This phase II trial studies how well lenalidomide works in treating patients with acute myeloid leukemia that have had a decrease in or disappearance of signs and symptoms of cancer, although cancer still may be in the body and may be likely to come back or spread. Biological therapies, such as lenalidomide, use substances made from living organisms that may kill cancer cells by blocking blood flow to the cancer and by stimulating white blood cells to kill the cancer cells.

PRIMARY OBJECTIVE:

I. To assess relapse-free survival (RFS) of patients with acute myeloid leukemia (AML) treated with lenalidomide maintenance therapy after achieving remission.

SECONDARY OBJECTIVES:

I. To assess overall survival (OS) of patients with AML treated with lenalidomide maintenance.

II. To assess event-free survival (EFS) of patients with AML treated with lenalidomide maintenance.

III. To assess the duration of remission (CRd) of patients with AML treated with lenalidomide maintenance.

IV. To assess toxicity and safety of lenalidomide maintenance in patients with AML.

V. To assess the effects of lenalidomide maintenance on natural killer (NK) cell modulation and dynamics of minimal residual disease and their relationship to outcomes.

OUTLINE:

Patients receive lenalidomide orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6-12 months.

Inclusion Criteria:

• Patients aged 18 to 55 years with high risk AML who have achieved their FIRST complete remission (CR) or complete remission with incomplete recovery (CRi) within 12 months of enrollment and are not immediately candidates for allogeneic stem cell transplant; patients above age 55 who are not eligible for other protocols may be considered for enrollment on a case by case basis after discussion with the principal investigator (PI)
• Patients in their FIRST CR or CRi may be eligible for enrollment only if they have a high risk feature, including, but not limited to: adverse karyotype, fms-related tyrosine kinase 3 (FLT3) mutation, history of antecedent hematologic disorder (AHD), presence of dysplasia in the bone marrow, therapy-related AML, history of requiring more than 1 cycle of intensive induction chemotherapy to achieve first remission, or presence of persistent minimal residual disease (detected by cytogenetics, molecular markers, or flow cytometry) at any point after initial induction cycle; patients aged >= 18 years with AML who have achieved a SECOND CR or CRi within 12 months of enrollment and are not immediately candidates for allogeneic stem cell transplant are also eligible
• Patients should have received induction chemotherapy for AML and at least 1 consolidation
• Patients with history of extramedullary AML, except for central nervous system (CNS) involvement that is currently controlled, will not be eligible for enrollment
• Eastern Cooperative Oncology Group (ECOG) performance status of < or = 3
• Serum total bilirubin < or = to 1.5 X the upper limit of normal (ULN)
• Serum creatinine < or = to 2.5 x ULN
• Absolute neutrophil count (ANC) > 0.5 x 10^9/L
• Platelet count > or = 30 x 10^9/L
• For females of childbearing age, they may participate it they: a. have a negative serum or urine pregnancy test within 10 to 14 days of enrolling (a second pregnancy test will be performed within 24 hours (hrs) of starting therapy and both negative pregnancy tests will be required for starting therapy); b. agree to either abstinence or 2 effective contraceptive methods throughout the treatment period and up to 28 days after discontinuing treatment
• For male patients with a female partner of childbearing age, they may participate if they agree to either abstinence or 2 effective contraceptive methods throughout the treatment period and up to 28 days after discontinuing treatment
• All study participants be willing and able to comply with the requirements of the Risk Evaluation and Mitigation Strategies (REMS) program
• Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS program
• Ability to understand and sign informed consent

Exclusion Criteria:

• Diagnosis of acute promyelocytic leukemia (APL), AML - M3 by French American British (FAB) classification based on morphology, immunophenotype, molecular, or cytogenetics studies
• Diagnosis of AML associated with the following karyotypes: inversion (inv)(16), t(16;16), t(8;21), t(15;17), or t(9;22)
• Uncontrolled intercurrent illness including, but not limited to ongoing or active uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Previous treatment with lenalidomide for AML
• Patients with documented hypersensitivity to any components of the study program
• Females who are pregnant
• Patients with active CNS disease

Up to 7 years