Obinutuzumab and Lenalidomide in Treating Patients With Previously Untreated Stage II-IV Grade 1-3a Follicular Lymphoma

• A diagnosis of follicular lymphoma (grades 1, 2, or 3a), untreated
• Able and willing to provide written informed consent and to comply with the study protocol
• Bi-dimensionally measurable disease, with at least one mass lesion >= 2 cm in longest diameter by computed tomography (CT), positron emission tomography (PET)/CT, and/or magnetic resonance imaging (MRI)

• Must be in need of therapy as evidenced by at least one of the following criteria:

  • Bulky disease defined as:

    • A nodal or extranodal (except spleen) mass > 7 cm in its greater diameter or,
    • At least 3 nodal or extranodal sites >= 3 cm in diameter

  • Presence of at least one B symptom:

    • Fever (> 38 C) not due to infectious etiology
    • Night sweats
    • Weight loss > 10% in the past 6 months
  • Fatigue due to lymphoma
  • Splenomegaly (> 13 cm)
  • Compression syndrome (ureteral, orbital, gastrointestinal)

  • Any of the following cytopenias due to lymphoma:

    • Hemoglobin =\< 10 g/dL
    • Platelets =\< 100 x 10\^9/L
    • Absolute neutrophil count (ANC) \< 1.5 x 10\^9/L
  • Pleural or peritoneal effusion
  • Lactate dehydrogenase (LDH) > upper limit of normal (ULN) or beta-2 microglobulin > ULN
• Stage II, III, or IV disease
• Eastern cooperative oncology group (ECOG) performance status =\< 2
• Absolute neutrophil count (ANC) > 1.0 x 10\^9/L
• Platelet count > 75 x 10\^9/L
• Serum aspartate transaminase (AST) or alanine transaminase (ALT) \< 3 x upper limit of normal (ULN)
• Creatinine clearance > 30 ml/min calculated by modified Cockcroft-Gault formula
• Bilirubin \< 1.5 x ULN unless bilirubin is due to Gilbert's syndrome, documented liver involvement with lymphoma, or of non-hepatic origin, in which case bilirubin should not exceed 3 g/dL
• Women of childbearing potential and men who are sexually active must practice reliable contraceptive measures started at least 4 weeks before study therapy and continued for at least 4 weeks following discontinuation therapy; females of childbearing potential must either completely abstain from heterosexual sexual contact or must use 2 methods of reliable contraception; reliable contraceptive methods include 1 highly effective method (intrauterine device, birth control pills, hormonal patches, injections, vaginal rings, or implants) and at least 1 additional method (condom, diaphragm, or cervical cap) every time they have sex with a male; males who are sexually active must be practicing complete abstinence or agree to a condom during sexual contact with a pregnant female or female of child bearing potential; men must agree to not donate sperm during and after the study
• Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [beta-hCG]) pregnancy test at screening; women who are pregnant or breastfeeding are ineligible for this study; females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid Risk Evaluation and Mitigation Strategies (REMS) program
• All study participants must be registered into the mandatory Revlimid REMS program, and be willing and able to comply with the requirements of the REMS program
• Sign (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study

Exclusion Criteria:

• Known active central nervous system lymphoma or leptomeningeal disease
• Follicular lymphoma with evidence of diffuse large B-cell transformation
• Grade 3b follicular lymphoma

• Any prior history of other malignancy besides follicular lymphoma, unless the patient has been free of disease for >= 5 years and felt to be at low risk for recurrence by the treating physician, except:

  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  • Adequately treated cervical carcinoma in situ without evidence of disease
• Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of lenalidomide capsules, or put the study outcomes at undue risk

• Known history of human immunodeficiency virus (HIV), active hepatitis C virus, active hepatitis B virus infection, or any uncontrolled active systemic infection

  • Patients with inactive hepatitis B infection must adhere to hepatitis B reactivation prophylaxis unless contraindicated
• Prior use of lenalidomide
• Concurrent systemic immunosuppressant therapy (e.g., cyclosporine, tacrolimus, etc., or chronic administration glucocorticoid equivalent of > 10 mg/day of prednisone) within 28 days of the first dose of study drug
• Known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or to any component of rituximab
• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification
• Significant screening electrocardiogram (ECG) abnormalities including left bundle branch block, 2nd degree atrioventricular (AV) block, type II AV block, or 3rd degree block
• Vaccinated with live, attenuated vaccines within 4 weeks of study entry
• Lactating or pregnant subjects
• Administration of any investigational agent within 28 days of first dose of study drug
• Patients who have undergone major surgery within 14 days

• Patients with the following:

  • Bleeding diathesis or patients in whom prophylactic antithrombotic therapy is otherwise contraindicated
  • Patients with prior deep vein thrombosis (DVT), pulmonary embolism (PE), or arterial thromboembolism
  • Patients with ischemic stroke or transient ischemic attack (TIA)