Inclusion Criteria:

1. Subject must be greater than or equal to 18 years of age.
2. Subjects must have an advanced hematologic malignancy including:
   • Phase 1/ Dose escalation:
     • Diagnosis of acute myelogenous leukemia (AML) according to World Health Organization (WHO) criteria;
       • Disease refractory or relapsed (defined as the reappearance of > 5% blasts in the bone marrow).
       • Untreated AML, greater than or equal to 60 years of age and are not candidates for standard therapy due to age, performance status, and/or adverse risk factors, according to the treating physician and with approval of the Medical Monitor;
     • Diagnosis of Myelodysplastic syndrome (MDS) according to WHO classification with refractory anemia with excess blasts (subtype RAEB-1 or RAEB-2), or considered high-risk by the Revised International Prognostic Scoring System (IPSS-R), that is recurrent or refractory, or the subject is intolerant to established therapy known to provide clinical benefit for their condition (i.e., subjects must not be candidates for regimens known to provide clinical benefit), according to the treating physician and with approval of the Medical Monitor.
   • Phase 1/Part 1 Expansion:
     • Arm 1: Relapsed or refractory AML and age greater than or equal to 60 years or any subject with AML regardless of age who has relapsed following a Bone marrow transplant (BMT).
     • Arm 2: Relapsed or refractory AML and age <60 years, excluding subjects with AML who have relapsed following a BMT.
     • Arm 3: Untreated AML and age greater than or equal to 60 years that decline standard of care chemotherapy.
     • Arm 4: Isocitrate dehydrogenase protein, 2 (IDH2)-mutated advanced hematologic malignancies not eligible for Arms 1 to 3.
   • Phase 2:
     • Diagnosis of AML according to World Health Organization (WHO) criteria and disease relapsed or refractory as defined by:
       • Subjects who relapse after allogeneic transplantation;
       • Subjects in second or later relapse;
       • Subjects who are refractory to second-line induction or re-induction treatment.
3. Subjects must have documented IDH2 gene-mutated disease:
   • For subjects in the dose escalation phase and Part 1 Expansion, IDH2 mutation may be based on local evaluation. (Centralized testing will be performed retrospectively.)
4. For subjects in The Phase 2 portion of the trial, central testing of IDH2 mutation is required during screening to confirm eligibility. Subjects must be amenable to serial bone marrow sampling, peripheral blood sampling and urine sampling during the study.
   • The diagnosis and evaluation of AML or MDS will be made by bone marrow aspiration and/or biopsy. If an aspirate is unobtainable (i.e., a "dry tap"), the diagnosis may be made from the core biopsy.
   • Screening bone marrow aspirate and peripheral blood samples are required of all subjects. A bone marrow biopsy must be collected if adequate aspirate is not attainable unless:
     • A bone marrow aspirate and biopsy was performed as part of the standard of care within 28 days prior to the start of the study treatment; and
     • Slides of bone marrow aspirate, biopsy and stained peripheral blood smear are available for both local and central pathology reviewers; and
     • A bone marrow aspirate sample acquired within 28 days prior to the start of study treatment has been sent for cytogenetic analysis.
5. Subjects must be able to understand and willing to sign an informed consent. A legally authorized representative may consent on behalf of a subject who is otherwise unable to provide informed consent, if acceptable to and approved by the site and/or sites Institutional Review Board (IRB)/Independent Ethics Committee (IEC).
6. Subjects must have Eastern Cooperative Oncology Group (ECOG) Performance status (PS) of 0 to 2.
7. Platelet count ≥20,000/μL (transfusions to achieve this level are allowed). Subjects with a baseline platelet count of <20,000/μL due to underlying malignancy are eligible with Medical Monitor approval.
8. Subjects must have adequate hepatic function as evidenced by:
   • Serum total bilirubin ≤1.5 × upper limit of normal (ULN), unless considered due to Gilbert's disease, a gene mutation in UGT1A1, or leukemic organ involvement, following approval by the Medical Monitor;
   • Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and Alkaline phosphatase (ALP) ≤3.0 × ULN (Upper limit of normal), unless considered due to leukemic organ involvement.
9. Subjects must have adequate renal function as evidenced by:
   • Serum creatinine ≤2.0 × ULN OR
   • Creatinine clearance greater than 40 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR) estimation: (140 - Age) x (weight in kg) x (0.85 if female)/72 x serum creatinine
10. Subjects must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of cancer. (Subjects with residual Grade 1 toxicity, for example Grade 1 peripheral neuropathy or residual alopecia, are allowed with approval of the Medical Monitor.)
11. Female subjects of child-bearing potential must agree to undergo medically supervised pregnancy test prior to starting study drug. The first pregnancy test will be performed at screening (within 7 days prior to first study drug administration), and on the day of the first study drug administration and confirmed negative prior to dosing and Day 1 before dosing all subsequent cycles.
12. Female subjects with reproductive potential must have a negative serum pregnancy test within 7 days prior to the start of therapy. Subjects with reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy or tubal occlusion or who have not been naturally postmenopausal (i.e., who have not menstruated at all) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Females of reproductive potential as well as fertile men and their partners who are female of reproductive potential must agree to abstain from sexual intercourse or to use two highly effective forms of contraception from the time of giving informed consent, during the study and for 90 days (females and males) following the last dose of AG-221. A highly effective form of contraception is defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, double-barrier method (e.g., synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), or male partner sterilization.
13. Able to adhere to the study visit schedule (ie, clinic visits at the study sites are mandatory, unless noted otherwise for particular study visits) and other protocol requirements.

