥ 25% of the bone marrow
• No concurrent erythroid-stimulating agents (e.g., Procrit, Aranesp)
• No other concurrent treatment for lymphoma
• No concurrent radiotherapy, chemotherapy, or immunotherapy for another active malignancy
• Able to receive concurrent prophylactic anticoagulation therapy (e.g., low-dose aspirin [81 mg] daily or an alternative prophylaxis [e.g., warfarin or low molecular weight heparin])