This is a European multicenter study of 90Yttrium-Ibritumomab Tiuxetan (90Y-Ibritumomab Tiuxetan) (Zevalin®) as a front line therapy for patients with follicular lymphoma grade I-IIIa and stage III-IV (as well as for selected patients with extended abdominal stage II). For patients with complete clinical remission but persistent molecular disease subsequent to 90Y-Ibritumomab Tiuxetan treatment a consolidation immunotherapy with Rituximab is added, to eradicate minimal residual disease.

Only patients requiring treatment (B-symptoms, lymphoma progression > 50% within an observation period of 6 months or less, organ compression by lymphoma or bulky disease as defined by lesions above 5 cm on one axis) may enter the study.

Inclusion Criteria:

• Patient > 50 years old
• Follicular lymphoma grade I, II, or IIIa according to REAL/WHO classification
• Ann Arbor stage III, or IV, or stage II with disseminated abdominal disease requiring extensive abdominal irradiation
• No prior chemotherapy, immunotherapy, or irradiation. Furthermore, when receiving therapy as part of this "Zevalin® first line in follicular lymphoma" trial and up to six months after therapy has ended, patients may not participate in another clinical trial. If patients receive consolidation therapy with Rituximab, the six months period is counted from the end of the consolidation therapy.
• Lymphoma cells positive for CD20
• Measurable disease (two perpendicular diameters by either physical or radiological examination)
• WHO/ECOG performance status 0 - 2
• Written informed consent

Exclusion Criteria:

• Bone marrow involvement only
• Bone marrow infiltration > 25%
• Leukocytopenia < 2.500 /µl
• Thrombocytopenia < 100.000 /µl
• Bulk lesions > 10 cm
• CNS lymphoma manifestation
• Circulating tumor cells > 500 /µl
• Extensive pleural effusion/ascites (> 1000 ml as estimated by ultrasound/CT)
• Severe concomitant diseases (e.g. congestive heart failure, myocardial infarction within 6 months of study, severe uncontrolled hypertension, renal insufficiency requiring hemodialysis, pulmonary disease, liver disease)
• Abnormal liver function: transaminases or total bilirubin > 2 x upper limit of normal (ULN) (unless caused by the lymphoma)
• Abnormal renal function: serum creatinine > 2 x upper limit of normal (unless caused by the lymphoma)
• Previous malignancy other than non-melanoma skin cancer
• Pregnant or breast feeding female patients (negative pregnancy test required for women of fertile age), no effective contraception
• HIV positivity
• Known hypersensitivity to foreign proteins, murine antibodies, presence of human anti-murine antibodies (HAMA) reactivity
• Severe psychiatric illness