Inclusion Criteria:

• Histological confirmation of follicular lymphoma grades I, II diagnosed within 12 months (365 days) prior to registration; NOTE: the day of biopsy should be used as day 1 of diagnosis for this calculation
• Stage I, II, III, or IV disease; NOTE: stage I disease are eligible only if the disease is not amenable to external beam radiation therapy
• No indication for chemotherapy; candidate for observation
• Measurable disease by tumor imaging with at least one lesion ≥ 1.5 cm in at least one dimension
• Previously untreated; NOTE: this includes any chemotherapy or immunotherapy or RIT; patients who received corticosteroids for diseases other than lymphoma are eligible as long as prednisone dose is ≤ 10 mg/day
• Low tumor burden as defined by Groupe d'Etudes des Lymphomes Folliculaires (GELF) criteria (2):  
  • No tumor mass (nodal or extranodal) ≥ 7 cm in one dimension on computed tomography (CT)
  • Fewer than 3 (2 or less) nodal masses > 3 cm
  • No systemic or B symptoms
  • No splenomegaly greater than 16 cm by CT scan
  • No risk of organ compression - ureteral, orbital, neurological, gastrointestinal
  • No leukemic phase (> 5.0 x 10^9/L circulating FL cells in the blood as detected by complete blood count [CBC] with differential and smear)
  • No cytopenias - absolute neutrophil count (ANC) < 1000 or platelets < 100,000
• Meet standard criteria for RIT:
  • < 25% marrow involvement with FL
  • No evidence of myelodysplasia
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
• Absolute neutrophil count (ANC) ≥ 1500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin > 10.0 g/dL
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) or if total bilirubin is > 1.5 x ULN, the direct bilirubin must be ≤ ULN
• Alkaline phosphatase ≤ 3 x ULN
• Aspartate transaminase (AST) ≤ 3 x ULN
• Creatinine ≤ 2 x ULN
• Negative pregnancy test done < 7 days prior to registration, for women of childbearing potential only
• Provide informed written consent
• Willing to travel to a radioimmunotherapy site for Zevalin, if necessary
• Willing to return to the enrolling institution for follow-up (during the Active Monitoring Phase of the study); Note: during the Active Monitoring Phase of a study (i.e., active treatment and observation), participants must be willing to return to the consenting institution for follow-up
• Willing to provide blood samples at baseline for correlative research purposes and tissue for central pathology review
• < 25% bone marrow involvement of cellular marrow with lymphoma as determined by bilateral bone marrow aspirate and biopsy; NOTE: the percent involvement should be estimated by the hematopathologist using all of the biopsy material
• Has insurance coverage or is willing to pay for protocol therapy (rituximab x 4 or Zevalin x 1)

Exclusion Criteria:  

• Any of the following:
  • Pregnant women
  • Nursing women
  • Men or women of childbearing potential who are unwilling to employ adequate contraception for at least three months after completing study treatment
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
• Patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Receiving any other investigational agent that would be considered as a treatment for the lymphoma
• Active other malignancy requiring treatment that would interfere with the assessments of response of the lymphoma to protocol treatment and would interfere with follow-up assessments through year 5
• Presence of central nervous system (CNS) lymphoma
• Known to have lymphoma related to HIV or acquired immune deficiency syndrome (AIDS)
• Abnormal renal function (serum creatinine > 2 x ULN)
• Received prior external beam radiation therapy for another reason to > 25% of active bone marrow
• Serious non-malignant disease such as active infection or other condition which in the opinion of the investigator would compromise other protocol objectives
• Major surgery other than diagnostic surgery ≤ 4 weeks prior to registration
• Any evidence of myelodysplastic syndrome or marrow chromosomal changes suggesting myelodysplasia (-7, -5 etc)
• Corticosteroid therapy at the time the patient enters the protocol; NOTE: patients using prednisone or its equivalent for adrenal failure or using ≤ 10mg of prednisone/day for other benign causes are accepted
• Follicular grades IIIA or IIIB are not eligible
• Marrow cellularity ≤ 15% (as determined on all bone marrow samples)
• Seropositive for or active viral infection with hepatitis B virus (HBV):
  • Hepatitis B surface antigen (HBsAg) positive
  • HBsAg negative, anti-hepatitis B surface antibody (HBs) positive and/or anti-hepatitis B core antibody (HBc) positive and detectable viral deoxyribonucleic acid (DNA)

Notes:

• Subjects who are HBsAg negative, anti-HBs positive, and/or anti-HBc positive, but viral DNA negative are eligible
• Subjects who are seropositive because of HBV vaccination are eligible (HBV surface antibody positive, HBV core antibody negative, and HBV surface antigen negative)
  • Known seropositive for or active infection with hepatitis C virus (HCV)