Early or Delayed Fludarabine and Rituximab in Treating Patients With Previously Untreated Chronic Lymphocytic Leukemia

OBJECTIVES: Primary * To determine if early treatment with chemoimmunotherapy comprising fludarabine phosphate and rituximab extends the time to second treatment in patients with genetically high-risk (unmutated IgV\_H), asymptomatic, previously untreated chronic lymphocytic leukemia (CLL). * To determine the time to disease progression that would warrant second treatment. * To determine overall survival. Secondary * To measure the proportion of patients with asymptomatic, previously untreated CLL who have mutated and unmutated IgV\_H genes. * To determine the differences in acute and chronic toxicity of administering chemoimmunotherapy early to patients with genetically high-risk CLL compared to waiting until symptoms develop. * To determine the effect of select pretreatment clinical and biological characteristics (such as interphase cytogenetic abnormalities, ZAP-70 expression, and p53 dysfunction \[primary and secondary\]) on response, time to second treatment, and overall survival of patients with genetically high-risk CLL randomized to early treatment. * To determine the effect of select pretreatment clinical and biological characteristics (such as interphase cytogenetic abnormalities, ZAP-70 expression, and p53 dysfunction) on response, time to first and second treatments, and overall survival of patients with genetically high-risk CLL randomized to standard treatment (observation until symptoms occur). * To describe the natural history of patients with genetically low-risk (mutated IgV\_H genes), asymptomatic, previously untreated CLL, in terms of time to initial treatment, response, progression, and survival. * To determine the effect of select pretreatment characteristics on time to first treatment, response, progression, and survival of patients with genetically low-risk CLL. * To correlate patterns of resistance that emerge in patients with unmutated IgV\_H genes who have relapsing or refractory CLL following receipt of chemoimmunotherapy with clonal evolution, including acquisition of high-risk karyotype abnormalities, p53 mutations, p53 dysfunction (primary and secondary), altered mRNA and protein expression related to treatment resistance, DNA mutations, microRNA gene expression, and methylation changes. * To determine whether highly sensitive flow cytometry negativity at completion of therapy in patients randomized to early treatment is an effective surrogate marker for prolonged time to second treatment, overall survival, and other clinical benefits. * To collect demographic data on familial CLL in newly diagnosed patients participating on this study. OUTLINE: This is a multicenter study. * Genetically high-risk disease: Patients are stratified according to age (\< 50 years vs 50 to 70 years vs \> 70 years) and presence of the high-risk genetic feature \[del(11)(q22.3) or del(17)(p13.1)\] by FISH (yes vs no). Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive rituximab IV over 4 hours on days 1, 3, and 5 of week 1 and then on day 1 of weeks 5, 9, 13, 17, and 21. Patients also receive fludarabine phosphate IV over 30 minutes on days 1-5 of weeks 1, 5, 9, 13, 17, and 21. After completion of chemoimmunotherapy, patients are followed every 3 months until disease progression. At the time of disease progression, patients receive retreatment with chemoimmunotherapy as above or another treatment regimen. * Arm II: Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in arm I. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen. * Genetically low-risk disease: Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in arm I. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen. Patients undergo blood sample collection periodically for correlative studies. After finishing treatment, patients are followed periodically.