• Second or greater relapse after chemotherapy or hematopoietic stem cell(HSCT)
• Refractory after >= 2 attempts at induction therapy

• Must not have received prior re-induction therapy for this relapse
• Each block of chemotherapy (i.e., cytarabine, daunorubicin and etoposide [ADE],ytarabine and mitoxantrone [MA]) is a separate re-induction attempt
• Donor lymphocyte infusion (DLI) is considered a re-induction attempt

• 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

• Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive.The duration of this interval must be discussed with the study chair and theudy-assigned research coordinator prior to enrollment
  • >= 14 days must have elapsed after the completion of other cytotoxic therapywith the exception of hydroxyurea. Additionally, patients must have fullyvered from all acute toxic effects of prior therapy. NOTE: Cytoreductionwith hydroxyurea must be discontinued >= 24 hours prior to the start ofherapy
  • Intrathecal chemotherapy must be completed >= 72 hours prior to the start ofhe 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 thedose of agent. The duration of this interval must be discussed with theudy chair and the study-assigned research coordinator prior to enrollment
• Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,d toxicity related to prior antibody therapy must be recovered to grade =< 1
• Corticosteroids: If used to modify immune adverse events related to priorherapy, >= 14 days must have elapsed since last dose of corticosteroid
• Hematopoietic growth factors: >= 14 days after the last dose of a long-actinggrowth factor (e.g., pegfilgrastim) or 7 days for short-acting growth factor. Forgents that have known adverse events occurring beyond 7 days afterdministration, this period must be extended beyond the time during which adversevents are known to occur. The duration of this interval must be discussed withhe study chair and the study research coordinator
• Interleukins, interferons and cytokines (other than hematopoietic growth): >= 21 days after the completion of interleukins, interferon orytokines (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 stemusion 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 orboost 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; >=2 days if other substantial bone marrow (BM) radiation
• Radiopharmaceutical therapy (e.g., radiolabeled antibody,131I-metaiodobenzylguanidine [MIBG]): >= 42 days after systemically administereddiopharmaceutical therapy
• Study-specific limitations on prior therapy: small molecule investigationalgents: >= 14 days or > 5 half-lives must have elapsed from the last dose of thegent, whichever is greater

Platelet count >= 20,000/mm^3 (may receive platelet transfusions). These patients must

• 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

• All patients and/or their parents or legal authorized representatives must sign awritten informed consent. Assent, when appropriate, will be obtained according toutional guidelines
• All institutional, Food and Drug Administration (FDA), and National Cancerute (NCI) requirements for human studies must be met

• Corticosteroids: Patients receiving corticosteroids who have not been on a stabledecreasing dose of corticosteroid for at least 7 days prior to enrollment aregible. If used to modify immune adverse events related to prior therapy,>= 14 days must have elapsed since last dose of corticosteroid. The use ofds to manage the side effect of IDH inhibitor-associateddifferentiation syndrome (IDH-DS), is permitted on study
• Investigational drugs: Patients who are currently receiving anothervestigational drug are not eligible
• Anti-cancer agents: Patients who are currently receiving other anti-cancer agentsgible (except leukemia patients receiving hydroxyurea, which may beued until 24 hours prior to start of protocol therapy; the use ofhydroxyurea to manage the side effect of IDH-DS, is permitted on study)
• Anti-GVHD agents post-transplant: Patients who are receiving cyclosporine,us or other agents to prevent graft-versus-host disease post bone marrowgible for this trial

• Patients with known hypersensitivity to any of the components of enasidenib aregible.
• Patients with prior exposure to enasidenib or another IDH2 inhibitor are notgible.
• Patients taking the following drugs will be excluded from study entry unlesshese drugs are discontinued or patients are transferred to a medicallyble alternative > 5 half-lives before the first dose of enasidenib.
  • Drugs with a narrow therapeutic range that are sensitive substrates of thewing cytochrome P450 (CYP) enzymes: CYP2C8 (e.g. paclitaxel), 2C9 (e.g.henytoin and warfarin), 2C19 (e.g. s-mephenytoin), 2D6 (e.g. thioridazine),d 1A2 (e.g. theophylline and tizanidine).
  • Breast cancer resistant protein (BCRP) transporter-sensitive substrateuvastatin

• No intrathecal chemotherapy is permitted on study. Prior to study enrollment,brospinal fluid (CSF) evaluation is only required if there is a clinicaluspicion for CNS leukemia. Clinical signs of CNS leukemia (such as facial nervey, brain/eye involvement or hypothalamic syndrome) are not eligible for this
• Immediately life-threatening, severe complications of leukemia includinguncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminatedvascular coagulation

Infection: Patients who have an uncontrolled infection or patients with known human