Rituximab, Fludarabine, Mitoxantrone, Dexamethasone (R-FND) Plus Zevalin for High-Risk Follicular Lymphoma

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).