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)