In research studies, lenalidomide (also called Revlimid) has shown some response in chronic lymphocytic leukemia (CLL); however, responses are usually partial responses that occur after several months of taking the study drug. It is thought that by adding the drug plerixafor (also called Mozobil) responses may be improved and/or occur sooner.

The main purpose of this study is to determine the dose of plerixafor that is safe to use in combination with lenalidomide. The study will also look at the response rates of the combination of lenalidomide and plerixafor and the effect the study drugs have on CLL cells.

The combination of lenalidomide and plerixafor will be evaluated in this single institution, open label clinical study of subjects with relapsed chronic lymphocytic leukemia (CLL). The overall design of the phase 1 study includes up to three treatment "stages."

Each subject will receive lenalidomide 5mg by mouth daily beginning on cycle 1 day 1. If tolerated, the dose will be increased by 2.5mg every 7 days to a maximum dose of 10mg by mouth daily (Stage 1). Once the subject is stably maintained on a daily dose of lenalidomide of 10mg daily and the white blood cell (WBC) count is <100.0 x 109 / L, and has been taking lenalidomide for at least 28 days, plerixafor will be added (Stage 2). In the dose escalation phase, 4 different doses of plerixafor in combination with lenalidomide will be studied in cohorts of 3 to 6 subjects each, following a standard "3 + 3" format:

• Cohort 1: plerixafor 0.24 mg/kg subcutaneous (SC) daily thrice weekly (Mon, Wed, Fri)
• Cohort 2: plerixafor 0.32 mg/kg SC daily thrice weekly (Mon, Wed, Fri)
• Cohort 3: plerixafor 0.42 mg/kg SC daily thrice weekly (Mon, Wed, Fri)
• Cohort 4: plerixafor 0.54 mg/kg SC daily thrice weekly (Mon, Wed, Fri) Plerixafor will be administered for 3 weeks of each cycle (days 1, 3, 5, 8, 10, 12, 15, 17, and 19) followed by a 1 week rest period. Lenalidomide dosing will be continuous.

An interim assessment of response will be performed after 4 cycles of combination therapy:

• Subjects achieving a complete response (CR) by National Cancer Institute (NCI)-96 criteria will continue lenalidomide monotherapy (plerixafor is discontinued) until disease progression.
• Subjects achieving a partial response (PR) will continue both lenalidomide and plerixafor. Additionally, rituximab 375mg/m2 will be added on day 1 of each subsequent cycle beginning with cycle 5, day 1 of combination therapy. (Stage 3). Treatment with the combination of lenalidomide and plerixafor will continue for a maximum of 12 cycles of combination therapy. Subjects may receive up to 8 doses of rituximab concurrent with lenalidomide and plerixafor on day 1 of each cycle. Subjects will then continue single agent lenalidomide until disease progression.
• Subjects with stable disease may continue lenalidomide and plerixafor at the discretion of the investigator and the subject. Rituximab 375 mg/m2 will be added on day 1 of each subsequent cycle. Treatment, dose, schedule, and duration are the same as for subjects achieving a PR.

Inclusion Criteria:

• Histologically confirmed diagnosis of chronic lymphocytic leukemia (CLL) or Small lymphocytic lymphoma (SLL) as established by the National Cancer Institute (NCI) Working Group Response Criteria (NCI 96 Criteria).
• Received one or more prior therapies for CLL.
• Subjects must have symptomatic disease requiring therapy as defined by the protocol.
• >/= 4 weeks from prior cancer therapy.
• Eastern Cooperative Oncology Group (ECOG) performance status of </= 2.
• All study subjects must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®.

Exclusion Criteria:

• Prolymphocytic leukemia (PLL).
• Richter's (large cell) transformation.
• Prior allogeneic transplant within 12 months or prior allogeneic transplant > 12 months currently receiving immunosuppressants.
• Active autoimmune hemolytic anemia.
• Central nervous system (CNS) involvement.
• Chronic enteral corticosteroids > 10mg prednisone or equivalent.
• Evidence of laboratory tumor lysis syndrome (TLS) by Cairo-Bishop Definition of Tumor Lysis Syndrome
• Use of any other experimental drug or therapy within 28 days of baseline
• Major surgery within 28 days of baseline.
• Known hypersensitivity to thalidomide.
• The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.
• Any prior use of lenalidomide.
• Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV).