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%
  • Or previous confirmed diagnosis of CLL/SLL with less than 5000/μl or less than 30% lymphocytes in BM

• 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 degrees Celsius (100.5 degrees F) or greater for greater than 2 weeks without evidence of infection
  • Massive or progressive splenomegaly defined as > 6 cm below the left costal margin
  • Massive (> 10 cm in longest diameter) or progressive lymphadenopathy
• Patients with progressive lymphadenopathy will need a biopsy of the lymphadenopathy within the previous six months to ensure that the disease entity remains chronic lymphocytic leukemia. Lymph node biopsy can be deferred if the patient does not have superficial lymphadenopathy that is easily accessible by surgery or by CT guided biopsy.
• The diagnosis of MCL is based upon the NCCN guidelines. The patient's 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.
• Patients with MCL and CLL will be eligible if they have relapsed or progressive disease after Rituximab therapy or a combination therapy including Rituximab. Any other number of previous treatments is allowed including autologous or allogeneic bone marrow transplantation. Patients who are younger than age 65 who have not had a bone marrow transplant must be ineligible or have declined a bone marrow transplant to participate in this study. Although a transplant is not the standard of care for this patient population, it does provide the best opportunity for a cure.
• Anticipated life expectancy of > 3 months
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

• 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.
• Ability to understand and the willingness to sign a written informed consent document
• Able to adhere to the study visit schedule and other protocol requirements
• Patients with uric acid levels > ULN at baseline must be corrected to ≤ULN prior to the initiation of study therapy.

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 and/or thalidomide
• Prior desquamating (blistering) 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 seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine are eligible.
• 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 patient from signing the informed consent form or will place the patient at unacceptable risk if he/she participates in the study
• Prior use of lenalidomide
• Prior severe hypersensitivity to Rituximab or other murine products