Inclusion Criteria:

• - Patients with AML or biphenotypic or bilineage leukemia (including a myeloid component) who have failed prior therapy.

Patients with isolated extramedullary AML are eligible. The World Health Organization (WHO) classification will be used for AML.

• - Elderly (> 60 years old) patients with newly diagnosed AML not eligible for intensive chemotherapy are also eligible.

• - AML patients with prior history of myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) regardless of prior therapy received, are eligible at the time of diagnosis of AML.

• - Subjects must have documented IDH2 gene mutation.

• - Eastern Cooperative Oncology Group (ECOG) performance status =< 3.

• - Adequate renal function including creatinine < 2 unless related to the disease.

• - Total bilirubin < 2 x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement.

• - Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 3 x ULN unless considered due to leukemic involvement.

• - Provision of written informed consent.

• - Oral hydroxyurea and/or cytarabine (up to 2 g/m2) for patients with rapidly proliferative disease is allowed before the start of study therapy, as needed, for clinical benefit and after discussion with the principal investigator (PI).

Concurrent therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted.

• - Females must be surgically or biologically sterile or postmenopausal (amenorrheic for at least 12 months) or if of childbearing potential, must have a negative serum or urine pregnancy test within 72 hours before the start of the treatment.

• - Women of childbearing potential must agree to use an adequate method of contraception during the study and until 3 months after the last treatment.

Males must be surgically or biologically sterile or agree to use an adequate method of contraception during the study until 3 months after the last treatment.

Exclusion Criteria:

• - Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British [FAB] class M3-AML) - Active and uncontrolled comorbidities including active uncontrolled infection, uncontrolled hypertension despite adequate medical therapy, active and uncontrolled congestive heart failure New York Heart Association (NYHA) class III/IV, clinically significant and uncontrolled arrhythmia as judged by the treating physician.

• - Any other medical, psychological, or social condition that may interfere with study participation or compliance, or compromise patient safety in the opinion of the investigator.

- Pregnant or breastfeeding

PRIMARY OBJECTIVES:

• I. To determine the clinical activity of enasidenib mesylate (AG221, IDHIFA) in combination with azacitidine (AZA) for patients with relapsed/refractory acute myeloid leukemia is measured by overall response rate (ORR).

SECONDARY OBJECTIVES:

• I. To determine duration of response, event-free survival (EFS), and overall survival (OS).

• II. To determine the safety of enasidenib in combination with azacitidine in patients with relapsed/refractory acute myeloid leukemia (AML).

EXPLORATORY OBJECTIVES:

• I. To evaluate occurrence of minimal residual disease (MRD) negative status by IDH2 mutation analysis and flow cytometry.

• II. To investigate possible relationships between baseline protein and gene expression signatures and mutation profile and clinical response to the combination.

• III. To evaluate the incidence and characteristics of IDH-inhibitor related differentiation syndrome (IDH-DS) with combination therapy.

OUTLINE: Patients receive azacitidine subcutaneously (SC) or intravenously (IV) over 30 minutes on days 1-7 and enasidenib mesylate orally (PO) once daily (QD) beginning on day 1. Cycles repeat every 4-6 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 3-6 months for up to 5 years.

Arms

Experimental: Treatment (azacitidine, enasidenib mesylate)

Patients receive azacitidine SC or IV over 30 minutes on days 1-7 and enasidenib mesylate PO QD beginning on day 1. Cycles repeat every 4-6 weeks in the absence of disease progression or unacceptable toxicity.

Interventions

Drug: - Azacitidine

Given SC or IV

Drug: - Enasidenib Mesylate

Given PO