The goal of the clinical research study is to learn if treatment with a combination of three drugs, Cytoxan (cyclophosphamide), Rituxan (rituximab) and Nipent (pentostatin), will help to control the disease in patients with previously untreated non-Hodgkin's lymphoma, CLL, or bulky lymphoma. The safety of this treatment will also be studied.

All of the drugs [Cytoxan (cyclophosphamide), Rituxan (rituximab) and Nipent (pentostatin)] in this study are commonly used in the treatment of this cancer. However, using these drugs in combination is investigational.

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 medical history and physical exam. You will have blood collected (around 2-3 tablespoons) for routine tests. You will have a chest x-ray and CT scans of the chest, abdomen (stomach), and pelvis (waist area). Tumors will be measured using x-rays. You will have a sample of bone marrow collected. To collect a bone marrow sample, an area of the hip or chest bone is numbed with anesthetic and a small amount of bone marrow is withdrawn through a large needle. If your doctor feels it is necessary, you may also have lymph node biopsy samples taken for special tests. Women who are able to have children must have a negative blood or urine pregnancy test.

During treatment you will be given a combination of three drugs in a 21 day (3 weeks) cycle. All drugs will be given through a needle in a vein over 4-6 hours. You will receive pentostatin first, then rituximab, and lastly cyclophosphamide. For each treatment cycle cyclophosphamide, rituximab, and pentostatin will be given on Day 1, followed by 20 days of rest.

During treatment, you will have around 2-3 tablespoons of blood collected at least once a week for routine tests. You will also provide a urine sample for routine urine tests. Depending on how the disease responds, treatment may be stopped after 3, 6, or 9 cycles. You will be taken off treatment if your disease gets worse. If your treatment is delayed for more than 2 weeks due to any side effect related to the treatment or for more than 3 weeks for any reason, you will be taken off of this study. If your doctor feels that you are having serious or intolerable side effects that are not improved by standard supportive care methods (such as medicine to control nausea or a transfusion to treat anemia) you will be taken off of this study.

After Cycles 3, 6, and 9, tumors will be measured using x-rays or other scans (CT or MRI). Bone marrow samples will be taken if they are needed to find out if the drug combination is working to control your disease.

The maximum number of cycles that you can receive is 9. If you wish to continue using this drug treatment, and it is beneficial to do so, you may continue to receive these drugs. However, these drugs are commercially available, so you will be financially responsible for the cost of these drugs.

After you receive the last cycle of chemotherapy, your doctor will decide your schedule of follow-up exams. You will have follow-up exams every 3 months for one year, every 6 months for 2nd year, then once after 1 year. During these exams, you will have a chest x-ray and CT scans of the chest, abdomen (stomach), and pelvis (waist area). You will also have blood collected (2-3 tablespoons) for routine tests.

This is an investigational study. All of the study drugs are approved by the FDA for cancer treatment and are commercially available. However, the use of the drugs in combination is investigational. Up to 100 patients will take part in this study. All enrolled will be at M. D. Anderson.

Inclusion Criteria:

1. Histologically or cytologically proven, stage III or IV, low-grade B-cell NHL, as defined by the updated WHO modification of the REAL classification for peripheral B-cell neoplasms: B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma; Lymphoplasmacytic lymphoma/immunocytoma; Follicular lymphoma; Extranodal marginal zone B-cell lymphoma of MALT type; Nodal marginal zone B-cell lymphoma (+/- monocytoid B-cells); Lymphoma with primarily bone marrow-only disease are considered eligible
2. Bulky lymphoma or Stage II disease requiring chemotherapy will be considered for enrollment with documented Sponsor Investigator approval prior to registration.
3. CT or MRI scans confirming measurable tumor size (lymph node must be >1cm in its longest transverse diameter). Measurement by physical exam is acceptable in the case of palpable and reproducibly measurable axillary or other superficial tumors.
4. Positive expression of cluster of differentiation antigen 20 (CD20) by biopsy or circulating lymphocytes.
5. Zero or one prior chemotherapeutic or immunotherapeutic treatment regimen for B-cell NHL.
6. Male or female greater than or equal to 18 years of age.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
8. Adequate renal function: Creatinine less than 1.5 mg/dL; blood urea nitrogen (BUN) less than 30 mg/dL or a creatinine clearance greater than or equal to 60 mL/min based on calculation of creatinine clearance using the Cockcroft-Gault method or from a 24-hour urine collection. Creatinine clearance 40- 59 mL/min from a 24-hour urine collection would require a Nipent dose reduction of 25%. Patients with a Creatinine clearance <40 mL/min from a 24-hour urine collection will be excluded.
9. Adequate bone marrow function: absolute neutrophil count (ANC) greater than or equal to 1,000 cells/µL; Platelet count greater than or equal to 75,000 cells/µL; Hemoglobin greater than or equal to 9 g/dL. Patients with idiopathic thrombocytopenia or autoimmune hemolytic anemia are eligible with prior approval of Sponsor Investigator.
10. Adequate liver function: Bilirubin less than or equal to 2.0 mg/dL; AST and ALT less than or equal to 5 times upper limit of normal (ULN).
11. Adequate cardiac function in the judgment of the Investigator, including New York Heart Association (NYHA) classification of I or II.
12. Female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to registration.
13. Patient agrees to use an acceptable method of birth control, if fertile patient (male or female), to avoid pregnancy for the duration of the study and for at least 3 months thereafter.
14. Completed Patient Informed Consent Form.

Exclusion Criteria:

1. Previous or current intermediate or high-grade lymphoma.
2. White blood cell count (WBC) greater than 30,000 cells/µL.
3. Received prior therapy using Rituxan, unless such therapy was completed at least 6 months prior to study registration. Patients whose disease was non-responsive to prior Rituxan therapy will be excluded.
4. Known sensitivity to Nipent, Rituxan, Cytoxan or any component of these drugs.
5. Patient received replacement steroid therapy less than 4 weeks prior to study registration.
6. History of other malignancy that could affect the diagnosis or assessment of the study treatment.
7. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) illness.
8. Known prior history of and/or active viral hepatitis (HBV or HCV).
9. Patient is unable to comply with the requirements of this study.
10. Patients with Richter's transformation will be excluded.

Adverse event reporting period begins upon first administration of study drug and continues until 30 calendar days after the last exposure to study drug. Treatment includes from one to nine 21-day cycles.