Inclusion Criteria:
1. Documented diagnosis of
* MDS according to WHO/FAB classification that meets IRSS-R classification of low or intermediate risk disease; and a diagnosed as denovo or secondary MDS (MDS-RS eligible if refractory to or declined luspatercept therapy) OR
* Dysplastic (nonproliferative) CMML with WBC \< 13.0/microL)
2. No disease-modifying therapy (HMA, hydrea) within 2 months of starting study
3. Age ≥ 18 years of age
4. ECOG ≤ 3
5. Negative for IDH2 mutation by NGS or multiplex PCR (SNaPshot)
6. Has symptomatic anemia defined as hemoglobin \< 10.5 g/dL with any of the following.
* Tachypnea
* Shortness of breath
* Fatigue
* Malaise
* Worsening of cardiovascular function
* Asthenia
* Dyspnea on exertion
* Angina
* Other subject symptoms the subject reports as being associated with being anemic.
7. Stated willingness to comply with all study procedures and availability for the duration of the study
8. Ability to take oral medication and be willing to adhere to the medication regimen.
9. Females of reproductive potential need to either commit to true abstinence from heterosexual contact or agree to use, and be able to comply with highly effective contraception without interruption, 28 days prior to starting enasidenib, during the study therapy, and for 30 days after last dose of enasidenib
10. For males of reproductive potential: agreement to use of condoms
11. Adequate organ function defined as:
* Hepatic function: total bilirubin \<1.5 x ULN (unless attributable to Gilbert's disease), AST or ALT \< 3x ULN
* Renal function: creatinine clearance \> 30 mL/minute, calculated by Cockcroft-Gault formula
12. Ability to understand and the willingness to sign the IRB approved informed consent document.
13. Women of childbearing potential must have negative urine or serum pregnancy test
Exclusion Criteria:
1. Use of concurrent other erythropoietic agents (including epoetin, darbepoetin), G-CSF within 30 days of study enrollment
2. Less than 3 months of life expectancy
3. Significant cardiac disease (NYHA Class IV congestive heart failure, or unstable angina or myocardial infarction within the last 6 months
4. Harbor IDH2 somatic mutations by NGS or PCR
5. Pregnant or breast feeding
6. Any uncontrolled bacterial, fungal, viral or other infection.
7. No known HIV+ or active hepatitis B or C infection, defined as positive viral load for HBV or HCV or a positive surface antigen (HBsAg) test for hepatitis B.
8. Have other causes of anemia: deficiencies in iron, B12, folate; nutritional deficiencies related to gastric surgery, anorexia nervosa, excessive zinc supplementation; gastrointestinal bleed. If nutritional deficiencies can be corrected, potential subject can be rescreened and enrolled if nutritionally replete and still meets eligibility criteria.
9. Any other medical history, including laboratory results, deemed by the Principal Investigator likely to interfere with their participation in the study, or to interfere with the interpretation of the results
10. Pregnant or breast feeding
