Lenalidomide and Combination Chemotherapy (DA-EPOCH-R) in Treating Patients With MYC-Associated B-Cell Lymphomas

Inclusion Criteria 1. B-cell lymphoma with comprehensive immunohistochemistry (IHC) panel establishing lineage (CD20, CD3) and cell of origin (CD10, BCL6 and MUM1) in addition to proliferative/prognostic markers (Ki-67, C-myc and BCL2). DHL will be identified using cytogenetics and/or immunohistochemistry as detailed in section 4.1.2 below. 2. To define DHL, patients must have evidence of C-myc \[defined as: Cytogenetic evidence (FISH or karyotype) of C-myc breaks (Increased copy number in itself is not considered positivity for C-myc) OR Positive IHC defined as \>40% of the lymphoma cells staining for C-myc\] PLUS either: 1. Breaks in BCL-2 via cytogenetic studies or 2. BCL-2 immunopositivity in \>70% of lymphoma cells. 3. Patients are allowed to have received radiotherapy before enrollment if radiation was given to alleviate pain and/or neurologic compromise as long as there remains areas of measurable disease present. Further, at the investigator's discretion and for patients who are unstable, one cycle of R-CHOP is allowed prior to enrollment but no more than one cycle. For purposes of this trial, prednisone or other corticosteroids used for non-lymphomatous conditions will be allowed. In addition, a prior/recent short course (\< 2 weeks) of steroids for symptom relief of lymphoma-related symptoms will be allowed. 4. AST and ALT \< 3 x upper limit of normal (ULN), and total bilirubin \<1.5 x ULN (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver involvement with NHL or stable chronic liver disease per investigator assessment). 5. Patients must have adequate renal function by virtue of GFR \> 50 ml/minute using Cockroft-Gault formula. 6. Patients must have adequate bone marrow function (platelets \>100,000 and ANC \>1,200). Patients with bone marrow involvement are allowed at the investigator's discretion regardless of cytopenias. 7. ECOG PS 0-2. 8. Age ≥ 18 years. 9. All study participants must be registered into the mandatory lenalidomide REMS® program, and be willing and able to comply with the requirements of the REMS® program. 10. Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the lenalidomide REMS® program. (Please see study schema for further details) 11. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin). 12. Ability to read, understand, and sign a written informed consent approved by each institutional IRB. Alternatively, patients with legal guardians who can read, understand, and sign written informed consent may also enroll. Exclusion Criteria 1. Prior therapy for lymphoma 2. Known CNS involvement 3. Known HIV positive status 4. Pregnant females 5. Burkitt and/or precursor lymphoblastic leukemia/lymphoma. 6. Prior pomalidomide exposure 7. Known hypersensitivity to lenalidomide or thalidomide 8. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs. 9. Subjects who have currently active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver involvement with NHL or stable chronic liver disease per investigator assessment). 10. Treatment with any known non-marketed drug substance or experimental therapy within 4 weeks prior to enrollment, or currently participating in any other interventional clinical study for NHL or any other illness (except observational, prevention, and/or registry trials). 11. No current malignancy. Subjects who have been free of malignancy for at least 2 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma (any site) are eligible. Women with a history of cervical cancers are allowed. 12. Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis and active Hepatitis C. 13. History of significant cerebrovascular disease in the past 3 months or ongoing event with active symptoms or sequelae. 14. Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive, the subject will be excluded if unable to tolerate and/or receive anti-Hepatitis-B therapy. Positive serology because of prior vaccination is allowed. 15. Positive serology for hepatitis C (HC) defined as a positive test for HCAb. 16. Inability to comply with study or follow-up testing and procedures.