Targeted Therapy With the IDH2-Inhibitor Enasidenib (AG221) for High-Risk IDH2-Mutant Myelodysplastic Syndrome

Inclusion Criteria: * Signed, informed consent must be obtained prior to any study specific procedures * Subjects with a histologically confirmed diagnosis of MDS, including both MDS and refractory anemia with excess blasts in transformation (RAEB-T) (acute myeloid leukemia \[AML\] with 20-30% blasts and multilineage dysplasia by French-American-British \[FAB\] criteria) by World Health Organization (WHO), and chronic myelomonocytic leukemia (CMML) are eligible * Subjects must have an IDH2 gene mutation (IDH2-R140 or R172) as determined by local laboratory result * (Arm A only): Subject must be hypomethylating agent naive (i.e. prior azacitidine, decitabine, SGI-110 is exclusionary). Receipt of other MDS-directed therapy such as lenalidomide is allowed * (Arm A only): Subjects with high-risk MDS (i.e. International Prostate Symptom Score \[IPSS\] intermediate-2 or high-risk; or revised \[R\]-IPSS high or very-high risk). Patients with intermediate-1 risk by IPSS or intermediate risk by R-IPSS with high-risk molecular features including TP53, ASXL1, EZH2, and/or RUNX1 mutations are also eligible * (Arm B only): Subject must be relapsed or refractory to prior hypomethylating agent therapy, defined as prior receipt of 6 cycles of HMA therapy with failure to attain a response, or relapse after prior response to HMA therapy * Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 * Serum bilirubin =\< 2 x the upper limit of normal (ULN) (except for patients with Gilbert's disease) * Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) =\< 3 x the laboratory ULN * Serum creatinine =\< 2 x the ULN * Able to understand and voluntarily sign a written informed consent, and willing and able to comply with protocol requirements * Resolution of all clinically significant treatment-related, non-hematological toxicities, except alopecia, from any previous cancer therapy to =\< grade 1 prior to the first dose of study treatment * Female patients of childbearing potential must have a negative serum or urine pregnancy test within 7 days of the first dose of study drug and agree to use dual methods of contraception during the study and for a minimum of 3 months following the last dose of study drug. Post-menopausal females (\> 45 years old and without menses for \> 1 year) and surgically sterilized females are exempt from these requirements. Male patients must use an effective barrier method of contraception during the study and for a minimum of 3 months following the last dose of study drug if sexually active with a female of childbearing potential Exclusion Criteria: * Any prior or coexisting medical condition that in the investigator's judgment will substantially increase the risk associated with the subject's participation in the study * Subject has received a prior targeted IDH2 inhibitor * Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study procedures * Active uncontrolled infection at study enrollment including known diagnosis of human immunodeficiency virus or chronic active hepatitis B or C infection * Clinically significant gastrointestinal conditions or disorders that may interfere with study drug absorption, including prior gastrectomy * Patients with known active central nervous system (CNS) disease, including leptomeningeal involvement * Impaired cardiac function, uncontrolled cardiac arrhythmia, or clinically significant cardiac disease including the following: a) New York Heart Association grade III or IV congestive heart failure, b) myocardial infarction within the last 6 months * Subjects with a corrected QT (QTc) \> 480 ms (QTc \> 510 msec for subjects with a bundle branch block at baseline * Nursing or pregnant women * Subjects with known hypersensitivity to study drugs or their excipients