A Phase II Study of Intensive Salvage Therapy Followed by Enasidenib for Patients With AML Harboring Mutations in IDH2 Who Have Failed or Been Refractory to One Prior Line of Therapy

• Confirmed diagnosis of AML harboring a mutation in IDH2 relapsed or refractory to first line cytarabine/anthracycline induction chemotherapy, failed to respond to or relapsed following at least 2 cycles of hypomethylating agent (azacitidine, decitabine, sgi-110) or at least 1 cycle of hypomenthylating agent with venetoclax or other targeted therapies

‣ Patients will be identified and deemed eligible based upon the identification of an IDH2 mutation identified at either at the time of disease relapse prior to re-induction chemotherapy or following 1-2 cycles of chemotherapy induction. Each institution will test using their standard local FDA-approved or cleared assay per the institutional standard of care workup for relapsed disease.

⁃ First relapse defined as untreated hematologic relapse (according to International Working Group criteria) after one line of intensive regimen for AML including at least one cytarabine containing induction block with a total dose no less than 700 mg/m\^2 per cycle and 3 days of an anthracycline that induced a complete remission (CR)/complete remission with incomplete hematologic recovery (CRi)/complete remission with incomplete platelet recovery (CRp). Subjects are allowed to receive induction, consolidation, transplant and/or maintenance therapy prior to achieving their first CR/CRi/CRp

⁃ Refractory to induction therapy is defined as never achieving CR, CRi or CRp (according to International Working Group criteria) after one line of intensive regimen for AML (reinduction, consolidation and/or transplant allowed) including at least one cytarabine containing induction block with a total dose no less than 700 mg/m\^2 per cycle and 3 days of an anthracycline

• Subjects considered eligible for intensive chemotherapy

• Subjects had received a first salvage within the last 60 days (day 15 to 60 following most recent cytarabine-based standard salvage number \[#\] 1 therapy) who achieved either \> 50% reduction in blast percentage from the pre-treatment bone marrow OR \< 20% cellularity with any blast percentage AND \< 5% peripheral blood blasts

• Have an Eastern Cooperative Oncology Group (ECOG) performance status of =\< 2

• Adequate liver function within 72 hours of enrollment, defined as:

• o Blood total bilirubin ≤ 1.5 x ULN, unless considered due to Gilbert's syndrome (eg, a gene mutation in UGT1A1) or leukemic organ involvement, following review by the Investigator

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 3.0 x upper limit of normal (ULN) (within 72 hours of enrollment)

• Adequate renal function within 72 hours of enrollment, defined as blood creatinine =\< 2.5 x ULN

• Females of childbearing potential (FCBP) may participate, providing they meet the following conditions:

‣ Agree to practice true abstinence from sexual intercourse or to use highly effective contraceptive methods (eg, combined \[containing estrogen and progestogen\] or progestogen-only associated with inhibition of ovulation, oral, injectable, intravaginal, patch, or implantable hormonal contraceptive; bilateral tubal occlusion; intra-uterine device; intrauterine hormone-releasing system; or male partner sterilization \[note that vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the FCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success\]) at screening and throughout the study, and for 4 months following the last study treatment (6 months following the last dose of cytarabine); and

⁃ Have a negative serumblood β-subunit of human chorionic gonadotropin (β-hCG) pregnancy test (sensitivity of at least 25 mIU/mL) at screening; and

⁃ Have a negative serum or urine (investigator's discretion under local regulations) β hCG pregnancy test (sensitivity of at least 25 mIU/mL) within 72 hours prior to the start of study treatment in the Treatment Phase (note that the screening serumblood pregnancy test can be used as the test prior to the start of study treatment in the Treatment Phase if it is performed within the 72 hour timeframe).

• Men must use a latex condom during any sexual contact with women of childbearing potential

• Willing to adhere to protocol specific requirements

• Clinically significant toxic effects of prior therapy (except hydroxyurea) resolved to grade =\< 1 before the start of study

• Participant or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure