Pinometostat With Standard Chemotherapy in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia and MLL Gene Rearrangement

Inclusion Criteria:

* Patients must have histologically confirmed acute myeloid leukemia by World Health Organization (WHO) criteria. Patients with treatment-related acute leukemia are eligible if they do not exceed lifetime anthracycline doses
* Presence of a cytogenetic rearrangement of KMT2A (MLL) by interphase fluorescent in-situ hybridization (FISH)
* Patients must have previously untreated (with exception of hydroxyurea for count control or all-trans retinoic acid \[ATRA\] for acute promyelocytic leukemia \[APML\] that was initially suspected but later ruled out) AML by World Health Organization (WHO) criteria. Treatment with hydroxyurea for count-control of hyperproliferative disease is permitted before and during treatment with pinometostat and chemotherapy
* Age \>=14 years at time of screening, although individual sites may further restrict age eligibility in accordance with local Institutional Review Board (IRB) and hospital policy.
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
* Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN), unless elevated due to Gilbert syndrome, hemolysis, or leukemia (at the time of eligibility screening)
* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional ULN, unless due to leukemia in which case \< 5 x ULN (at the time of eligibility screening)
* Creatinine =\< 1.5 x institutional ULN OR glomerular filtration rate (GFR) \>= 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal (at the time of eligibility screening)
* Glomerular filtration rate (GFR) =\> 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal
* Prothrombin time (PT) and activated partial thromboplastin time (aPTT) =\< 1.5 x ULN (both) (at the time of eligibility screening)
* Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial (at the time of eligibility screening)
* If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated (at the time of eligibility screening)
* If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV viral load (at the time of eligibility screening)
* For pediatric patients, a serum creatinine based on age/gender as follows:

  * 10 to \< 13 years: male = 1.2; female = 1.2
  * 13 to \< 16 years: male = 1.3; female = 1.4
  * \>= 16 years: male = 1.7; female = 1.4
* Be medically fit, in the opinion of the investigator, for intensive (7+3) induction chemotherapy
* Left ventricular ejection fraction (LVEF) \>= 45% confirmed by echocardiogram or multi-gated acquisition scan (MUGA), AND no symptoms of congestive heart failure exceeding New York Heart Association (NYHA) class II
* Willingness to comply with all study procedures, including scheduled visits, investigational and standard of care drug administration plans, imaging studies, laboratory tests (including all biomarkers), procedures, and study- and disease-related restrictions
* The effects of pinometostat on the developing human fetus are unknown. For this reason and because other small molecule inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry 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 barrier contraception prior to the study, for the duration of study participation, and for 90 days after completion of pinometostat administration
* Ability to understand and the willingness to sign a written informed consent document or, for patients with impaired decision-making capacity, the consent of a close legal guardian who is readily available

Exclusion Criteria:

* Acute promyelocytic leukemia with t(15;17)(q22;q12) and/or PML-RARA molecular rearrangement, or other atypical RARA translocation partner
* Patients who have received prior chemotherapy for AML, excluding hydroxyurea for count control, or ATRA for APML that was initially suspected but later ruled out
* Patients who have received any prior investigational agent for acute myeloid leukemia
* Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
* Patients who have a cumulative lifetime exposure (prior to study entry) of greater than 300 mg/m\^2 doxorubicin equivalent anthracycline
* Patients who have received chest radiation (unless organ-sparing) and who have a cumulative lifetime exposure (prior to study entry) of greater than 240 mg/m\^2 doxorubicin equivalent anthracycline
* Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) with the exception of alopecia, or peripheral neuropathy (up to grade 2 is permitted)
* Patients who are receiving any other investigational agents
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to pinometostat or other agents used in study
* Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 are ineligible unless the offending medication can be safely stopped prior to enrollment. 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
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring antibiotics (with exception), symptomatic congestive heart failure, unstable angina pectoris, unstable cardiac arrhythmia not controllable with medications, electrocardiographic evidence of ischemia, or psychiatric illness/social situations that would limit compliance with study requirements. Patients receiving an anti-microbial agent may be eligible if the patient remains afebrile and hemodynamically stable for 72 hours
* Patients with an active bleeding diathesis
* Pregnant women are excluded from this study because pinometostat is a small molecule inhibitor 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
* Subjects with known symptomatic leukemia of the central nervous system including leptomeningeal leukemic involvement
* History of active other malignancy that limits survival to less than 1 year
* Ongoing viral or drug induced liver injury, including active chronic hepatitis C virus (HCV), chronic active hepatitis B, clinically known alcoholic liver disease, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, primary biliary cirrhosis, other cirrhosis of the liver, history of hepatic encephalopathy, or portal hypertension
* Any other prior condition that could, in the opinion of the investigator, compromise patient safety or evaluation of the primary outcome