Inclusion Criteria:

• Patients must be diagnosed with CLL in accordance with International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria that includes all of the following:
  • ≥ 5 x10^9 B lymphocytes (5000/uL) in the peripheral blood
  • On morphologic review, the leukemic cells must be small mature lymphocytes, and prolymphocytes must not exceed 55% of the blood lymphocytes
  • CLL cells on immunophenotype (performed locally) must reveal a clonal B-cell population, which express the B cell surface markers of CD19 and CD20, as well as the T-cell antigen CD5; patients with bright surface immunoglobulin expression or lack of CD23 expression in > 10% of cells must lack t(11;14) translocation by interphase cytogenetics
• Patients must be intermediate or high-risk Rai stage CLL
  • Intermediate risk (formerly Rai stage I/II) is defined by lymphocytosis plus enlarged lymph nodes at any site, with or without hepatomegaly or splenomegaly
  • High risk (formerly Rai stage III/IV) is defined by fulfilling criteria for intermediate risk disease plus disease-related anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelet count < 100 x 10^9/L) that is not attributable to autoimmune hemolytic anemia or thrombocytopenia
• Patients must meet criteria for treatment as defined by IWCLL 2008 guidelines which includes at least one of the following criteria:
  • Evidence of marrow failure as manifested by the development or worsening of anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or thrombocytopenia)
  • Massive (≥ 6 cm below the costal margin), progressive or symptomatic splenomegaly
  • Massive nodes (≥ 10 cm) or progressive or symptomatic lymphadenopathy
  • Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy
  • Constitutional symptoms, which include any of the following:
    • Unintentional weight loss of 10% or more within 6 months
    • Significant fatigue
    • Fevers > 100.5 degrees F for 2 weeks or more without evidence of infection
    • Night sweats > 1 month without evidence of infection
• Prior Treatment
  • Patients must not have had prior therapy for CLL (except palliative steroids or treatment of autoimmune complications of CLL with rituximab or steroids)
  • Treatment with rituximab and/or high dose corticosteroids for autoimmune complications of CLL must be complete at least 4 weeks prior to enrollment; palliative steroids must be at a dose not higher than 20 mg/day of prednisone or equivalent corticosteroid at the time of registration
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Patients with active hepatitis B defined by hepatitis B surface antigen positivity or core antibody positivity in the presence of hepatitis B DNA are not eligible for this study; patients with a positive hepatitis B core antibody but with negative hepatitis B DNA may participate, but must have hepatitis serologies and hepatitis B DNA monitored periodically by the treating physician
  • Intravenous immunoglobulin (IVIG) can cause a false positive hepatitis B serology; if patients receiving routine IVIG have core antibody or surface antigen positivity without evidence of active viremia (negative hepatitis B DNA) they may still participate in the study, but should have hepatitis serologies and hepatitis B DNA monitored periodically by the treating physician
• Patients must not be receiving active systemic anticoagulation with heparin or warfarin; patients must be off warfarin therapy for at least 30 days prior to enrollment
• Patients with class III or class IV heart failure by New York Heart Association, those with unstable angina, and those with uncontrolled arrhythmia are not eligible
• Patients who have had a myocardial infarction, intracranial bleed, or stroke within the past 6 months are not eligible
• Patients with human immunodeficiency virus (HIV) are eligible if their CD4 count is ≥ 350 cells/mm^3 and if they are not taking prohibited cytochrome (CYP)-interacting medications
• Patients must not have any history of Richter's transformation or prolymphocytic leukemia (prolymphocytes in blood > 55%)
• Patients must not require more than 20 mg prednisone or equivalent corticosteroid daily
• Patients must not have uncontrolled active systemic infection requiring intravenous antibiotics
• Patients must not have continued requirement for therapy with a strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitor or inducer
• Patients must not have a known allergy to mannitol
• Patients must not have prior significant hypersensitivity to rituximab (not including infusion reactions)
• Patients may not have had major surgery within 10 days of enrollment, or minor surgery within 7 days of enrollment; examples of minor surgery include dental surgery, insertion of a venous access device, skin biopsy, or aspiration of a joint; the decision about whether a surgery is major or minor can be made at the discretion of the treating physician
• Absolute neutrophil count (ANC) ≥ 1,000/uL unless due to bone marrow involvement
• Aspartate aminotransferase (AST) or alanine aminotransferase (AST) ≤ 2.5 x upper limits of normal except if due to disease
• Bilirubin ≤ 1.5 x upper limits of normal (unless due to liver involvement, hemolysis, or Gilbert's disease)
• Creatinine clearance ≥ 40 mL/min
  • To be calculated by modified Cockcroft-Gault formula
• Platelet count (untransfused) ≥ 30,000/uL