Inclusion Criteria:

• Histologically confirmed CD20+ DLBCL of the below World Health Organization (WHO) sub-classifications as assessed by Central Pathology. In the rare case that local and Central pathology disagree on DLBCL diagnosis and/or CD20+ status and, if ABC type is confirmed by Central Pathology, then the subject may still be enrolled on the basis of a local DLBCL diagnosis and/or CD20+ status at investigator discretion. A retrospective adjudication will be performed by a second Central Pathologist.
  • Not otherwise specified (NOS);
  • Associated with chronic inflammation;
  • Epstein-Barr virus positive (EBV+) of the elderly.
• ABC type determined using a validated GEP assay performed on NanoString’s nCounter® Dx Analysis System as assessed by Central Pathology. (ABC type subjects are reported by the GEP assay as eligible for this inclusion criterion, whereas subjects with an indeterminate, unclassifiable, or GCB type are not eligible).
• Adequate lymph node or tumor biopsy specimen available for Central Pathology review and GEP profiling by the NanoString nCounter® Dx Analysis System. A formalin fixed paraffin embedded lymph node or tumor biopsy acquired by a surgical incision or excision biopsy is strongly preferred. Core needle biopsy is allowed, and typically 3 – 4 passes embedded in two FFPE blocks are adequate for both local and Central Pathology evaluation (one block for local and one block for Central Pathology). Other commonly used devices (e.g., endoscopy forceps or grasp biopsy) are also acceptable provided they yield an equivalent amount of tissue. Material from a fine needle aspiration is not acceptable. If an archival specimen is not available or is not acceptable, a re-biopsy is required prior to randomization.
• Measurable disease on cross section imaging by CT that is at least 1.5 cm in the longest diameter and measurable in two perpendicular dimensions.
• Ann Arbor stage II-IV disease.
• No prior treatment for DLBCL.
• Appropriate candidate for 6 cycles of R-CHOP21.
• International Prognostic Index score of 2 or greater.
• Performance status < 2 on the Eastern Cooperative Oncology Group (ECOG) scale.
• Must be between the ages of 18 and 80 years on the date of the informed consent document signature. At the discretion of the investigator, subjects over 80 years may be included if their ECOG performance status is ≤ 1; each of their individual organ system scores is ≤ 2 using the Modified Cumulative Illness Rating Scale (CIRS) for co-morbidity (Salvi, 2008; Salvi, 2008a); and if they would otherwise be eligible for full-dose RCHOP per local practice.
• Must fulfill the following laboratory requirements:
  • Absolute neutrophil count (ANC) ≥ 1,500 cells/mm^3 (1.5 x 109/L) unless secondary to bone marrow or spleen involvement by lymphoma; in this case the limit is ≥ 1,000 cells/mm^3 (1.0 x 10^9/L). Bone marrow involvement by lymphoma is  demonstrated by recent bone marrow aspiration, bone marrow biopsy, or PET scan finding. Spleen involvement by lymphoma is demonstrated by splenomegaly;
  • Platelet count ≥ 75,000/mm3 (75 x 10^9/L) unless secondary to bone marrow or spleen involvement by lymphoma; in this case the limit is ≥ 50,000/ mm^3 (50 x 10^9/L). Bone marrow involvement by lymphoma is demonstrated by recent bone marrow aspiration, bone marrow biopsy, or PET scan finding. Spleen involvement by lymphoma is demonstrated by splenomegaly;
  • Hemoglobin ≥ 7.5 g/dL (4.7 mmol/L);
  • Serum aspartate transaminase (AST/SGOT) and alanine transaminase (ALT/SGPT) ≤ 3.0 x upper limit of normal (ULN). In the case of documented liver involvement by lymphoma, the requirement is ≤ 5.0 x ULN;
  • Serum total bilirubin ≤ 2.0 mg/dl (34 μmol/L). In the case of Gilberts Syndrome, or documented liver or pancreatic involvement by lymphoma, the requirement is ≤ 5.0 mg/dl (86 μmol/L);
  • Calculated creatinine clearance (Cockcroft-Gault formula) of ≥ 30 mL/min.
• Understand and voluntarily sign an informed consent document prior to conducting study assessments or procedures.
• Able to adhere to the study visit schedule and other protocol requirements.
• Females of childbearing potential (FCBP) must:
  • Have two negative pregnancy tests as verified by the study doctor prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices complete abstinence* from heterosexual contact;
  • Either commit to complete abstinence* from heterosexual contact (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting study therapy, during the study therapy (including dose interruptions), and for 12 months after discontinuation of study therapy.
  • * True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• Male subjects must:
  • Practice complete abstinence1 or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 28 days following investigational product discontinuation, even if he has undergone a successful vasectomy;
  • Agree to not donate semen during investigational product therapy and for 28 days after discontinuation of investigational product therapy.
• All subjects must:
  • Have an understanding that the investigational product could have a potential teratogenic risk;
  • Agree to abstain from donating blood while taking investigational product therapy and for 28 days after discontinuation of investigational product therapy;
  • Agree not to share investigational product with another person;
  • Agree to be counseled about pregnancy precautions and risk of fetal exposure;
  • Females must agree to abstain from breastfeeding during study participation and for at least 12 months after investigational product discontinuation.

