Inclusion Criteria:

PRE-REGISTRATION (STEP 0)

• Histologically confirmed DLBCL expressing CD20 antigen; patients with transformed lymphoma are excluded; in this regard, patients with composite lymphoma in the diagnostic tissue (concomitant DLBCL and follicular or other low-grade lymphoma component) are excluded; however, patients with DLBCL in primary diagnostic tissue but a bone marrow that shows low grade or indeterminate lymphoma are eligible; patients with known primary mediastinal large B-cell lymphoma (PMLBCL) are excluded; similarly, patients with known c-myc translocation (by fluorescence in situ hybridization) positive DLBCL are encouraged to participate in trials specifically designed for these patients; however patients with known c-myc DLBC positive are NOT excluded from this study; c-myc testing prior to study enrollment is NOT required
• Stages II bulky disease (defined as mass size of more than 10 cm), stage III, or IV (Ann Arbor staging); patients with stage I and stage II non-bulky disease are excluded from this study
• A paraffin-embedded tumor tissue specimen from the initial diagnostic biopsy has been located and ready to ship to the Mayo Clinic Lymphoma Laboratory following pre-registration; Note: excisional tumor biopsy is preferred; core needle biopsies will be considered adequate if there is enough tissue for the mandatory central pathology review immunohistochemistry and Genomics Education Partnership (GEP); submission of a tumor block is preferred, but if unavailable submit alternative materials
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Previously untreated and not receiving any other agent that would be considered as a treatment for the lymphoma; for subjects with severe systemic symptoms, compressive disease, or rapidly progressing symptomatic adenopathy, are allowed for lymphoma associated symptom treatment with up to 1 mg/kg/day prednisone, or equivalent, for a maximum of 7 days is permitted prior to beginning the treatment, at the discretion of the investigator; a washout period does not apply
• No known central nervous system (CNS) lymphoma or cerebrospinal fluid involvement with malignant lymphoma cells; these patients are usually treated with CNS directed therapy; screening for cerebrospinal fluid (CSF)/CNS involvement is NOT required but can be performed per treating medical doctor (MD) discretion; intrathecal (IT) methotrexate or IT cytarabine prophylaxis in patients with negative CSF who are felt to be at high risk of CNS relapse is allowed per local MD discretion; this should be noted on the treatment form
• Absence of history of myocardial infarction =< 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
• Absence of history of deep venous thrombosis/embolism, threatening thromboembolism or known thrombophilia; patients with a history of deep vein thrombosis(DVT)/pulmonary embolism (PE) or thrombophilia may participate if they are willing to be on full anticoagulation during the treatment if randomized to rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R2CHOP) arm A; full anticoagulation is defined as warfarin, factor X inhibitors, or low molecular weight heparin at therapeutic doses
• Patient must be able and willing to receive anticoagulation therapy with aspirin 70-325 mg daily prophylaxis, low molecular weight heparin, factor X inhibitors or warfarin; patients unable or unwilling to take any prophylaxis are NOT eligible
• Absence of history of acquired immune deficiency syndrome (AIDS)-related conditions (other than the presenting DLBCL) or post-transplant lymphoproliferative disorder (PTLD) in immunocompromised patients; patients with human immunodeficiency virus (HIV) on antiretroviral therapy other than zidovudine (AZT) and/or stavudine and without prior AIDS defining conditions and adequate CD4 count (> 400) are eligible
• No other active malignancy requiring therapy such as radiation, chemotherapy, or immunotherapy; exceptions to this are as follows: localized non-melanotic skin cancer and 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 history of radiation therapy to ≥ 25% of the bone marrow for other diseases or history of anthracycline therapy
• Patients must not be receiving erythroid stimulating agents (EPO: Procrit, Aranesp)

RANDOMIZATION (STEP 1)

• Patient meets the eligibility criteria outlined above
• Site has received notification from Mayo Clinic - Rochester Division of Hematopathology of the central confirmation of diagnosis and tissue adequacy for mandatory research studies
• Patients must have measurable disease (at least 1 lesion of ≥ 1.5 cm in one diameter) as detected by computed tomography (CT) or the CT images of the positron emission tomography (PET)/CT
• International Prognostic Index (IPI) of 2 or greater
• Ejection fraction of ≥ 45% by either multi-gated acquisition (MUGA) scan or echocardiogram (ECHO)
• Absence of co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens, including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Absolute neutrophil count (ANC) ≥ 1500
• Platelets (PLT) ≥ 100,000
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) or if total bilirubin is > 1.5 x ULN, the direct bilirubin must be normal
• Alkaline (Alk.) phosphatase ≤ 3 x ULN unless evidence of the direct liver involvement by lymphoma - then ≤ 5 x ULN
• Aspartate aminotransferase (AST) ≤ 3 x ULN unless evidence of the direct liver involvement by lymphoma - then ≤ 5 x ULN
• Creatinine ≤ 2 x ULN or creatinine clearance (CrCl) > 30 ml/min
• Women must not be pregnant or breast-feeding
• Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days prior to and again within 24 hours of starting lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide; FCBP must also agree to ongoing pregnancy testing; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy; all patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure