This phase II trial studies how well lenalidomide and ofatumumab work in treating participants with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Drugs used in chemotherapy, such as lenalidomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as ofatumumab, may interfere with the ability of tumor cells to grow and spread. Giving lenalidomide and ofatumumab may work better in treating participants with chronic lymphocytic leukemia or small lymphocytic lymphoma

PRIMARY OBJECTIVES:

I. To evaluate efficacy and tolerability of the combination of ofatumumab and lenalidomide in patients with recurrent chronic lymphocytic leukemia (CLL).

OUTLINE:

Participants receive ofatumumab intravenously (IV) over 4 hours on days 1, 8, 15, and 22 of course 1, day 1 of courses 2-6, and day 1 of every even course beginning course 8. Beginning day 9 of course 1, participants also receive lenalidomide orally (PO) daily. Courses repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at 6 months, then every 3 months thereafter.

Inclusion Criteria:

• Understand and voluntarily sign an informed consent
• Patients with CLL or small lymphocytic lymphoma (SLL) with active disease: B-CLL Rai III-IV or earlier stage disease with evidence of "active disease" as defined by the National Cancer Institute (NCI)-sponsored working group 1) weight loss of > 10% in prior 6 months, 2) extreme fatigue, 3) fever or night sweats without evidence of infection, 4) worsening anemia or thrombocytopenia, 5) progressive lymphocytosis with a rapid lymphocyte doubling time, 6) marked hypogammaglobulinemia or paraproteinemia, 7) lymphadenopathy > 5 cm in diameter
• Prior treatment with purine analog based chemotherapy or chemoimmunotherapy
• Platelet count > or = to 30,000 mm^3
• Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO) performance status of 0-2
• Creatinine clearance > 30 ml/min (calculated by 24 hours urine collection) or a glomerular filtration rate (GFR) > 30 ml/min estimated using the Cockcroft-Gault equation
• Total bilirubin less or equal to 2 mg/dl
• Alanine aminotransferase (ALT) less or equal to two times the upper limit of normal
• Disease free of prior malignancies for 3 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast. Patients with malignancies with indolent behavior such as prostate cancer treated with radiation or surgery can be enrolled in the study as long as they have a reasonable expectation to have been cured with the treatment modality received
• Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10-14 days prior to starting lenalidomide and again within 24 hours prior to prescribing lenalidomide (prescriptions must be filled within 7 days) and prior to first ofatumumab administration and must either commit to continued abstinence from heterosexual intercourse or begin two acceptable methods of birth control, one highly effective method and one additional effective method at the same time, at least 28 days before she starts taking lenalidomide and continue it for 6 months after therapy has been completed. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist

Exclusion Criteria:

• Known sensitivity to lenalidomide, other thalidomide derivatives or ofatumumab
• Documented prolymphocytic leukemia (prolymphocytes more than 55% in the blood)
• Known positivity for human immunodeficiency virus (HIV) or active hepatitis B or C. Positive serology for hepatitis B (HB) defined as a positive test for hepatitis B surface antigen (HBsAg). In addition, if negative for HBsAg positive but HBcAb positive regardless of HBsAg status, a HB deoxyribonucleic acid (DNA) test will be performed and if positive the subject will be excluded
• Pregnant or breast feeding females. Women of childbearing potential must have a negative pregnancy test at screening. Male subjects unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy
• Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis and tuberculosis. History of tuberculosis treated within the last five years or recent exposure to tuberculosis
• Any serious medical condition, laboratory abnormality, or psychiatric illness that places the subject at unacceptable risk if he/she were to participate in the study
• Patients with a recent history of deep vein thrombosis (DVT) or pulmonary embolus (PE), in the six months prior to enrollment are not eligible for this study
• Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer, or currently participating in any other interventional clinical study
• Prior treatment with other monoclonal antibodies within 4 weeks prior to enrollment