Exclusion Criteria:

• The following WHO subcategories of DLBCL:
  • Active CNS or meningeal lymphoma;
  • Primary cutaneous, leg type;
  • Primary mediastinal (thymic);
  • Lymphomatoid granulomatosis;
  • ALK-positive lymphoma;
  • Plasmablastic lymphoma;
  • Large B-cell lymphoma arising in HHV8 associated multicentric Castleman disease;
  • Primary effusion lymphoma;
  • Intravascular large B-cell;
  • B-cell unclassifiable cases with features intermediate between DLBCL and Burkitt;
  • Unclassifiable cases with features intermediate between DLBCL and classical Hodgkin’s lymphoma;
  • T cell / histiocyte rich.
• Post-transplant Lymphoproliferative Disorder (PTLPD) cases, even if they are B-cell type and ABC subtype, are excluded.
• Histology other than DLBCL. Evidence of composite DLBCL and FL, or of transformed NHL.
• Seropositive for or active viral infection with hepatitis B virus (HBV):
  • HBV surface antigen (HBsAg) positive;
  • HBV surface antigen (HBsAg) negative, HBV surface antibody (anti-HBs) positive and/or HBV core antibody (anti-HBc) positive, and detectable viral DNA;
  • Notes:
    • Subjects who are seropositive because of a successfully treated, prior infection are eligible (HBsAg negative, anti-HBs positive, and/or anti-HBc positive, but viral DNA negative);
    • Subjects who are seropositive because of HBV vaccination are eligible (anti-HBs positive, anti-HBc negative, and HBsAg negative).
• Hepatitis C virus (HCV) positive subjects with chronic hepatitis C, or subjects with an active hepatitis C infection requiring anti-viral medication (at time of randomization).
  • Note:
    • HCV positive subjects who do not have active hepatitis C, and who are otherwise acceptable candidates for R-CHOP chemotherapy, as documented by the investigator, are eligible.
• Known seropositive for or active viral infection with human immunodeficiency virus (HIV).
• Contraindication to any drug in the chemotherapy regimen, and specifically:
  • LVEF < 45% as assessed by MUGA, or LVEF < local institutional normal limits for R-CHOP administration as assessed by echocardiography;
  • Peripheral neuropathy ≥ Grade 2.
• Major surgery (excluding lymph node or bone marrow biopsy) within 28 days from signing the informed consent document, unless the subject is recovered. \
• Life expectancy < 6 months.
• History of other malignancies, unless the subject has been free of the disease for ≥ 5 years. Exceptions to the ≥ 5-year time limit include history of the following:
  • Localized non-melanoma skin cancer;
  • Carcinoma in situ of the cervix.
• Prior use of lenalidomide.
• Known allergy to thalidomide.
• Known sensitivity or allergy to murine products.
• Use of any investigational agent within 28 days or five half lives, whichever is longer, of Cycle 1 Day 1.
• Subjects who are unwilling to take VTE prophylaxis.
• Pregnant or lactating females.
• Uncontrolled intercurrent illness.
• Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
• Any condition, such as an active, severe infection, or the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
• Any condition that confounds the ability to interpret data from the study.