Testing the Addition of an Anti-cancer Drug, M3814, to the Usual Treatment (Mitoxantrone, Etoposide, and Cytarabine) for Relapsed or Refractory Acute Myeloid Leukemia

Inclusion Criteria: * An established and confirmed diagnosis of AML by World Health Organization criteria, excluding acute promyelocytic leukemia (APL) (with promyelocytic leukemia -retinoic acid receptor alpha \[PML-RARA\]) * Patients with R/R AML, defined as: * Relapsed: \>= 5% bone marrow blasts by morphology, reappearance of peripheral blood blasts, or development of extramedullary leukemia after achieving prior CR or CRi. First or second relapse is eligible. First relapse is restricted to participants with CR 1 duration of less than 9-12 months * Refractory: no CR or CRi after one or more cycles of induction. Induction cycles include regimens with the intent to achieve remission and can include high intensity and/or low intensity regimens * Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of M3814 in combination with mitoxantrone, etoposide, and cytarabine in patients \< 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials * Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (or Karnofsky \>= 60%) * Serum bilirubin =\< 1.5 institutional upper limit of normal (ULN) (For patients with hemolysis, Gilbert's syndrome or liver infiltration with leukemia, serum bilirubin =\< 3 x institutional ULN) * Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase \[SGPT\]) =\<…