This research study will look at the effects (good or bad) of administering cyclophosphamide, fludarabine, and rituximab. Clinical studies with combination therapy have shown higher response rates than using single drugs, and this study will evaluate the side effects and effectiveness of this combination.

This study is designed to expand on the highly successful combination of rituximab, fludarabine and cyclophosphamide for patients with previously untreated CLL. Responses in the range of 90-98% with 55% complete responses are reported. However, bone marrow toxicity has been a significant problem. This trial is designed to reduce the bone marrow toxicity by decreasing the doses of fludarabine and cyclophosphamide, but doubling the dose of rituximab with a maintenance dose of rituximab for up to two years, to maintain or even enhance efficacy.

Inclusion Criteria:

• Diagnosis of CD20 + CLL
• Peripheral blood absolute lymphocyte count of > 5,000/mm3 obtained within 2 weeks prior to randomization.
• The lymphocytosis must consist of small to moderate size lymphocytes, with ≤55% (no greater than 55%) prolymphocytes, atypical lymphocytes, or lymphoblasts morphologically.
• Phenotypically characterized CD20 + CLL defined as: 1) the predominant population of cells share B-cell antigens with CD5 in the absence of other pan-T-celI markers (CD3, CD2, etc.); 2) B-cell expresses either kappa or lambda light chains; and 3) surface immunoglobulin (slg) with low-cell surface density expression.
• Splenomegaly, hepatomegaly or lymphadenopathy are not required for the diagnosis of CLL.
• Must require chemotherapy. Indications for chemotherapy are one or more of the following:
• One or more of the following disease-related symptoms
• Weight loss >10% within the previous 6 months.
• Fevers of greater than 100.0° F for 2 weeks without evidence of infection.
• Night sweats without evidence of infection.
• Evidence of progressive marrow failure as manifested by the development of or worsening of anemia (< 10 g/dl) and/or thrombocytopenia (< 100,000/mm3).
• Massive (i.e., > 6 cm below left costal margin) or progressive splenomegaly.
• Massive nodes or clusters (i.e., > 10 cm in longest diameter) or progressive
• adenopathy.
• Progressive lymphocytosis with an increase of> 50% over 2 month period, or an anticipated doubling time of less than 6 months.
• NOTE: Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease are not sufficient for protocol therapy.
• Serum creatinine <1.5 mg/dl.
• Bilirubin must be <2 mg/dl, unless secondary to tumor, obtained within 2 weeks prior to randomization.
• Age >18 years.
• Not pregnant (confirmed by serum pregnancy test in females of reproductive potential) or breast feeding, because it is unknown what effect these drugs will have on children.
• ECOG performance status 0-2.
• AST or ATL >2x upper limit of normal unless related to CLL.
• Subject has provided written informed consent.

Exclusion criteria:

• Subjects with autoimmune anemia or thrombocytopenia are not eligible.
• No prior cytotoxic chemotherapy. Patients with a history of steroid treatment for CLL, autoimmune hemolytic anemia, or autoimmune thrombocytopenia are not eligible.
• Subjects with active infections requiring oral or intravenous antibiotics until resolution of the infection and completion of therapeutic antibiotics.
• Women of childbearing potential and sexually active males who refuse to use an accepted and effective method of contraception.
• Subjects with a second malignancy other than basal cell carcinoma of the skin or in situ carcinoma of the cervix are not eligible unless the tumor was treated with curative intent at least two years previously.
• History of HIV
• CNS disease
• History of psychiatric disorder that would make it difficult to enroll and follow the patient on trial.
• New York Heart Classification III or IV heart disease.
• Hepatitis BsAg or Hepatitis C positive.