Azacitidine in Combination With Mitoxantrone, Etoposide Phosphate, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

Inclusion Criteria:

* Patients must have histologically or cytologically confirmed relapsed or refractory acute myeloid leukemia (AML) according to 2008 World Health Organization (WHO) classification; must have failed at least one cycle of induction chemotherapy or relapsed after achieving a complete remission following induction chemotherapy; patients with prior autologous or allogeneic stem cell transplant are permitted
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
* Life expectancy of greater than 6 months for any comorbid conditions
* Total bilirubin =\< 1.5 X institutional upper limit of normal
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 X institutional upper limit of normal
* Creatinine =\< 1.5 mg/dL
* Left ventricular ejection fraction \>= 40%
* Ability to understand and the willingness to sign a written informed consent document
* Patients must have recovered from the non-hematologic toxicity of prior therapy to less than grade 2

Exclusion Criteria:

* Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
* Patients receiving any other investigational agents or patients that have received any other investigational agents within 14 days of enrollment
* Patients with active central nervous system disease or with granulocytic sarcoma as sole site of disease
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to azacitidine, mannitol, or other agents used in study
* Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; patients with active infection are permitted to enroll provided that the infection is under control; myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any echocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevant
* Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with azacitidine
* Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible