• Efficacy to be assessed by clinical response rate following 3 cycles of treatment and the NCI-CLL working group response rate assessed after completion of all treatment. [ Time Frame: clinical response assessment after 3 cycles of therapy and 3 months following completion of all therapy for NCI-CLL working group response assessment ] [ Designated as safety issue: No ]
  

• Safety - type, frequency, severity, and relationship of adverse events to study treatment [ Time Frame: Throughout the study period ] [ Designated as safety issue: Yes ]
  
• Time To Progression [ Time Frame: Following therapy until disease progression ] [ Designated as safety issue: No ]
  
• Evaluate response to lenalidomide in relationship to molecular and genetic prognostic features in CLL; including ZAP-70 status, IgVH gene mutational status, and FISH. [ Time Frame: Following final response assessment ] [ Designated as safety issue: No ]
  
• Compare the efficacy and tolerability of the combination of Revlimid and rituximab for patients younger than 65 years, and for those 65 and older. • [ Time Frame: following final response assessment ] [ Designated as safety issue: No ]
  
• Evaluate change in hematological parameters including neutropenia, anemia, and thrombocytopenia following treatment with the combination of Revlimid and rituximab. [ Time Frame: Following final response assessment ] [ Designated as safety issue: No ]
  

The CLL Research Consortium (CRC) is conducting a two-arm, multi-center phase II trial of Revlimid® and rituximab for the first-line treatment of patients with CLL.

Revlimid® (lenalidomide) a derivative of thalidomide with immune-modulating properties. Revlimid® is FDA approved for treatment of relapsed multiple myeloma and 5q- myelodysplastic syndrome. Revlimid® has promising clinical activity in relapsed CLL in two early clinical trials. However, the mechanism(s) whereby Revlimid® is active in CLL is unknown. Rituximab (Rituxan®) is a protein that binds to CD20 expressed on normal and leukemia B cells. Rituximab is FDA approved for the treatment of lymphoma and is used commonly for the treatment of CLL. The purposes of this study are to evaluate the safety and activity of the combination of Revlimid® and rituximab in CLL, elucidate the mechanism of Revlimid® in CLL, and to assess whether prognostic factors might predict those patients likely to benefit from this therapy in the future.

As older patients are commonly under-represented in CLL clinical trials and are less tolerable of frontline therapy that utilizes combinations of fludarabine and cyclophosphamide the trial has two arms; one to specifically assess for the tolerability of the regimen in older subjects.

The primary objective of this study is to determine the response rate of the combination of Revlimid® and Rituximab in previously untreated CLL patients in two arms- those aged 65 years and above and those younger than 65. Secondary objectives will evaluate the safety of the combination of Revlimid® and Rituximab, response duration, improvement in hematologic parameters, activity of the combination in high-risk CLL subsets, and the significance of the tumor flare reaction.

All patients will have baseline assessment of known CLL prognostic factors including: immunoglobulin variable heavy chain (IgVH) gene mutational status, interphase cytogenetics, intracellular ZAP-70 expression, and CD38 expression through the CRC tissue core. These known prognostic features in CLL together with novel prognostic factors will be evaluated for the ability to predict response to treatment with Revlimid® and the combination of Revlimid® and Rituximab. Extensive biologic corollary studies are designed to evaluate the mechanism of Revlimid® in CLL, the impact of Revlimid® on the CLL microenvironment, and Revlimid®'s impact on and rituximab mediated cytotoxicity.

All patients will receive the same treatment. Revlimid® will be started at a low dose and slowly escalated based on patient tolerability. Rituximab will be administered following 21 days of Revlimid® monotherapy. Patients will continue treatment for up to 7 cycles unless there is toxicity or progressive disease. There are three planned response assessments for the subjects: a single agent Revlimid® response assessment prior to the addition of rituximab, after 3 cycles of treatment, and following all the therapy.