STUDY OBJECTIVES

Primary Objective:

To determine the complete response (CR) rate and overall response (OR) rate [CR + partial response (PR) rate] to a regimen of bendamustine and rituximab (B-R), followed by radioimmunotherapy (RIT) with 90-yttrium(Y) ibritumomab tiuxetan in subjects with untreated follicular lymphoma.

Secondary Objectives:

To characterize the safety profile of bendamustine and rituximab followed by 90-yttrium(Y) ibritumomab tiuxetan in subjects with untreated follicular lymphoma

To determine the CR and OR rate after B-R

To determine the CR and OR rate after 90-yttrium(Y) ibritumomab tiuxetan specifically the conversions from PR to CR

To determine the progression-free survival (PFS)

To determine time to next treatment (TTNT)

Exploratory Objectives:

To determine the molecular response after B-R as determined by qualitative polymerase chain reaction (PCR) of BCL2 from blood and bone marrow examination (required after B-R)

To determine the molecular response after 90-yttrium(Y) ibritumomab tiuxetan radioimmunotherapy from blood and bone marrow examination (required after RIT)

Inclusion Criteria:

Previously untreated, histologically confirmed follicular lymphoma classification grade 1, 2 or 3a (>15 centroblasts per high power field with centrocytes present)

Ann Arbor stages of II to IV with either symptomatic or bulky disease (>5 cm); or disease progression

Male or female subject 18 years of age or older

ECOG performance status <2

Patients must have normal organ and marrow function as defined below:

Adequate hematologic function

- Absolute neutrophil count (ANC) >1,000/mm3

- Platelet count >100,000/mm3

- Patients with an ANC less than 1,000/mm3 and/or platelets below 100,000/mm3 are still eligible for study entry as long as there is >50% bone marrow involvement with lymphoma

Adequate hepatic function

- Total bilirubin within normal institutional limits

- AST(SGOT) <2.5 X institutional upper limit of normal

- ALT(SGPT) <2.5 X institutional upper limit of normal

Adequate renal function

- Calculated creatinine clearance >40 mL/min/1.73m2

Creatinine clearance should be calculated using the Cockcroft-Gault Equation (Appendix F) or per institutional standard

Measureable disease with at least one lesion measuring > 2 cm in its greatest transverse diameter

Female subjects of childbearing potential must have a negative pregnancy

test (urine or serum b-HCG) at screening. Both male and female subjects must employ effective contraceptive measures prior to the start of therapy until 12 months after the last dose of study drug. Men must agree not to father a child and agree to use effective birth control during therapy and for 12 months after the last dose of study drug, even if they have had a successful vasectomy, if their partner is of childbearing potential.

Voluntary written informed consent must be given before performance of any study-related procedure, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. The subject must have the ability to understand and the willingness to sign a written informed consent document.

Fol-BRITe study

Exclusion Criteria:

Patients who have had prior chemotherapy or immunotherapy

Patients receiving any other investigational agents

Prior chemotherapy or monoclonal antibody therapy; prior radiation will be allowed if <25% of active bone marrow was exposed

Patients with primary CNS lymphoma

Patients with known HIV

Treatment with therapeutic doses of systemic steroids within 4 weeks of beginning study treatment (cycle 1, day -7); topical use of corticosteroids and systemic replacement of corticosteroids for adrenal insufficiency are allowed

Patients who have had malignant pleural, pericardial or peritoneal effusions at any time

Patients with a known history of myelodysplastic syndrome (MDS) or found to have MDS on review of the staging bone marrow aspirate and biopsy

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would, in the judgment of the investigator, limit compliance with study requirements

Pregnant or lactating female subjects

Concurrent active malignancy other than lymphoma or history of invasive malignancy within the past 5 years. The only exception is completely excised, non-melanoma skin cancer

Known Hepatitis B and/or Hepatitis C Infection

Any other condition, that in the judgment of the investigator places the patient at unacceptable risk if he/she were to participant in the study