Enasidenib (AG-221) Maintenance Post Allogeneic HCT in Patients With IDH2 Mutation

Inclusion Criteria: * Documented informed consent of the participant and/or legally authorized representative * Agreement to allow the use of archival tissue from diagnostic tumor biopsies * If unavailable, exceptions may be granted with study principal investigator (PI) approval * Eastern Cooperative Oncology Group (ECOG) =\< 2 or Karnofsky performance status (KPS) \>= 70 * Recipients of allogeneic HCT - all stem cell sources including sibling, unrelated, mismatched related/unrelated, cord and haploidentical transplant patients will be included * Conditioning regimen: Investigator's choice based on center guidelines * GvHD prophylaxis: sirolimus + tacrolimus or tacrolimus + methotrexate or investigator choice * Patients must have acute myeloid leukemia (AML) with IDH2 mutation at diagnosis. Day 30 marrow post HCT should show evidence of morphologic remission with \< 5% bone marrow blasts. Patients with MRD either by flow cytometry or IDH2 mutation testing will be allowed * Patients with previous therapy with IDH2 inhibitors will be included * Absolute neutrophil count (ANC) \> 1000 (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated) * Hemoglobin \>= 9.5 gm% (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated) * Platelets \> 50,000/mm\^3 (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated) * Platelets \>= 20,000/mm\^3 (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated) * NOTE: Patients with lower counts can enroll if infection cytomegalovirus (CMV)/human herpesvirus 6 (HHV6) etc. is being treated actively * Total bilirubin =\< 1.5 X upper limit of normal (ULN) (unless has Gilbert's disease) (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated) * Total bilirubin \< 2.0 mg/dl-exception permitted in patients with Gilbert's Syndrome (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated) * Aspartate aminotransferases (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2 x ULN, patients with abnormal liver function tests (LFTs) in the context of active GVHD will not be included (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated) * Creatinine clearance of \>= 40/min/1.73 m\^2 for participants with creatinine levels above institutional normal per 24 hour urine test or the Cockcroft-Gault formula (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated) * Corrected QT (QTc) =\< 480 ms * Note: To be performed within 28 days prior to day 1 of protocol therapy * Seronegative for human immunodeficiency virus (HIV) antigen/antibody (Ag/Ab) combo, hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative), and syphilis (rapid plasma reagin \[RPR\]) * If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed * Women of childbearing potential (WOCBP): negative urine or serum pregnancy test * If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 3 months after the last dose of protocol therapy * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only) Exclusion Criteria: * History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent * Active diarrhea considered clinically significant and may impair oral drug administration * Clinically significant uncontrolled illness * Active infection requiring antibiotics * Active infection. Patients with treated viral, bacterial or fungal infections that are controlled on therapy will be allowed to participate * Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection * Diagnosis of Gilbert's disease * Other active malignancy. Participants with history of prior malignancy treated with curative intent who achieved complete response (CR) more than 2 years before study entry are eligible. This exclusion rule does not apply to non-melanoma skin tumors and in-situ cervical cancer * Females only: Pregnant or breastfeeding * Active grade II-IV acute GVHD and/or requiring systemic steroids with prednisone dose equivalent of \>= 0.25 mg/kg at end of 4 weeks * Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures * Prospective participants, who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)