Rituximab, Lenalidomide, and Ibrutinib in Treating Patients With Previously Untreated Stage II-IV Follicular Lymphoma

Inclusion Criteria

• •Previously untreated, histologically confirmed follicular lymphoma, World Health Organization (WHO) classification grade I, II, or IIIa (\> 15 centroblasts per high power field with centrocytes present) that is stage III, IV, or bulky (i.e., single mass \>= 7 cm in any unidimensional measurement) stage II and requires therapy at the discretion of the primary physician
• •* Bone marrow biopsies as the sole means of diagnosis are not acceptable, but they may be submitted in conjunction with nodal biopsies; fine needle aspirates are not acceptable for diagnosis
• •* Failure to submit pathology specimens within 60 days of patient registration will be considered a major protocol violation
• •* Institutional flow cytometry or immunohistochemistry must confirm cluster of differentiation 20 (CD20) antigen expression
• •* All risk by follicular lymphoma international prognostic index (FLIPI): 0-5 risk factors
• •No prior systemic therapy for non-Hodgkin lymphoma (NHL) including chemotherapy or immunotherapy (e.g., monoclonal antibody-based therapy), radiation therapy, or radioimmunotherapy
• •For non-NHL conditions, no chemotherapy, radiotherapy, or major surgery within 4 weeks (6 weeks for nitrosoureas or mitomycin C) of enrollment; no patients who have ongoing adverse events from agents administered more than 4 weeks previously
• •No prior exposure to any of the study agents
• •No corticosteroids within two weeks prior to study entry, except for maintenance therapy for a non-malignant disease; dose of corticosteroid or prednisone (or its equivalent) should not exceed 20 mg per day; corticosteroid premedication for rituximab is allowed
• •Eastern Cooperative Oncology Group (ECOG) performance status must be =\< 2
• •Measurable disease must be present either on physical examination or imaging studies; non-measurable disease alone is not acceptable; any tumor mass \> 1 cm is acceptable; lesions that are considered non-measurable include the following:
• •* Bone lesions (lesions if present should be noted)
• •* Ascites
• •* Pleural/pericardial effusion
• •* Lymphangitis cutis/pulmonis
• •* Bone marrow (involvement by NHL should be noted)
• •Patients with human immunodeficiency virus (HIV) infection are eligible, provided they meet the following:
• •* No evidence of coinfection with hepatitis B or C
• •* CD4+ cell count \>= 400/mm\^3
• •* No evidence of resistant strains of HIV
• •* If not on anti-HIV therapy, HIV viral load \< 10,000 copies HIV ribonucleic acid (RNA)/mL
• •* If on anti-HIV therapy, HIV viral load \< 50 copies HIV RNA/mL
• •* No history of acquired immunodeficiency syndrome (AIDS)-defining conditions
• •* No use of strong cytochrome P450, family 3, subfamily A, polypeptide 4/5 (CYP3A4/5) inhibitors or inducers
• •No known central nervous system (CNS) involvement by lymphoma
• •No treatment with strong inhibitors or inducers of CYP3A4/5
• •No history of erythema multiforme, toxic epidermal necrolysis or Stevens-Johnson syndrome
• •No history of uncontrolled seizures
• •No autoimmune disorder that requires active immunosuppression
• •No intracranial hemorrhage within the last 6 months
• •Patients must be non-pregnant and non-nursing; 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 and again within 24 hours prior to starting cycle 1 of lenalidomide; further, they 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 starting lenalidomide; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP, even if they have had a successful vasectomy; a FCBP is a sexually mature woman who: 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 preceding 24 consecutive months); all patients must be counseled by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure
• •No known human anti-chimeric antibody (HACA) positivity
• •No anticoagulation with warfarin is allowed; patients must not have received warfarin within 28 days prior to registration; alternative anticoagulant may be used
• •Patients must not be receiving concurrent treatment with other investigational drugs
• •Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to lenalidomide, ibrutinib, or other agents used in study
• •Patients must not have presence of transfusion-dependent thrombocytopenia
• •No currently active clinically significant cardiovascular disease including the following:
• •* No uncontrolled arrhythmia
• •* No congestive heart failure
• •* No class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification
• •* No history of myocardial infarction, deep venous or arterial thrombosis within 6 months prior to registration
• •No prior malignancy with the exceptions listed below:
• •* Malignancy treated with curative intent and with no evidence of active disease for more than 3 years prior to screening and felt to be at low risk for recurrence by the treating physician
• •* Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current evidence of disease
• •* Adequately treated cervical carcinoma in situ without current evidence of disease
• •Patients must be \>= 18 years of age
• •Absolute neutrophil count (ANC) \>= 1,000/microliter (should be present independent of growth factor or transfusion support for at least 7 days prior to first dose of study drug)
• •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x upper limit of normal (ULN) (should be present independent of growth factor or transfusion support for at least 7 days prior to first dose of study drug)
• •Total bilirubin =\< 1.5 x ULN unless attributable to Gilbert's syndrome (should be present independent of growth factor or transfusion support for at least 7 days prior to first dose of study drug)