Exclusion Criteria:

1. Subjects who have undergone hematopoietic stem cell transplant (HSCT) within 60 days of the first dose of AG-221, or subjects on immunosuppressive therapy post HSCT at the time of screening, or with clinically significant graft-versus-host disease (GVHD). (The use of a stable dose of oral steroids post GVHD and/or topical steroids for ongoing skin GVHD is permitted with Medical Monitor approval.)
2. Subjects who received systemic anticancer therapy or radiotherapy <14 days prior to their first day of study drug administration. (Hydroxyurea is allowed for up to 28 days after the start of AG-221 for the control of peripheral leukemic blasts in subjects with white blood cell [WBC] counts >30,000/μL as well as prior to enrollment).
3. Subjects who received a small molecule investigational agent <14 days prior to their first day of study drug administration. In addition, the first dose of AG-221 should not occur before a period ≥5 half-lives of the investigational agent has elapsed.
4. Subjects taking the following sensitive cytochrome P450 (CYP) substrate medications that have a narrow therapeutic range are excluded from the study unless they can be transferred to other medications within ≥5 half-lives prior to dosing: paclitaxel (CYP2C8) warfarin, phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline and tizanidine (CYP1A2).
5. Subjects taking the P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) transporter-sensitive substrates digoxin and rosuvastatin should be excluded from the study unless they can be transferred to other medications within ≥5 half-lives prior to dosing.
6. Subjects for whom potentially curative anticancer therapy is available.
7. Subjects who are pregnant or lactating.
8. Subjects with an active severe infection that required anti-infective therapy or with an unexplained fever >38.5°C during screening visits or on their first day of study drug administration (at the discretion of the Investigator, subjects with tumor fever may be enrolled).
9. Subjects with known hypersensitivity to any of the components of AG-221.
10. Subjects with New York Heart Association (NYHA) Class III or IV congestive heart failure or left ventricular ejection fraction (LVEF) <40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within approximately 28 days of C1D1.
11. Subjects with a history of myocardial infarction within the last 6 months of screening.
12. Subjects with uncontrolled hypertension (systolic blood pressure [BP] >180 mmHg or diastolic BP >100 mmHg) at screening are excluded. Subjects requiring 2 or more medications to control hypertension are eligible with Medical Monitor approval.
13. Subjects with known unstable or uncontrolled angina pectoris.
14. Subjects with a known history of severe and/or uncontrolled ventricular arrhythmias.
15. Subjects with heart-rate corrected QT (QTc) interval ≥450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) at screening.
16. Subjects taking medications that are known to prolong the QT interval unless they can be transferred to other medications within ≥5 half-lives prior to dosing.
17. Subjects with known infection with human immunodeficiency virus (HIV) or active hepatitis B or C.
18. Subjects with any other medical or psychological condition, deemed by the Investigator to be likely to interfere with a subject's ability to sign informed consent, cooperate, or participate in the study.
19. Subjects with known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally.
20. Subjects with clinical symptoms suggesting active central nervous system (CNS) leukemia or known CNS leukemia.
21. Subjects with immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation.
22. In the Phase 2 portion of the trial only, subjects who have previously received treatment with an inhibitor of Isocitrate dehydrogenase protein (IDH).