Inclusion Criteria:
* Patients must have established and confirmed diagnosis of intermediate or adverse-risk AML according to the European LeukemiaNet 2022 classification criteria
* Previously untreated AML excluding hydroxyurea and all-trans retinoic acid (ATRA). ATRA would only be used for suspected AML
* Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of iadademstat in combination with venetoclax and azacitidine in patients \< 18 years of age, children are excluded from this study
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
* Patient is able to swallow oral medications
* Patient must have a body weight of at least 50 kg due to the use of flat doses
* Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) OR direct bilirubin ≤ ULN for patients with total bilirubin levels \> 1.5 x ULN or ≤ 3 x ULN if patient has Gilbert's disease
* Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/ alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 × institutional ULN or \< 5 ULN if due to AML
* Chronic kidney disease (CKD)-epidemiology collaboration (EPI) glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 m\^2
* Peripheral white blood cell (WBC) count \< 25 x 10\^9/L on day 1 prior to treatment initiation. Hydroxyurea for up to 2 weeks is allowed for cytoreduction until 24 hours prior to study treatment
* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
* Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
* Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better. Patients with a troponin leak (i.e. elevated troponin levels at presentation without evidence of an active myocardial infarction (MI) are eligible
* The effects of iadademstat on the developing human fetus are unknown. For this reason and because LSD1 inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, females 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 180 days after the last dose of study medication. 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. Males with female partners of child-bearing potential treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 180 days after the last dose of study medication. Women of child-bearing potential agree not to donate or freeze egg(s) during the course of this study or within 180 days after receiving their last dose of study drug. Male patients agree not to donate sperm during the course of this study or within 180 days after receiving their last dose of study drug
* Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants
Exclusion Criteria:
* Patients are willing and able to receive intensive induction chemotherapy
* Patients have isolated myeloid sarcoma or acute promyelocytic leukemia (APL) French-American-British (FAB) M3
* Patients who have not recovered from adverse events of grade 3 or more due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) with the exception of alopecia
* Patients who are receiving any other investigational agents
* Patients who have active central nervous system (CNS) involvement by AML
* Patients who have disseminated intravascular coagulopathy with active systemic bleeding or venous or atrial signs of thrombosis
* Patients who require treatment while on study with concomitant drugs that target the 5HT2B receptor or the sigma nonspecific receptor (e.g., escitalopram, fluoxetine, sertraline) except for drugs that are considered absolutely essential for the care of the patient and with appropriate treatment monitoring
* Patients with manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of oral drugs. In addition, patients with enteric stomata are also excluded
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to iadademstat, azacitidine, mannitol, or venetoclax
* Iadademstat Concomitant Medication Considerations: Patients are not allowed to receive prophylactic hematopoietic colony stimulating factors, any complementary or alternative medicine (any of various systems of healing or treating disease \[as non-prescription drugs, herbal medicine and homeopathy\])
* Patients should not use strong CYP3A inhibitors with the exception of antifungals for which standard of care (SOC) dose modifications of venetoclax exist
* Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous. This includes, but is not limited to:
* Myocardial infarction with evidence of residual abnormalities within 3 months prior to enrollment (Troponin leak alone not included if no residual dysfunction);
* New York Heart Association (NYHA) Class III or IV heart failure;
* Severe uncontrolled ventricular arrhythmias;
* Electrocardiographic evidence of acute ischemia or active life-threatening conduction system abnormalities:
* Since patients with AML frequently require supportive care with agents that affect the corrected QT interval (QTc), if clinically indicated, obtain an electrocardiogram (ECG) prior to enrollment
* As infection is a common feature of AML, patients with active infection are permitted to enroll provided that the infection is under control (i.e., no signs of severe systemic inflammatory response that makes patient clinically unstable in the opinion of the investigator, and the patient is hemodynamically stable). Patients with uncontrolled infection shall not be enrolled until the infection is treated and brought under control
* Pregnant women are excluded from this study because iadademstat is LSD1 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 iadademstat, breastfeeding should be discontinued if the mother is treated with iadademstat. These potential risks may also apply to other agents used in this study
