Fludarabine and Rituximab With or Without Lenalidomide or Cyclophosphamide in Treating Patients With Symptomatic Chronic Lymphocytic Leukemia

PRIMARY OBJECTIVES: I. To determine the two-year progression-free survival (PFS) after remission induction with four different chemo-immunotherapy combinations for patients with untreated, symptomatic, lower-risk and high-risk chronic lymphocytic leukemia (CLL) to decide which of the four arms, if any, to take forward into a randomized phase III trial. II. To determine the induction response to fludarabine phosphate and rituximab (FR) and fludarabine phosphate, cyclophosphamide, and rituximab (FCR) in each of these arms, along with the consolidation response to lenalidomide in patients with CLL. III. To determine the toxicity from these four chemoimmunotherapy combinations and that of consolidation therapy with lenalidomide. IV. To determine the induction response and toxicity of FCR in patients with deletion (del) (11q22.3) along with consolidation response, 2-year PFS and toxicity of lenalidomide in this specific genetic group. V. To determine the effect of pretreatment biologic characteristics on clinical outcomes, such as attaining a complete response to induction therapy and progression-free survival. VI. To collect relapse samples to determine the frequency of clonal evolution among patients with immunoglobulin heavy chain variable region (IgVH) mutated and unmutated disease and to study mechanisms of resistance to chemoimmunotherapy. VII. To determine if flow cytometry-negative status immediately post-therapy and at 24 months after study entry is an effective surrogate marker for prolonged progression-free survival and overall survival. OUTLINE: Patients are randomized to 1 of 3 treatment arms (Arms A, B, or C). Patients on Arm A or B who are found to be del (11q22.3) positive are assigned to Arm D beginning with course 2 of induction therapy. ARM A (remission-induction \[RI\] therapy with fludarabine phosphate and rituximab): Participants receive induction therapy (every 28 days for up to 6 cycles) of: rituximab intravenously (IV) over 1-4 hours on days 1 (50 mg/m\^2), 3 (325 mg/m\^2), and 5 (375 mg/m\^2) of course 1 and on day 1 (375 mg/m\^2) of all subsequent courses. Patients also receive fludarabine phosphate 25 mg/m\^2/day IV over 30 minutes or orally (PO) on days 1-5. ARM B (RI therapy with fludarabine phosphate and rituximab followed by remission-consolidation \[RC\] therapy with lenalidomide): Participants receive induction therapy (every 28 days for up to 6 cycles) of: rituximab IV over 1-4 hours on days 1 (50 mg/m\^2), 3 (325 mg/m\^2), and 5 (375 mg/m\^2) of course 1 and on day 1 (375 mg/m\^2) of all subsequent courses. Patients also receive fludarabine phosphate 25 mg/m\^2/day IV over 30 minutes or PO on days 1-5. Participants without progression receive consolidation therapy: lenalidomide 5mg/day cycle 1, 10 mg/day cycles 2-6 PO once daily (QD) on days 1-21 of 28 day cycle. ARM C (RI therapy with fludarabine phosphate, rituximab, and cyclophosphamide): Participants receive induction therapy (every 28 days for up to 6 cycles) of: rituximab IV over 4 hours on days 1 (50mg/m\^2) and 3 (325 mg/m\^2) of course 1 and on day 1 (500 mg/m\^2) of all subsequent courses. Patients then receive fludarabine phosphate (age \< 70: 25 mg/m\^2/day; age \>= 70: 20 mg/m\^2/day) IV piggyback over 30 minutes or PO (32 mg/m\^2/day) followed by cyclophosphamide (age \< 70: 250 mg/m\^2/day; age \>= 70: 150 mg/m\^2/day) IV piggyback over 30 minutes on days 1-3. ARM D (RI therapy with fludarabine phosphate, rituximab, and cyclophosphamide followed by RC therapy with lenalidomide): Patients receive the first course of induction therapy as in Arm A or B before being re-assigned to Arm D. Beginning in course 2, patients receive rituximab IV (500 mg/m\^2) on day 1 and fludarabine phosphate (age \< 70: 25 mg/m\^2/day; age \>= 70: 20 mg/m\^2/day) IV piggyback over 30 minutes or PO (32 mg/m\^2/day) and cyclophosphamide IV (age \< 70: 250 mg/m\^2/day; age \>= 70: 150 mg/m\^2/day) piggyback over 30 minutes on days 1-3. Participants without progression receive consolidation therapy: lenalidomide 5mg/day cycle 1, 10 mg/day cycles 2-6 PO QD on days 1-21 of 28 day cycle. After completion of study therapy, patients are followed up every 3 months for 1 year and then every 6 months for up to 15 years.