Inclusion Criteria:

          -  Patient must have AML with an IDH2 mutation identified from a peripheral blood or bone
             marrow sample at the time of diagnosis and/or relapsed/refractory disease

          -  Patient must have bone marrow assessment (aspiration or biopsy) with > 5% leukemic
             blasts by morphology and/or flow cytometry in at least one of the following clinical
             scenarios:

               -  Second or greater relapse after chemotherapy or hematopoietic stem cell
                  transplant (HSCT)

               -  Refractory after >= 2 attempts at induction therapy

          -  Relapsed patients

               -  Must not have received prior re-induction therapy for this relapse

               -  Each block of chemotherapy (i.e., cytarabine, daunorubicin and etoposide [ADE],
                  cytarabine and mitoxantrone [MA]) is a separate re-induction attempt

               -  Donor lymphocyte infusion (DLI) is considered a re-induction attempt

          -  Refractory patients

               -  Each attempt at induction therapy may include up to two chemotherapy courses

          -  Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16
             years of age. Patients who are unable to walk because of paralysis, but who are up in
             a wheelchair, will be considered ambulatory for the purpose of assessing the
             performance score

          -  Patient's current disease state must be one for which there is no known curative
             therapy or therapy proven to prolong survival with an acceptable quality of life

          -  Evaluation of cerebrospinal fluid (CSF) is only required if there is a clinical
             suspicion of central nervous system (CNS) involvement by leukemia during eligibility
             screening. Should a patient be found to have CNS2 or CNS3 status by CSF prior to
             eligibility screening, patient may receive intrathecal chemotherapy > 72 hours prior
             to starting study drug. CNS1 status must be established before starting study drug

          -  Patients must have fully recovered from the acute toxic effects of all prior
             anti-cancer therapy and must meet the following minimum duration from prior
             anti-cancer directed therapy prior to enrollment. If after the required timeframe, the
             numerical eligibility criteria are met, e.g., blood count criteria, the patient is
             considered to have recovered adequately

               -  Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive.
                  The duration of this interval must be discussed with the study chair and the
                  study-assigned research coordinator prior to enrollment

                    -  >= 14 days must have elapsed after the completion of other cytotoxic therapy
                       with the exception of hydroxyurea. Additionally, patients must have fully
                       recovered from all acute toxic effects of prior therapy. NOTE: Cytoreduction
                       with hydroxyurea must be discontinued >= 24 hours prior to the start of
                       protocol therapy

                    -  Intrathecal chemotherapy must be completed >= 72 hours prior to the start of
                       the first cycle of treatment

               -  Anti-cancer agents not known to be myelosuppressive (e.g. not associated with
                  reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the
                  last dose of agent. The duration of this interval must be discussed with the
                  study chair and the study-assigned research coordinator prior to enrollment

               -  Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,
                  and toxicity related to prior antibody therapy must be recovered to grade =< 1

               -  Corticosteroids: If used to modify immune adverse events related to prior
                  therapy, >= 14 days must have elapsed since last dose of corticosteroid

               -  Hematopoietic growth factors: >= 14 days after the last dose of a long-acting
                  growth factor (e.g., pegfilgrastim) or 7 days for short-acting growth factor. For
                  agents that have known adverse events occurring beyond 7 days after
                  administration, this period must be extended beyond the time during which adverse
                  events are known to occur. The duration of this interval must be discussed with
                  the study chair and the study research coordinator

               -  Interleukins, interferons and cytokines (other than hematopoietic growth
                  factors): >= 21 days after the completion of interleukins, interferon or
                  cytokines (other than hematopoietic growth factors)

               -  Stem cell Infusions (with or without total body irradiation [TBI]):

                    -  Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem
                       cell infusion including DLI or boost infusion:

                         -  >= 60 days after infusion for bone marrow or stem cell transplant and

                         -  >= 4 weeks after infusion for any stem cell infusion including DLI or
                            boost infusion

                         -  There must be no evidence of graft versus host disease (GVHD)

                    -  Autologous stem cell infusion including boost infusion: >= 42 days

               -  Cellular Therapy: >= 42 days after the completion of any type of cellular therapy
                  (e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)

               -  XRT/external beam irradiation including protons: >= 14 days after local XRT; >=
                  150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >=
                  42 days if other substantial bone marrow (BM) radiation

               -  Radiopharmaceutical therapy (e.g., radiolabeled antibody,
                  131I-metaiodobenzylguanidine [MIBG]): >= 42 days after systemically administered
                  radiopharmaceutical therapy

               -  Study-specific limitations on prior therapy: small molecule investigational
                  agents: >= 14 days or > 5 half-lives must have elapsed from the last dose of the
                  agent, whichever is greater

