Pinometostat and Azacitidine in Treating Patients With Relapsed, Refractory, or Newly Diagnosed Acute Myeloid Leukemia With 11q23 Rearrangement

Inclusion Criteria:

* Patients must have histologically or cytologically confirmed acute myeloid leukemia
* Patients must have an 11q23 translocation or partial tandem duplication, confirmed by cytogenetics, fluorescence in situ hybridization (FISH), or myeloid panel. Both de novo and therapy-related acute myeloid leukemia (AML) with an 11q23 rearrangement or partial tandem duplication (PTD) are considered eligible
* Patients may not have any other targetable mutations (such as FLT3, IDH1, and IDH2) identified on myeloid mutational panel testing or must refuse treatment with a targeted agent if such a mutation is detected
* Eastern Cooperative Oncology Group (ECOG) performance status \< 3 (Karnofsky \> 60%)
* Prothrombin time (PT) and activated partial thromboplastin time (aPTT) =\< 1.5 x upper limit of normal (ULN)
* Total bilirubin \< 2 times the upper limit of institutional normal (ULN) unless due to Gilbert's disease
* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) =\< 2.5 x institutional upper limit of normal
* Creatinine =\< 2 times the upper limit of institutional normal (ULN) OR creatinine clearance glomerular filtration rate (GFR) \>= 30 mL/min/1.73 m\^2
* Patients treated in the up-front setting must decline standard-of-care therapy
* Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity with a close legal guardian/caregiver may be considered
* Patients must have measurable disease, defined as abnormal blasts detectable in the peripheral blood or bone marrow or the presence of extramedullary disease, including leukemia cutis. Patients with extramedullary disease but no bone marrow disease are still considered eligible
* Patients may have had previous treatment with standard-of-care or experimental agents. Patients who have previously undergone bone marrow transplantation may also be included
* Patients who are human immunodeficiency virus (HIV) positive (+), hepatitis B virus (HBV)+, and/or hepatitis C virus (HCV)+ may be eligible as follows:

  * Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial. The antiretroviral therapy should not strongly induce or inhibit CYP3A4
  * If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated
  * If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV viral load
* The effects of pinometostat on the developing human fetus are unknown. For this reason and because histone methyltransferase inhibitors as well as hypomethylating agents are known to be teratogenic, women of child-bearing potential and 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 and for 4 weeks after the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 90 days after completion of pinometostat and azacitidine administration

Exclusion Criteria:

* Patients who are receiving any other investigational agents
* Patients with active central nervous system (CNS) disease are excluded from this clinical trial because they may develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with a prior history of CNS disease will not be excluded
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to pinometostat or azacitidine
* Patients receiving any medications or substances that are inhibitors or inducers of the CYP3A4 or CYP450 system should have their medications reviewed and adjusted for interactions as appropriate for local institutional practice. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
* Patients receiving any medications or substances that are inhibitors or inducers of MATE1 and MATE2-K transporters should have their medications reviewed and adjusted for interactions as appropriate for local institutional practice. Pinometostat has been demonstrated to be an inhibitor of MATE1 and MATE2-K transporters in vitro, although the clinical significance of this is unclear. Drug interactions may occur between pinometostat and other therapies that are MATE substrates, including metformin. Consultation with a frequently updated medical reference and/or pharmacist should be sought to guide necessary changes in the patient's other medications
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled or clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Patients with these conditions that are medically well controlled may be considered for enrollment
* Pregnant women are excluded from this study because pinometostat is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pinometostat, breastfeeding should be discontinued if the mother is treated with pinometostat. These potential risks may also apply to other agents used in this study
* HIV-positive patients on combination antiretroviral therapy should have their regimen reviewed for potential pharmacokinetic interactions with pinometostat and azacitidine. In the event of a potential interaction, alternative therapies may be considered in consultation with the patient's primary HIV physician
* Absence of an 11q23 rearrangement or absence of an 11q23 partial tandem duplication
* Patients with an active bleeding diathesis
* Patients at increased risk of QT prolongation (e.g. from known long-QT syndrome) or who have a corrected QT interval that is persistently longer than 450 ms despite adjustments to other medications
* Patients who are eligible for or willing to receive intensive induction therapy for de novo AML