A Study of Enasidenib in People With Clonal Cytopenia of Undetermined Significance

Inclusion Criteria:

* Age ≥18 years at the time of signing the informed consent form.
* Willing and able to adhere to the study visit schedule and other protocol requirements.
* Unexplained cytopenia for at least 6 months. Cytopenia is defined as the presence of ≥1 blood count indexes below the following thresholds:
* Hgb \<10 g/dL
* ANC \<1.8 × 10\^9/L
* Platelets \<100 × 10\^9/L
* Results of bone marrow biopsy within 1 month of study entry (screening bone marrow biopsy) must not indicate hematologic disease.
* IDH2 gene mutation (R140 or R172), performed locally, at a frequency \>2%.
* ECOG performance status of 0-2.
* Adequate organ function, defined as:

  * Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤3x upper limit of normal (ULN), unless the subject has Gilbert's syndrome.
  * Serum total bilirubin \<1.5x ULN. Higher levels are acceptable if these can be attributed to ineffective erythropoiesis. In these cases, approval from the study Principal Investigator is required.
  * Creatinine clearance greater than 50 mL/min based on the Cockroft-Gault glomerular filtration rate estimation.
* Patients being enrolled on study on the basis of anemia, will only be eligible if folate, B12, serum iron, serum ferritin, total iron binding capacity, haptoglobin and peripheral smear within normal limits
* Women of childbearing potential may participate provided they have a negative serum pregnancy test at screening and a negative serum or urine pregnancy test within 72 h of starting treatment.
* Women of childbearing potential (WOCBP) and males with partners who are WOCBP must agree to abstain from sexual intercourse or to use 1 highly effective form of contraception during the study and for at least 4 months following the last dose of enasidenib. Males with partners who are WOCBP must agree to use a barrier method.

Exclusion Criteria:

* Active malignancy defined as \>1-cm disease on most recent CT scan in the past 6 months or recent history of cancer (i.e. within the past 5 years) with \>50% chance of cancer recurrence in the next 5 years.
* Current or prior history of hematologic malignancy.
* Therapy (including maintenance therapy) for solid-tumor malignancy within the last 6 months.
* Known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally.
* Active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment).
* Positive direct Coombs test
* Evidence of hypersplenism on physical exam
* Pregnant or lactating (women).