Metabolically Optimized, Non-cytotoxic Low Dose Weekly Decitabine/Venetoclax in MDS and AML

Inclusion Criteria: * Patient must have a diagnosis of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN) with a histopathologic diagnosis confirmed by hematopathology review * Indication for therapy with potential sensitivity to hypomethylating agents (HMA) therapy, defined as prior published evidence of response to HMA * Patients must be 18 years of age or older * Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≥ 3 * Patients must have adequate end organ function defined as. * Aspartate aminotransferase (AST) and Alanine transaminase (ALT) \< 4× the upper limit of normal (ULN) * Bilirubin ≤ 2× the ULN (upper limit of normal). If elevated bilirubin is due to impaired conjugation (e.g., Gilbert's disease or concomitant medication) or disease related hemolysis, then direct bilirubin ≤ 1.5× the ULN * As decitabine and venetoclax have little renal metabolism, and have proven safety even in dialysis patients, renal function with a creatinine clearance ≥30 mL/min or on dialysis is allowed * Subjects must have the ability to understand and the willingness to sign a written informed consent document and complete study related procedures. Exclusion Criteria: * Acute promyelocytic leukemia (APL) * Core binding factor AML who are candidates for chemotherapy * Prior Treatment with azacitidine, decitabine or venetoclax * No other disease directed therapy, save for hydroxyurea, including experimental or investigational drug therapy for 14 days prior to study entry * Currently pregnant or breast-feeding. Females of childbearing potential (FOCBP) must have negative serum pregnancy test within 72 hours from treatment start. (NOTE: FOCBP is any biologic 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) * 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. As patients with myeloid malignancies are prone to infections, if patients are actively being treated with appropriate antibiotics or antifungal therapy with clinical evidence of infection control, then they will be considered eligible for study. 2. Uncontrolled concurrent malignancy 3. Congestive heart failure of xNew York Heart Association (NYHA) class III/IV. Patients with compensated heart failure are permitted 4. Unstable angina pectoris 5. New or unstable cardiac arrhythmia. Stable or controlled arrhythmias are permitted 6. Decompensated liver cirrhosis (Child-Pugh score ≥12 or a Model for Enst-Stage Liver Disease (MELD) score ≥21 7. Psychiatric illness/social situations that would limit compliance with study requirements 8. Any other prior or ongoing condition, in the opinion of the investigator, that could adversely affect the safety of the patient or impair the assessment of study results * Women of Child-Bearing Potential (WOCBP) and males that are unwilling to agree to use dual contraceptive measures (i.e., hormonal or barrier method of birth control; abstinence, condom) prior to study entry and for the duration of study participation. Should a female subject become pregnant or suspect she is pregnant while participating in this study, she should inform the treating physician immediately * Sexually active male who is unwilling to use a condom when engaging in any sexual contact with a female with child-bearing potential, beginning at the screening visit and continuing until 4 weeks after taking the last dose of Decitabine/venetoclax * Patients with uncontrolled active HIV infection, as this will further increase the risk for opportunistic infections. However, patients with HIV with undetectable viral load by polymerase chain reaction (PCR), without opportunistic infection, and on a stable regimen of antiretroviral therapy would be eligible * Known allergy or hypersensitivity to any component of decitabine or venetoclax formulations