Lenalidomide and AT-101 in Treating Patients With Relapsed B-Cell Chronic Lymphocytic Leukemia

Inclusion Criteria:

* Understand and voluntarily sign an informed consent form
* Able to adhere to the study visit schedule and other protocol requirements
* Diagnosis of B-CLL, confirmed by flow cytometric analysis and as per the criteria outlined by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL)/Hallek December 2008
* Any prior therapy for B-CLL must have been discontinued \>= 28-days prior to registration
* Patients must have absolute lymphocyte counts (ALC) of more than 5,000 cell/mm\^3
* During phase I: all patients with relapsed disease will be eligible if they have received at least 1 prior standard CLL therapy and no more than 4 prior therapies (one of which must be a purine analog and/or an alkylating agent)
* During phase II: all patients with relapsed disease will be eligible if they have received a minimum of 1 prior standard therapy and a maximum of 2 prior treatments (one of which must be a purine analog and/or an alkylating agent) for B-CLL and have developed relapse disease

  * Note: patients who have refractory disease (defined as - progressive disease on last treatment, or less than 6 months of clinical response to the last treatment) will not be eligible
* Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 at registration
* Absolute neutrophil count \>= 1500/mm\^3
* Platelet count \>= 30,000/mm\^3
* Serum creatinine =\< 1.5 x upper limit of normal (ULN)
* Total bilirubin =\< 1.5 mg/dL or direct bilirubin =\< 1.0 mg/dL for patients with Gilberts syndrome
* Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 2 x ULN or =\< 5 x ULN if hepatic disease is present
* Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL 10-14 days prior to and again within 24 hours before starting lenalidomide 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; 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 patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure

  * A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
* All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist
* Patient must require treatment for symptomatic B-CLL as defined by the by the IWCLL/Hallek, December 2008 criterion or as determined clinically necessary by the treating physician
* Willing to provide blood and baseline bone marrow aspirate samples for correlative research purposes

Exclusion Criteria:

* Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form
* Pregnant or lactating females
* Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
* Use of any other experimental drug or therapy =\< 28 days prior to registration
* Known hypersensitivity to thalidomide or lenalidomide
* The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs
* Patients with of history of any other cancer (except nonmelanoma skin cancer or carcinoma in-situ of the cervix, unless in complete remission and off therapy for that disease for \> 3 years)
* Patient with history of cardiac arrest within the past 6 months
* Patients with history of prior bowel resection, malabsorption syndrome, inflammatory bowel disease, prior bowel obstruction (partial or complete), Crohn disease, or any other disease significantly affecting the gastrointestinal tract
* Prior use of gossypol or AT-101