This phase II trial studies how well giving rituximab, lenalidomide, and ibrutinib with chemotherapy works in treating patients with high-risk diffuse large B-cell lymphoma. High-risk large B-cell lymphoma is a type of cancer of the immune system that is usually fast-growing in the body. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Biological therapies, such as lenalidomide, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Drugs used in chemotherapy, such as etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving rituximab, ibrutinib, and lenalidomide with combination chemotherapy may kill more cancer cells.

PRIMARY OBJECTIVES:

I. To determine the overall response rate at the end of 2 cycles of therapy with rituximab, lenalidomide, and ibrutinib in patients with high risk newly diagnosed non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB DLBCL).

II. To determine the complete response rate at the end of 6 cycles of therapy with rituximab, lenalidomide, and ibrutinib combined with chemotherapy (cyclophosphamide, doxorubicin hydrochloride [hydroxydaunorubicin hydrochloride], vincristine sulfate [Oncovin], prednisone [CHOP] or etoposide, prednisone, vincristine sulfate [Oncovin], cyclophosphamide, doxorubicin hydrochloride [hydroxydaunorubicin hydrochloride] [EPOCH]) in patients with high risk newly diagnosed non-GCB DLBCL.

SECONDARY OBJECTIVES:

I. To determine the overall response rate, landmark survival outcomes (progression free and overall survival), and safety of lenalidomide and ibrutinib with chemotherapy (CHOP or EPOCH) in patients with high risk newly diagnosed non-GCB DLBCL.

II. To evaluate descriptively the complete response rate in rituximab, lenalidomide, ibrutinib (RLI)-CHOP and in RLI-EPOCH.

EXPLORATORY OBJECTIVES:

I. To evaluate the baseline and therapy induced changes in the profile of mutations, gene expression, minimal residual disease clonotype levels, immune cell subsets, and tumor protein expression in tumor biopsy and blood samples in patients with high risk newly diagnosed non-GCB DLBCL.

OUTLINE:

SMART START: Patients receive rituximab intravenously (IV) over 4-6 hours on day 1, lenalidomide orally (PO) once daily (QD) on days 1-10, and ibrutinib PO QD on days 1-21. Treatment repeats every 21 days for 2 cycles in the absence of disease progression or unacceptable toxicity.

RLI WITH EPOCH: After SMART START therapy, patients receive rituximab IV over 4-6 hours on day 1, lenalidomide PO QD on days 1-10, and ibrutinib PO QD on days 1-21. Patients also receive etoposide IV over 24 hours on days 1-4, prednisone PO QD on days 1-5, vincristine sulfate IV over 24 hours on days 1-4, doxorubicin hydrochloride IV over 24 hours on days 1-4, and cyclophosphamide IV over 1 hour on day 5. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

RLI WITH R-CHOP: After SMART START therapy, patients receive rituximab IV over 4-6 hours on day 1, lenalidomide PO QD on days 1-10, and ibrutinib PO QD on days 1-21. Patients also receive prednisone PO QD on days 1-5, vincristine sulfate IV over 1 hour on day 1, doxorubicin hydrochloride IV over 1 hour on day 1, and cyclophosphamide IV over 1 hour on day 1. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year, and then every 4 months for another year.

Inclusion Criteria:

• Histopathologically confirmed diagnosis of previously untreated DLBCL of the non-GCB DLBCL subtype

• No prior treatment except a prior limited-field radiotherapy, a short course of glucocorticoids =< 25 mg daily of prednisone equivalent which must cease prior to day 1 of cycle 1, and/or cyclophosphamide for an urgent lymphoma related problem at diagnosis (e.g. epidural cord compression, superior vena cava syndrome)

• Patient or durable power of attorney (DPA) for healthcare must be able to understand and voluntarily sign an Institutional Review Board (IRB) -approved informed consent form

• Patients must have bi-dimensional measurable disease, as defined as radiographically apparent disease with the longest dimension of >= 1.5 cm

• Patients with performance status of =< 3 (3 only allowed if decline in status is deemed related to lymphoma and felt potentially reversible by the treating physician)

• Serum bilirubin < 1.5 x upper limit of normal (ULN) except in patients with Gilbert's syndrome as defined by > 80% unconjugated bilirubin

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN or < 5 x ULN if hepatic metastases are present

• Absolute neutrophil count (ANC) > 1000/mm^3 unless deemed related to lymphoma involvement in the bone marrow and felt potentially reversible by the treating physician

• Platelets > 100,000/mm^3 unless deemed related to lymphoma involvement in the bone marrow and felt potentially reversible by the treating physician

• Renal function assessed by calculated creatinine clearance:

  • Calculated creatinine clearance >=30 ml/min by Cockcroft-Gault formula

• Patients must be willing to receive transfusions of blood products

• All study participants must be registered into the mandatory Revlimid Risk Evaluation and Mitigation Strategy (REMS) program, and be willing and able to comply with the requirements of the REMS program

• Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [beta-hCG]) or urine pregnancy test at screening and must adhere to the scheduled pregnancy testing as required in the Revlimid REMS program

• Women of childbearing potential and men who are sexually active with a woman of childbearing potential must be practicing a highly effective method of birth control during and after the study (12 months for women and 3 months for men), consistent with local regulations regarding the use of birth control methods for subjects participating in this clinical study; men must agree to not donate sperm during and for up to 3 months after their conclusion of therapy on study

• Able to take aspirin (81 mg) daily or alternative therapy as prophylactic anticoagulation

Exclusion Criteria:

• Any serious medical condition including but not limited to uncontrolled hypertension, uncontrolled congestive heart failure within past 6 months prior to screening (class 3 [moderate] or class 4 [severe] cardiac disease as defined by the New York Heart Association Functional Classification), uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), left ventricular ejection fraction (LVEF) less than 40%, renal failure, active infection, history of invasive fungal infection, moderate to severe hepatic disease (Child Pugh class B or C), active hemorrhage, laboratory abnormality, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form; patients with history of cardiac arrhythmias should have cardiac evaluation and clearance
• Pregnant or lactating females
• Known hypersensitivity to lenalidomide or thalidomide, ibrutinib, rituximab, etoposide, vincristine, doxorubicin, cyclophosphamide, or prednisone
• Known human immunodeficiency virus (HIV) infection; patients with active hepatitis B infection (not including patients with prior hepatitis B vaccination; or positive serum hepatitis B antibody); known hepatitis C infection is allowed as long as there is no active disease and is cleared by gastrointestinal (GI) consultation
• All patients with central nervous system involvement with lymphoma
• Diagnosis of prior malignancy within the past 2 years with the exception of successfully treated basal cell carcinoma, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast; history of other malignancies are allowed if in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated, with a life expectancy > 3 years
• Significant neuropathy (grades 2 or grade 1 with pain) within 14 days prior to enrollment
• Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis not due to lymphoma
• Patients with active pulmonary embolism or deep vein thrombosis (diagnosed within 30 days of study enrollment)
• Patients with severe bradycardia (heart rate < 40 beats per minute [bpm], hypotension, light-headedness, syncope)
• Major surgery within 4 weeks of study entry, or wound that is not healed from prior surgery or trauma
• History of stroke or intracranial hemorrhage within 6 months prior to study entry
• Requires anticoagulation with warfarin or equivalent vitamin K antagonists
• Requires chronic treatment with strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitors
• Vaccinated with live, attenuated vaccines within 4 weeks of study entry

2 years