Azacitidine, Cytarabine, and Mitoxantrone Hydrochloride in Treating Patients With High-Risk Acute Myeloid Leukemia

Inclusion Criteria:

* Patients must have one of the following disease characteristics:

  * Therapy-related myeloid neoplasm (t-MN) age \>= 18 years

    * Patients must have received cytotoxic chemotherapy, radiation, or a drug known to affect the properties of deoxyribonucleic acid (DNA) or cell growth, prior to current diagnosis of therapy-related myeloid neoplasm (t-MN); this broad definition is meant to include any prior therapy with chemicals that affect DNA replication, DNA integrity, or DNA structure, or chemicals that alter cell growth; this includes traditional cytotoxic chemotherapy, newer immunologic agents that have been shown to have cytotoxic activities in addition to immunosuppressive functions, and other chemicals; note that patients with primary AML could be diagnosed with a t- MN if morphology/cytogenetic analysis clearly indicated that the second process is not a relapse of the original disease
  * AML arising from an antecedent hematological disorder age \>= 18 years
  * De novo AML in patients age \>= 60 years
  * Relapsed and/or refractory AML \>= 18 years
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment
* Male and female patients must use an effective contraceptive method during the study and for at least 6 months after study treatment
* Patients must be at least 2 weeks from major surgery, radiation therapy, participation in other investigational trials and must have recovered from clinically significant toxicities of these prior treatments
* Ability to understand and willingness to sign the informed consent form

Exclusion Criteria:

* Concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in this protocol
* Diagnosis of acute promyelocytic leukemia (APL)
* Use of investigational agents/any anticancer therapy within 2 weeks before study entry with the exception of hydroxyurea (note: for patients with hyperleukocytosis \[white blood cell (WBC) \> 20,000/uL\], hydroxyurea \[and leukapheresis, if clinically indicated\] will be initiated and these patients will receive 5-azacytidine when the WBC count has decreased to =\< 20,000/uL; hydroxyurea can be overlapped with 5-azacytidine in selected cases, after consultation with the study chair; hydroxyurea must be discontinued before the initiation of the HiDAC/mitoxantrone chemotherapy)
* Prior treatment with 5-azacytidine followed immediately by HiDAC and mitoxantrone as proposed in this study (note: prior therapy with 5-azacytidine or decitabine or HiDAC or mitoxantrone would be allowed-in patients with relapsed/refractory disease- unless the prior therapy was identical to the schema/schedule proposed in this study)
* Active second cancer other than specified; active cancer refers to cancer that requires systemic chemotherapy or biological therapy within 6 months of the study entry; patients who have received only hormonal therapy in the neoadjuvant or adjuvant setting in the past 6 months may participate in this study
* Have any other severe concurrent disease, or have a history of serious organ dysfunction (e.g. uncontrolled or severe cardiovascular disease, diabetes, pulmonary disease, infection, psychiatric illness) that may in the judgment of the treating physician/ principal investigator place the patient at undue risk to undergo treatment
* Pregnant or lactating patients
* Any significant concurrent illness that would, in the judgment of the treating physician/principal investigator, compromise patient safety or compliance, or study participation