Lenalidomide With or Without Rituximab in Treating Patients With Progressive or Relapsed Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Prolymphocytic Leukemia, or Non-Hodgkin Lymphoma Previously Treated With Donor Stem Cell Transplant

This phase II trial studies how well giving lenalidomide with or without rituximab works in treating patients with progressive or relapsed chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), prolymphocytic leukemia (PLL), or non-Hodgkin lymphoma (NHL). Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving lenalidomide together with or without rituximab may kill more cancer cells.

PRIMARY OBJECTIVES:

I. To improve overall survival in patients with relapse of NHL or CLL/SLL/PLL within 180 days after allogeneic hematopoietic cell transplant (HCT).

SECONDARY OBJECTIVES:

I. Rate of response (complete response \[CR\], partial response \[PR\], or stable disease \[SD\]) and time to progression.

II. Grade III-IV toxicity.

III. Incidences of grades II-IV acute graft-versus-host disease (GVHD) and limited or extensive chronic GVHD.

IV. Compare efficacy and safety between the first, second and third cohorts.

V. Laboratory research studies for efficacy and toxicity: blood samples will be stored at baseline, day 7, and day 28 of cycle 1 and day 28 of cycle 3 to investigate:

1. changes in plasma cytokines and peripheral blood lymphocytes in correlation to treatment with lenalidomide;
2. pharmacokinetics of rituximab;
3. donor and host polymorphisms of the FCgamma RIIIa receptor and their impact on disease response and relapse.

OUTLINE: Patients are assigned to 1 of 2 treatment arms.

ARM I: Patients who have relapsed/progressed within 180 days post-transplant (Cohort 1), beyond day 180 post-transplant (Cohort 2), or within 6 months but were not started within 3 months of relapse, receive lenalidomide orally (PO) once daily (QD) on days 1-28 (patients with CLL/SLL/PLL) or days 1-21 (patients with NHL). Patients in Cohorts 1 and 2 also receive rituximab intravenously (IV) on days 1, 8, 15, and 22 of course 1 and then every two months for courses 3, 5, 7, 9, and 11.

ARM II: Patients who have relapsed/progressed at any time point post-transplant and who have contraindications, prior severe hypersensitivity reaction to rituximab infusion, to receive rituximab or have CD20 negative disease (Cohort 3) receive lenalidomide as in Arm I.

Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 and 60 days and then every 3 months for up to 18 months.

Eligibility Criteria:
Inclusion Criteria:

* Understand and voluntarily sign an informed consent form
* Able to adhere to the study visit schedule and other protocol requirements
* Patients with CLL/SLL/PLL or NHL and who:

  * Met the criteria of relapse or progression after allogeneic HCT according to the HCT protocol or the attending discretion and who,
  * Not responding to appropriate tapering of immunosuppressive medications
* Absolute neutrophil count (ANC) \>= 1500/mm\^3 or \>= 1000/mm\^3 if ANC has persistently \< 1500/ mm\^3 for more than 2 weeks
* Platelet count (transfusion independent) \>= 50,000/mm\^3 or \>= 20,000/mm\^3 if platelet count has persistently \< 50,000/mm\^3 for more than 2 weeks
* Creatinine clearance \>= 30ml/min by Cockcroft-Gault formula
* Total bilirubin =\< 1.5 x upper limit of normal (ULN) or =\< 3 x ULN if total bilirubin has been persistently \> 1.5 x ULN for more than 2 weeks
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine transaminase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) =\< 3 x ULN or =\< 5 x ULN if AST or ALT have been persistently \> 3 x ULN for more than 2 weeks
* 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 and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days) 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 study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist
* Study participants with risk factors for venous thrombo-embolism (VTE), such as previous VTE, cardiac disease, chronic renal insufficiency, and/or poorly controlled diabetes, should be able to comply with some degree of prophylactic anticoagulation using aspirin 81 or 325 mg daily, coumadin, or low molecular weight heparin

Exclusion Criteria:

* Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing the informed consent form
* Pregnant or breast feeding females; (lactating females must agree not to breast feed while taking lenalidomide)
* 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
* Known hypersensitivity to thalidomide
* The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs
* Resistance to prior use of lenalidomide, defined as progression on full dose lenalidomide within the first two cycles of therapy
* Concurrent use of other anti-cancer agents or treatments
* Known seropositive for or active viral infection with human immunodeficiency virus
* Karnofsky performance status \< 50%
* Active grades III or IV acute graft-versus-host disease (GVHD)