FHD-286 With Low-Dose Weekly Decitabine/Venetoclax in Patients With Acute Myeloid Leukemia

Inclusion Criteria: 1. Newly diagnosed adverse risk AML, including Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML), per the 2022 ELN criteria, with a histopathologic diagnosis confirmed by hematopathology review OR AML that has progressed after 1 prior line of therapy with ≥5% blasts Inclusion Criteria 2 to 4 apply only for patients who are individuals with newly diagnosed AML: 2. Aged ≥75 years, or aged 18-74 years and either refuse to receive intensive induction chemotherapy or are not a candidate for intensive induction chemotherapy due to one or more of the following comorbidities: 1. Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 or 3 2. Cardiac history of congestive heart failure requiring treatment, ejection fraction ≤50%, or chronic stable angina pectoris 3. Diffusing capacity of the lung for carbon monoxide ≤65% or forced expiratory volume in 1 second ≤65% 4. Creatinine clearance ≥30 mL/min to \<45 mL/min 5. Moderate hepatic impairment with total bilirubin \>1.5 to ≤3.0×upper limit of normal (ULN) 6. Any other comorbidity that the investigator judges to be incompatible with intensive chemotherapy 3. Bone marrow blasts ≥10% 4. Have not received a hypomethylating agent (HMA) or VEN for their disease under study 5. No other disease-directed therapy, except hydroxyurea or cytarabine, and including experimental or investigational drug therapy, for at least 14 days before study entry 6. ECOG PS: 1. New diagnosed AML: * 75 years: ≤2 * 18 years to \<75 years: ≤3 2. AML that has progressed after 1 prior line of therapy (Any age): * 3 if R/R AML 7. Life expectancy ≥3 months 8. Adequate end organ function, defined as: 1. Adequate hepatic function, including: * Serum total bilirubin ≤3.0×ULN, unless considered due to advanced hematologic malignancy involvement or documented Gilbert syndrome with direct bilirubin ≤1.5×ULN * Aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase ≤3.0×ULN, unless considered due to advanced hematologic malignancy involvement 2. Prothrombin time ≤1.5×ULN or international normalized ratio ≤1.4 3. Activated partial thromboplastin time ≤1.5×ULN Note: Individuals who have been receiving a stable dose of anticoagulation therapy without bleeding episodes for ≥12 weeks may be considered for the study 4. No known portal vein thrombosis 5. Glomerular filtration rate (GFR) ≥30 mL/min (based on a contemporary, widely accepted, and clinically applicable equation that estimates GFR or a measure of GFR) 9. Adequate cardiovascular, respiratory, and immune system function as evidenced by the below criterion and in the opinion of the investigator: a. Left ventricular ejection fraction (LVEF) of ≥40% by echocardiogram (ECHO) 10. White blood cell count ≤20×10\^9/L (treatment with hydroxyurea or cytarabine ≤1 g/m2 to achieve this count is allowed before the start of study treatment and for up to 28 days after the start of study treatment) 11. Agree to abide by dietary and other considerations required during the study 12. Ability to understand and willingness to sign a written informed consent form and complete study-related procedures Exclusion Criteria: 1. Acute promyelocytic leukemia 2. Core binding factor AML who is a candidate for intensive chemotherapy 3. Eligible for and willing to receive standard HMA/VEN therapy (only applicable for individuals with newly diagnosed AML) 4. Evidence (or suspicion) of central nervous system (CNS) involvement 5. Prior treatment with azacitidine, DAC, VEN, or FHD-286. For individuals with AML that has progressed after 1 prior line of therapy, prior treatment with Azacitidine, Decitabine and VEN is allowed 6. Currently pregnant or breast-feeding. Women of child-bearing potential (WOCBP) must have negative serum pregnancy test within 72 hours before treatment start. (NOTE: WOCBP is any biological female, regardless of sexual or gender orientation, having undergone tubal ligation, or remaining celibate by choice, who has not undergone a documented hysterectomy or bilateral oophorectomy or has had a menses any time in the preceding 12 months \[therefore not naturally post-menopausal for \>12 months\].) 7. Planning to become pregnant within 1 year after start of study treatment 8. Uncontrolled intercurrent illness that could limit life expectancy or ability to complete study correlates. This includes, but is not limited to: 1. Ongoing or active infection. Because patients with myeloid malignancies are prone to infections, if individuals are actively being treated with appropriate antibiotics or antifungal agents with clinical evidence of infection control, they may be considered for the study. If treatment with a triazole antifungal agent is indicated, isavuconazonium sulfate should be used preferentially. If isavuconazonium sulfate cannot be used, a different triazole antifungal agent may be used. Refer to Exclusion Criterion 10a regarding strong Cytochrome P450, family 3, subfamily A (CYP3A) inhibitors 2. Uncontrolled concurrent malignancy 3. Heart rate-corrected QT interval (QTc) by Fridericia method (QTcF) \>470 milliseconds (ms) or other factors that increase the risk of QTc prolongation. Participants with QTcF \>470 ms and bundle branch block and/or pacemaker rhythm may be considered for the study 4. Congestive heart failure of New York Heart Association class III/IV. Individuals with compensated heart failure are permitted 5. Unstable angina pectoris 6. New or unstable cardiac arrhythmia. Patients with stable or controlled arrhythmias may be considered for the study. 7. Decompensated liver cirrhosis (Child-Pugh score ≥12 or a Model for End-Stage Liver Disease (MELD) score ≥21) 8. Psychiatric illness/social situation that would limit compliance with study requirements 9. Any other prior or ongoing condition that, in the opinion of the investigator, could adversely affect the