Testing the Addition of an IDH2 Inhibitor, Enasidenib, to Usual Treatment (Cedazuridine-Decitabine) for Higher-Risk Myelodysplastic Syndrome (MDS) With IDH2 Mutation (A MyeloMATCH Treatment Trial)

Inclusion Criteria:

* GENERAL MYLEOMATCH MSRP REGISTRATION CRITERIA:

* Patients must be registered to the Master Screening and Reassessment Protocol (MSRP) and assigned to this protocol by the MATCHBox Treatment Verification Team.
* Participants must not have received prior anti-cancer therapy for AML or MDS.

* Note: Hydroxyurea to control the white blood cell count (WBC) is allowed.
* Note: Prior erythroid stimulating agent (ESA) is not considered prior therapy for the purposes of eligibility.
* Participants must not be currently receiving any cytarabine-containing therapy other than up to 1 g/m\^2 of cytarabine, which is allowed for urgent cytoreduction. The use of prior hydroxyurea, all-trans retinoic acid (ATRA), BCR-ABL directed tyrosine kinase inhibitor, erythropoiesis-stimulating agent, thrombopoietin receptor agonist and lenalidomide is allowed.
* REGISTRATION ELIGIBILITY CRITERIA (STEP 1)
* Patients must have a morphologically-confirmed diagnosis of MDS with a Revised International Prognostic Scoring System (IPSS-R) score ≥ 4.
* Patients must have a detectable pathogenic IDH2 mutation based on the National Cancer Institute (NCI) Myeloid Panel.
* No prior treatment with deoxyribonucleic acid (DNA) methyltransferase inhibitors (ASTX727, azacitidine, or decitabine).
* Prior treatment with growth factors (ESA, granulocyte colony-stimulating factor \[g-CSF\], TPO agonist), lenalidomide or luspatercept is allowed with a maximum limit of 1 month of exposure.
* Age ≥ 18 years
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
* Total bilirubin ≤ 2.0 x upper limit of normal (ULN)

* Unless elevated due to Gilbert's syndrome. In patients with Gilbert's syndrome if direct bilirubin is within normal limits, then they are eligible for enrollment.
* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase \[SGPT\[) ≤ 3.0 x upper limit of normal (ULN)
* Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73m\^2
* Not pregnant and not nursing, because this study involves: an agent that has known genotoxic, mutagenic and teratogenic effects.

* Therefore, for women of childbearing potential only, a negative pregnancy test done as part of screening lab work prior to registration is required.
* Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
* HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial.
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
* RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2)
* Patients on the ASTX727 monotherapy arm (Arm A) that do not achieve a CR (complete response), CRL (CR with limited count recovery), or CRh (CR with partial count recovery) after completing 6 cycles of study treatment.
* ECOG performance status ≤ 2
* Total bilirubin ≤ 2.0 x upper limit of normal (ULN).

* Unless elevated due to Gilbert's syndrome. In patients with Gilbert's syndrome if direct bilirubin is within normal limits, then they are eligible for enrollment.
* AST (SGOT)/ALT (SGPT) ≤ 3.0 x upper limit of normal (ULN)
* GFR ≥ 30 mL/min/1.73m\^2
* Not pregnant and not nursing, because this study involves: an agent that has known genotoxic, mutagenic and teratogenic effects.