The purpose of this study is to find out if lenalidomide when given along with rituximab can help to control the disease and also increase the length of your response (complete or partial response) compared to the standard of care rituximab chemotherapy treatment.

Follicular Lymphoma (FL) is a cancer of a B lymphocyte, a type of white blood cell. FL is typically a slowly progressing but incurable disease. Follicular lymphoma cells produce a specific defect in the patient's immune system impairing their ability to control their cancer. Lenalidomide has been shown to reverse the specific immune defect caused by FL in the patient. By including lenalidomide, the RELEVANCE study aims to eliminate the cancer while restoring the patient's immune competence.

Inclusion Criteria:

• Histologically confirmed CD20+ follicular lymphoma grade 1, 2 or 3a
• Have no prior systemic treatment for lymphoma.
• Must be in need of treatment
• Bi-dimensionally measurable disease with at least one mass lesion > 2 cm that was not previously irradiated.
• Stage II, III or IV disease.
• Must be ≥ 18 years and sign an informed consent.
• Performance status ≤ 2 on the ECOG scale.
• Adequate hematological function (unless abnormalities are related to lymphoma infiltration of the bone marrow)
• Willing to follow pregnancy precautions

Exclusion Criteria:

• Clinical evidence of transformed lymphoma by investigator assessment or Grade 3b follicular lymphoma.
• Patients taking corticosteroids during the last 4 weeks, unless administered at a dose equivalent to < 10 mg/day prednisone (over these 4 weeks).
• Major surgery (excluding lymph node biopsy) within 28 days prior to signing informed consent.
• Known Seropositive for or active viral infection with hepatitis B virus (HBV), hepatitis C virus (HCV)or human immunodeficiency virus (HIV).
• Life expectancy < 6 months.
• Known sensitivity or allergy to murine products.
• Prior history of malignancies, other than follicular lymphoma, unless the patient has been free of the disease for ≥ 10 years.
• Prior use of lenalidomide.
• Neuropathy > Grade 1.
• Presence or history of CNS involvement by lymphoma.
• Patients who are at a high risk for a thromboembolic event and are not willing to take venous thromboembolic (VTE) prophylaxis.
• serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) > 3x upper limit of normal (ULN), except in patients with documented liver or pancreatic involvement by lymphoma
• total bilirubin > 2.0 mg/dl (34 µmol/L) except in cases of Gilberts Syndrome and documented liver involvement by lymphoma
• creatinine clearance of < 30 mL/min
• Pregnant or lactating females.
• Any condition, including the presence of laboratory abnormalities, which places the patient at unacceptable risk if he/she were to participate in the study, or which confounds the ability to interpret data from the study.