Azacitidine, Mitoxantrone Hydrochloride, and Etoposide in Treating Older Patients With Poor-Prognosis Acute Myeloid Leukemia

Inclusion Criteria:

* Acute myeloid leukemia (AML) as defined by World Health Organization (WHO) criteria, any subtype, de novo or secondary, except acute promyelocytic leukemia (APL)
* One of the following:

  * Previously untreated, with adverse-risk cytogenetics, including any one of the following:

    * Complete or partial deletion of chromosome 7
    * Complete or partial deletion of chromosome 5
    * At least 3 numerical or structural abnormalities, other than t(15;17), t(8;21) or inv(16) or variant
    * 11q23 abnormalities
    * Inv(3) or variant such as t(3:3)
  * Previously untreated, transformed from prior myelodysplastic syndrome (MDS) or myeloproliferative disorder (MPD) other than CML
  * Persistent leukemia following one cycle of 3+7 induction therapy (cytarabine plus either daunorubicin or idarubicin), any cytogenetic risk group
* Left ventricular ejection fraction (LVEF) \> 50% based on multi gated acquisition scan (MUGA) scan or 2-dimensional (2-D) echocardiogram
* Serum creatinine =\< 1.5 x upper limit of normal (ULN)
* Serum bilirubin =\< 1.5 x ULN
* Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x ULN
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Karnofsky \>= 60%)
* Patients with high initial white blood cell (WBC) should have the WBC reduced to below 50 x 10\^9/L with hydroxyurea, to minimize the risk of leukostasis related-complications; hydroxyurea is permitted up to 24 hours prior to starting azacitidine
* Men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; men should not father a child while participating in this study
* Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

* Patients who have had chemotherapy, radiotherapy or investigational agents within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
* Patients who have received prior radiation greater than 3000 cGy to marrow producing areas
* Patients may not be receiving any other investigational agents
* Patients with active central nervous system (CNS) leukemia; prior CNS leukemia is permitted provided the cerebrospinal fluid has cleared and there is no other evidence of active CNS leukemia
* Prior therapy for AML with decitabine, azacitidine, mitoxantrone, or etoposide
* Prior therapy with azacitidine or decitabine for pre-existing MDS
* History of allergic reactions attributed to decitabine, azacitidine, etoposide, mitoxantrone, or compounds of similar chemical or biologic composition
* Uncontrolled intercurrent illness including, but not limited to, active uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Human immunodeficiency virus (HIV)-positive patients with cluster of differentiation (CD) counts less than 500/mm\^3 and/or a history of HIV/acquired immune deficiency syndrome (AIDS)-related complications will be excluded from the study