          -  Platelet count >= 20,000/mm^3 (may receive platelet transfusions). These patients must
             not be known to be refractory to red cell or platelet transfusion

          -  Hemoglobin >= 8.0 g/dL at baseline (may receive red blood cell [RBC] transfusions)

          -  Creatinine clearance or radioisotope glomerular filtration rate [GFR] >= 70
             ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

               -  Age: Maximum serum creatinine (mg/dL)

                    -  2 to < 6 years: 0.8 (male and female)

                    -  6 to < 10 years: 1 (male and female)

                    -  10 to < 13 years: 1.2 (male and female)

                    -  13 to < 16 years: 1.5 (male); 1.4 (female

                    -  >= 16 years: 1.7 (male); 1.4 (female)

          -  Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for
             age

          -  Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 225
             U/L. For the purpose of this study, the ULN for SGPT is 45 U/L

          -  Serum albumin >= 2 g/dL

          -  Left ventricular ejection fraction of >= 50% by echocardiogram

          -  Regulatory Requirements

               -  All patients and/or their parents or legal authorized representatives must sign a
                  written informed consent. Assent, when appropriate, will be obtained according to
                  institutional guidelines

               -  All institutional, Food and Drug Administration (FDA), and National Cancer
                  Institute (NCI) requirements for human studies must be met

        Exclusion Criteria:

          -  AML associated with Down syndrome or t(15;17) is not eligible for study

          -  Pregnant or breast-feeding women will not be entered on this study due to risks of
             fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests
             must be obtained in girls who are post-menarchal. Males or females of reproductive
             potential may not participate unless they have agreed to use an effective
             contraceptive method for the duration of study therapy and for 4 months after the last
             dose of enasidenib. Abstinence is an acceptable method of birth control. It is not
             known if enasidenib is present in breast milk. Breastfeeding is not recommended during
             therapy or for at least 30 days after the last dose of enasidenib

          -  Concomitant Medications:

               -  Corticosteroids: Patients receiving corticosteroids who have not been on a stable
                  or decreasing dose of corticosteroid for at least 7 days prior to enrollment are
                  not eligible. If used to modify immune adverse events related to prior therapy,
                  >= 14 days must have elapsed since last dose of corticosteroid. The use of
                  corticosteroids to manage the side effect of IDH inhibitor-associated
                  differentiation syndrome (IDH-DS), is permitted on study

               -  Investigational drugs: Patients who are currently receiving another
                  investigational drug are not eligible

               -  Anti-cancer agents: Patients who are currently receiving other anti-cancer agents
                  are not eligible (except leukemia patients receiving hydroxyurea, which may be
                  continued until 24 hours prior to start of protocol therapy; the use of
                  hydroxyurea to manage the side effect of IDH-DS, is permitted on study)

               -  Anti-GVHD agents post-transplant: Patients who are receiving cyclosporine,
                  tacrolimus or other agents to prevent graft-versus-host disease post bone marrow
                  transplant are not eligible for this trial

          -  Patients must be able to swallow intact tablets whole.

               -  Patients with known hypersensitivity to any of the components of enasidenib are
                  not eligible.

               -  Patients with prior exposure to enasidenib or another IDH2 inhibitor are not
                  eligible.

               -  Patients taking the following drugs will be excluded from study entry unless
                  these drugs are discontinued or patients are transferred to a medically
                  acceptable alternative > 5 half-lives before the first dose of enasidenib.

                    -  Drugs with a narrow therapeutic range that are sensitive substrates of the
                       following cytochrome P450 (CYP) enzymes: CYP2C8 (e.g. paclitaxel), 2C9 (e.g.
                       phenytoin and warfarin), 2C19 (e.g. s-mephenytoin), 2D6 (e.g. thioridazine),
                       and 1A2 (e.g. theophylline and tizanidine).

                    -  Breast cancer resistant protein (BCRP) transporter-sensitive substrate
                       rosuvastatin

          -  Patients with the following leukemia complications are not eligible for this trial:

               -  No intrathecal chemotherapy is permitted on study. Prior to study enrollment,
                  cerebrospinal fluid (CSF) evaluation is only required if there is a clinical
                  suspicion for CNS leukemia. Clinical signs of CNS leukemia (such as facial nerve
                  palsy, brain/eye involvement or hypothalamic syndrome) are not eligible for this
                  trial

               -  Immediately life-threatening, severe complications of leukemia including
                  uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated
                  intravascular coagulation

          -  Infection: Patients who have an uncontrolled infection or patients with known human
             immunodeficiency virus (HIV) or active hepatitis B or C are not eligible

          -  Patients who have received a prior solid organ transplantation are not eligible

          -  Patients who in the opinion of the investigator may not be able to comply with the
             safety monitoring requirements of the study are not eligible