The goal of this clinical research study is to learn if using a combination of fludarabine, cyclophosphamide, and rituximab, with sargramostim (GM-CSF) can help to control previously untreated chronic lymphocytic leukemia (CLL). The safety of this combination will also be studied. This study will evaluate antibody-dependent cellular cytotoxicity (ADCC) and its relationship to response.

Fludarabine and cyclophosphamide are designed to enter CLL cells and destroy the "machinery" that allows CLL cells to multiply. Rituximab is designed to bind to CLL cells and cause cell death. GM-CSF is designed to help the bone marrow to produce white cells. It may also increase the target molecule called cluster of differentiation antigen 20 (CD20) for rituximab on the surface of the CLL cells which may improve the activity of rituximab.

Before you can start treatment on this study, you will have what are called "screening tests." These tests will help the doctor decide if you are eligible to take part in the study. You will have a complete physical exam. Blood (about 2 tablespoons) will be drawn for routine tests. The routine blood draw will include a test for hepatitis B, unless this has been done within the last 6 months. This routine blood draw will also include a pregnancy test for women who are able to have children. To be eligible to take part in this study, the pregnancy test must be negative. A bone marrow aspirate and biopsy will be collected. To collect a bone marrow aspirate and biopsy, an area of the hip or chest bone is numbed with anesthetic and a small amount of bone marrow and bone is withdrawn through a large needle.

If you are found to be eligible to take part in the study, you will receive GM-CSF thorough a needle under your skin on Day 1. Each study cycle is about 4 weeks, but may be longer depending on side effects or leukemia response.

You will receive rituximab through a needle in your vein on Day 2. The first infusion may take up to 8 hours. For every dose of rituximab after that, the infusion may take 2-4 hours. The length of the infusion time depends on whether you have any reactions to the infusion. The dose level of rituximab may be increased for Cycles 2-6 as well. The drugs Tylenol (acetaminophen) and Benadryl (diphenhydramine hydrochloride) will be given before each dose of rituximab. This will be done to decrease the risk of side effects. If side effects do occur during rituximab treatment, the drug may have to be stopped until the side effects go away and then restarted, so your time in the outpatient area may be longer if that occurs.

On Days 3-5 of the first treatment cycle, fludarabine and cyclophosphamide will be given through a needle in your vein. Each infusion will take about 30 minutes. After the first treatment cycle, fludarabine and cyclophosphamide will be given on Days 2, 3, and 4 for every cycle after that.

During each cycle, the day after you receive fludarabine and cyclophosphamide, you will begin to receive GM-CSF. You will receive the drug for 1 week or until your white cell count has returned to an acceptable level.

Cycle 1 will be given at M.D. Anderson's outpatient clinic. In some cases, Cycle 1 may be given in the inpatient area. The other 5 cycles can be given either at M.D. Anderson or at another location.

With the exception of rituximab, the same doses of all other drugs will be used throughout the study unless side effects become severe. In that case, the dose may be lowered, or the treatment may be stopped.

During each cycle, blood (about 1 tablespoon) will be drawn once every 1-2 weeks for routine tests.

You will have a bone marrow biopsy performed at the end of Cycles 3 and 6 to check the status of the disease.

You may remain on study for up to 6 cycles. You will be taken off study if the disease gets worse or if intolerable side effects occur.

Once you are off study, blood (about 2 teaspoons) will be drawn every 6-12 months for routine tests.

This is an investigational study. Fludarabine, cyclophosphamide, rituximab, and GM-CSF are all FDA approved and commercially available. However, their use in this study and in this combination is considered investigational. Up to 60 patients will take part in the study. All will be enrolled at M.D. Anderson.

Inclusion Criteria:

• Untreated CLL, CLL/PLL, or SLL (small lymphocytic lymphoma) with indication for therapy. Indications for therapy include at least one of the following: (1) one or more disease-related symptoms [fever, night sweats, weight loss > 10% in prior 6 months, pronounced fatigue]; (2) advanced stage disease (Rai stage >/= 3 or Binet stage C); (3) autoimmune anemia and/or thrombocytopenia that is unresponsive to other therapies; (4) massive or progressive hepatomegaly and/or splenomegaly and/or lymphadenopathy; (5) recurrent infections; (6) rapid lymphocyte doubling time of < 6 months.
• Patients who have been treated with not more than one regimen of immunotherapy (e.g. rituximab, alemtuzumab, rituximab plus alemtuzumab) for a diagnosis of CLL, CLL/PLL, or SLL (small lymphocytic lymphoma).
• Beta-2-microglobulin </= 4 mg/dL.
• Adequate liver function (total bilirubin </= 2.5 mg/dL, serum glutamate pyruvate transaminase (SGPT) </=4 x ULN) and renal function (serum creatinine </= 2.0 mg/dL and/or creatinine clearance < 30 mL/hour). Patients with renal or liver dysfunction due to suspected organ infiltration by lymphocytes may be eligible after discussion with the Principal Investigator, but upper limits for creatinine even under these circumstances must be creatinine < 3mg/dL and bilirubin < 6 mg/dL. Patients with Gilbert's syndrome may be entered on study with bilirubin levels </= 4 mg/dL.
• Eastern Cooperative Oncology Group (ECOG) performance status </= 2.
• Signed informed consent in keeping with the policies of the hospital.
• Male and female patients who are fertile agree to use an effective barrier method of birth control (ie, latex condom, diaphragm, cervical cap, etc) to avoid pregnancy. Female patients of childbearing potential (non-childbearing is defined as >/= 1 year after menses cease and/or surgically sterilized) need a negative serum or urine pregnancy test within 2 days of study enrollment..

Exclusion Criteria:

• Active hepatitis B (at least one of the following markers positive: HBsAg, hepatitis B e antigen (HBeAg), immunoglobulin M (IgM) anti-HBc, hepatitis B virus (HBV) DNA).
• Concurrent chemotherapy or immunotherapy.
• Pregnant patients.
• History of HIV
• Symptomatic central nervous system (CNS) disease

Adverse event collection through total of 6 courses administered, courses are 28 to 42 days (+/- 7 days) depending on recovery of peripheral blood counts and assessments for toxicities after 3 and 6 courses, up to 252 days.