The goal of this clinical research study is to learn if chemotherapy given with rituximab, followed by Ibritumomab tiuxetan (Zevalin), and then followed by rituximab can help to control lymphoma. The safety of this treatment schedule will also be studied.

Objectives:

1. To assess whether the time to progression for these high-risk patients can be prolonged to a median of 36 months, compared to the historical expectation of approximately 24 months.
2. To assess the tolerance and efficacy of Y2B8 (Zevalin) after R-FND (rituximab, fludarabine, mitoxantrone, dexamethasone) in patients with high-risk stage III-IV follicular lymphoma
3. To assess overall response, failure-free survival, and survival of this strategy compared to our historical experience with FND (fludarabine, mitoxantrone, dexamethasone) alone or R-FND
4. To assess the tolerance and efficacy of maintenance therapy with rituximab.
5. To maximize the 12-month molecular remission rate for patients with high-risk stage III-IV follicular lymphoma
6. to correlate the results of quantitative PCR assay with classical PCR and with clinical outcome

The treatments used in this program include several standard chemotherapy agents (fludarabine, mitoxantrone, and dexamethasone). Also, immune therapy agents will be given, including rituximab (a monoclonal antibody that attacks B-cells, which is what this type of lymphoma is made of), and Ibritumomab tiuxetan (another similar monoclonal antibody, which delivers radiation to the lymphoma cells to strengthen the attack).

You will receive rituximab on Days 1 and 8 of the first cycle, and on Day 1 only of Cycles 2-4 of the monthly cycles of chemotherapy, called R-FND. R-FND includes rituximab and fludarabine, mitoxantrone, and dexamethasone. Fludarabine will be given for 3 days, mitoxantrone for 1 day, and dexamethasone for 5 days of each 28-day cycle (FND). After 4 cycles of R-FND, you will receive Ibritumomab tiuxetan. After the Ibritumomab tiuxetan, you will receive rituximab every 2 months for 1 year. All are given by vein. Sometimes dexamethasone can be given in pill form.

During the study, you will have blood tests (about 2 tablespoons), sometimes every week. Every 2 cycles, you will have a chest x-ray and CT scans of the abdomen and pelvis. Bone marrow samples will be taken. Heart function tests will be done as needed.

If you desire, it may be possible for you to receive some of your study treatment at home (from your home doctor). Your study doctor will discuss this possibility with you. If this is the case, your home doctor will receive a letter telling him about this study and asking him if he wishes to participate in your treatments. He will be asked to provide the study doctors at M. D. Anderson specific information about your treatments and any side effects you may have. All communications between your home doctor and your study doctors will be included as part of your M. D. Anderson medical record.

After the study ends, you will return for checkups every 3 months in the first year, every 4 months in Years 2 and 3, and every 6 months in Years 4 and 5. After that, checkups will be needed once a year. Blood (about 2 tablespoons) and bone marrow samples will be taken at these visits.

This is an investigational study. Ibritumomab tiuxetan and rituximab are approved by the FDA for commercial use. The other drugs used in the study are also approved for commercial use by the FDA. About 50 patients will take part in the study. All will be enrolled at M. D. Anderson.

Inclusion Criteria:

1. Patients with high-risk Ann Arbor stage III-IV follicular lymphoma. High-risk is defined by advanced stage (III or IV), plus any 2 of the following features: age 60 or greater; elevated LDH; Hgb < 12; or number of involved nodal sites 5 or more .
2. Patients will be previously untreated.
3. Adequate organ function.
4. Follicular lymphoma, grade 3 (follicular large cell lymphoma): If eligible for a current large cell lymphoma protocol, that alternative protocol is recommended, particularly grade 3b or FLCL patients characterized as large non-cleaved cell. However, both FND and rituximab have established efficacy in FLCL, so if a patient is not eligible for a protocol for aggressive lymphoma (e.g., because of SCCL in the marrow), then registration on this trial is permitted.
5. Biopsy or fine-needle aspiration (FNA) material is strongly recommended for bcl-2 studies to verify rearrangement status of all patients who are designated "germline". (see section 6.4). For other patients, tissue availability is desirable but not mandatory.
6. Patients must have a performance status of Zubrod 3 or better
7. Patients must have adequate renal and hepatic function (creatinine < 2mg%; bilirubin < 2 mg%). Patients with renal or liver dysfunction due to organ infiltration by lymphoma may be eligible after discussion with the study chairman.
8. Patients may not receive other concurrent chemotherapy, radiotherapy, or immunotherapy.
9. Patients must sign an informed consent indicating that they are aware of the investigational nature of this study in keeping with the policies of the hospital.

Exclusion Criteria:

1. Patients who are unable or unlikely to be able to adhere to the treatment plan or to return to Houston for follow-up visits because of geographical, economic, emotional, or social considerations are not eligible for this study. Note: some follow-up care may be provided by outside physicians as long as the MD Anderson Cancer Center (MDACC) protocol for outside physician participation is strictly adhered to.
2. Patients with an absolute peripheral granulocyte count of < 1,000 and platelet count < 100,000 unless due to marrow infiltration or hypersplenism.
3. Patients with organ dysfunction, including bilirubin of > 2 mg% or serum creatinine level > 2 mg%, unless the alteration is due to lymphoma.
4. Patients with HIV infection should not be registered on this protocol.
5. Patients with an antecedent malignancy whose prognosis is poor (< 90% probability of surviving for 5 yrs).
6. All patients should have a cardiac ejection fraction of 50% or more by echocardiography or multiple gated acquisition scan (MUGA).
7. Patients who will not accept transfusions of blood products or supportive care measures such as antibiotics are not eligible for this study.
8. Female patients must not be pregnant or lactating, and men and women of reproductive potential must follow accepted birth control methods.
9. Patients who have received prior murine antibody therapy will be excluded.
10. Patients with evidence of active or prior infection of Hepatitis B are excluded. (Note: Persons vaccinated for Hepatitis B who have + antibodies are not excluded).

Adverse event reporting per patient done beginning at the start intervention per protocol through 30 days post intervention completion, up to 10 years