Inclusion Criteria:

• Have histologically or cytologically confirmed CD5+/CD20+ B-Cell Chronic Lymphocytic Leukemia or Mantle Cell Lymphoma

• Meet the following CLL criteria to participate in this study:

  • Absolute lymphocyte count > 5000/μL
  • CD20+ and CD5+
  • Atypical cells representing < 55% on the peripheral smear
  • Bone marrow lymphocytes ≥ 30%

• CLL Patients are eligible if they have stage III or IV disease. Patients with stage 0, I or II disease will be eligible if they have evidence of active disease defined as one or more of the following signs/symptoms:

  • Documented weight loss of ≥ 10% over a six month period
  • Febrile episodes of ≥ 38˚ Celsius for > 2 weeks without evidence of infection
  • Massive or progressive splenomegaly, or lymphadenopathy
• Progressive lymphadenopathy will require biopsy of the lymphadenopathy within previous 6 months to ensure disease entity remains chronic lymphocytic leukemia.
• MCL patients will have biopsy proven CD5+/CD20+/CD23- mantle cell lymphoma with the characteristic cytogenetic abnormality t(11;14) or a cyclin D1 positive immunophenotype. If malignancy is CD23+ but FISH positive for t(11;14), diagnosis of mantle cell lymphoma can be made. Patients with mantle cell lymphoma require appropriate staging which would include upper and lower endoscopy within 2 months of enrollment per NCCN guidelines without additional treatment since the endoscopies.
• MCL and CLL patients are eligible if they have relapsed or progressive disease after Rituximab therapy, but must have had at least a response time of ≥ 6 months to previous Rituximab therapy. Patients < age 65 who have not had a bone marrow transplant must be ineligible or have declined a bone marrow transplant to participate.
• Anticipated life expectancy of > 3 months

• Baseline organ and marrow function as follows:

  • Absolute neutrophil count >1,500/µL
  • Platelets >50,000/µL
  • Total bilirubin <2.0 mg/dL (34 µmol/L)
  • AST(SGOT)/ALT(SGPT) <2.5 X institutional upper limit of normal(ULN)
  • Creatinine < institutional ULN OR
  • Creatinine clearance >60 mL/min/m² for patients with creatinine levels above institutional ULN
• Women of childbearing potential, and men with a partner of childbearing potential must follow pregnancy test and birth control guidelines outlined for this study.
• Signed written informed consent document

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
• May not be receiving any other investigational agents
• Known brain metastases
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to lenalidomide such as thalidomide or other agents used in the study.
• Prior desquamating rash with thalidomide
• Neuropathy ≥ grade 2
• Uncontrolled intercurrent illness including (not limited to) ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric illness/social situations that would limit compliance with study requirements.
• Women currently pregnant or breastfeeding
• Known to be HIV positive or have Hepatitis B or C
• History of another malignancy besides CLL or MCL who have been disease-free ≤ 3 years (with exception of basal cell or squamous cell carcinoma of skin or carcinoma in situ of cervix or breast)
• Any serious medical condition or psychiatric illness that will prevent subject from signing the informed consent form or will place the subject at unacceptable risk if he/she participates in the study
• Prior use of lenalidomide
• Prior severe hypersensitivity to Rituximab or other murine products