Oral Azacitidine (CC-486) Epigenetic Priming and Maintenance for Adult Acute Myeloid Leukemia (AML) Patients

Inclusion Criteria: * Patients must have acute myeloid leukemia (AML) of Intermediate or High risk (IR or HR per National Comprehensive Cancer \[NCCN\] Criteria) in first CR/CRi achieved with 1 or 2 cycles of cytarabine based induction therapy. Zero to 1 cycle of cytarabine based consolidation will be allowed post CR1. OR Nucleophosmin 1(NPM 1) positive AML ((in the absence of FMS like tyrosine kinase 3 (FLT3) mutation)) at diagnosis with positive NPM1 PCR (measurable residual disease \[MRD\]) after at least 1 cycle of cytarabine-based consolidation chemotherapy OR Secondary AML(s-AML) based on prior MDS or CMML in first CR/CRi. OR Therapy-related AML (t-AML) with IR or HR criteria * Vyxeos induction (up to 2 cycles to reach CR1) and 0-1 cycle of vyxeos consolidation will be allowed. * Eligible to receive RIC or Non myeloablative (NMA) transplant preparative regimen with post-transplant cyclophosphamide (PTCY) based GVHD prophylaxis, at the discretion of study investigator. * Patients must have a calculated creatinine clearance (Cockcroft-Gault equation) \> 50 mL/min. * Patients must have a related or unrelated donor. Sibling donor must be a 6/6 match for human leukocyte antigen A (HLA-A) and HLA-B at intermediate or higher resolution, and DRB1 at high resolution using DNA-based typing; must be willing to donate peripheral blood stem cells; and meet institutional criteria for donation. Unrelated donor must be a 7/8 or 8/8 match at HLA-A, -B, -C, and -DRB1 at high resolution using DNA-based typing; must be willing to donate peripheral blood mononuclear cells (PBSCs); and be medically eligible to donate stem cells according to National Marrow Donor Program (NMDP) criteria. * Patients must be willing to have peripheral blood stem cells as the graft source. * Patients must have adequate hepatic function (i.e., serum bilirubin level ≤1.5 times the upper limit of normal \[ULN\], aspartate aminotransferase (AST), and alanine aminotransferase (ALT), defined as ≤2.5 × ULN). Higher levels of bilirubin are acceptable in the setting of Gilbert's disease with no other provable etiologies for altered liver function. * Patients must have a Karnofsky performance score (KPS) ≥70 and/or ECOG score of ≤2. * Patients must have recovered from the toxicities of the most recent induction/consolidation chemotherapy. Recovery is defined by the absence of persistent treatment-related AE of grade 2 or above. Persistent cytopenia meeting the criteria for a CRi and controlled infections on antimicrobials is acceptable. * Women of childbearing potential must be surgically sterile or agree to practice abstinence or utilize acceptable contraception (intrauterine, injectable, transdermal, or combination oral contraceptive) during the period while receiving study medication and for at least 6 months after the last dose of CC-486. Males who are sexually active with women of childbearing potential must be surgically sterile or using an acceptable method of contraception (defined as barrier methods in conjunction with spermicides) from time of screening through at least 3 months after the last dose of CC-486. * Patients must be able to understand the study procedures, agree to participate in the study program, and voluntarily provide written Informed Consent * Patients must have no active COVID-19 infection symptoms at the time of enrollment. Those who tested positive in the past or made recovery post infection must be symptom free for at least 2 weeks prior to enrollment. * Patients must be able to start transplant preparative regimens no later than 35 days from Day 1 of the most recent CC-486 cycle administration. Exclusion Criteria: * Patients may not have Acute Promyelocytic leukemia * Patients may not have favorable risk AML per National Comprehensive Cancer Network (NCCN) guidelines ((Core binding factor leukemias, CCAAT/enhancer-binding protein-alpha (CEBPA) double mutant, AML with concomitant mutations in Nucleophosmin 1 (NPM1) and FLT3)) * Patients must not have received more than two rounds of chemotherapy to achieve first CR or CRi * Patients may not have had exposure to hypomethylating agent (HMA) to treat the leukemia or prior hematologic malignancy ((i.e., myelodysplastic syndrome (MDS), Chronic Myelomonocytic Leukemia (CMML)) in the 6 months prior to study enrollment. * Patients may not be, per investigator evaluation, currently in need of other leukemia-directed therapy such as FLT3- or Isocitrate dehydrogenase (IDH)-directed therapy. * Patients may not have myeloproliferative neoplasm progressing to AML (except for CMML) * With related and unrelated donors, patients may not have high pre-transplant donor-specific HLA antibodies warranting need for desensitization or other maneuvers per discretion of the treating physician. * Patients may not have previously received radiation to maximum tolerable limits to any critical normal organ. * Patients with prior Central Nervous System (CNS) involvement or extramedullary disease will be excluded. * Patients may not have previously received allogeneic Hematopoietic Cell Transplantation (HCT). * Patients may not have clinically significant cardiac disease ((New York Heart Association (NYHA) Class III or IV)); clinically significant arrhythmia i.e., ventricular tachycardia, ventricular fibrillation, or "Torsade de Pointes." Significant active cardiac disease within the previous 6 months including NYHA class 4 Congestive Heart Failure (CHF), Unstable angina, and Myocardial Infarction * Patients may not have abnormal QTcF (\>480 msec) after electrolytes have been corrected (at least two different ECG readings and at least 15 minutes between readings). Subjects with paced rhythm or prolonged QTcF may be exempt from this exclusion if considered eligible for transplant per treating physician clinical judgement with optional cardiology consultation. * Patients may not have positive test results for human immunodeficiency virus (HIV) or hepatitis B (HBV) or C (HCV). Subjects with a past positive HBV test results due to previous exposure but who have cleared the virus or are vaccinated against hepatitis B, as evidenced by negative hepatitis B surface antigen (HbsAg), negative HBV viral load, and positive antibody to the HbsAg (anti-HBs) are not excluded. Subjects who have positive hepatitis test results with adequate organ function as defined in the protocol are not excluded. * Patients may not have uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment) * Patients may not have had an active malignancy within 1 year of entry. Active malignancy is defined as those malignancies requiring treatment with anti-cancer therapy or with a survival prognosis of less than 2 years at the time of inclusion. Exceptions to this exclusion include myelodysplastic syndrome/CMML, treated non-melanoma skin cancer, completely resected Stage 0 or 1 melanoma no less than 1 year from resection, cervical carcinoma in situ or cervical intraepithelial neoplasia, Breast cancers on long term hormonal therapy (1 year or more), and successfully treated organ-confined prostate cancer with no evidence of progressive disease based on prostate specific antigen (PSA) levels and not on active therapy. * Patients may not be currently receiving any other investigational agents for relapse reduction. * Patients seeking umbilical cord blood transplants, or bone marrow graft, or mismatched unrelated donor (MMUD) with \<9/10 HLA match are ineligible. * Ex-vivo T cell depletion or use of campath, antithymocyte globulin (ATG), or other anti-T cell antibodies as GVHD prophylaxis are not allowed. Patients are allowed to receive abatacept as approved by FDA. * Patients may not have known uncontrolled and active alcohol or substance abuse * Patients may not have any ongoing medical and non-medical condition that may render the patient ineligible for ASCT * Pregnant or breast-feeding females are not eligible. (Lactating females must agree not to breast feed while taking CC-486). * Patients may not have a history of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), celiac disease (i.e., sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption, distribution, metabolism, or excretion of the study drug and/or predispose the subject to an increased risk of gastrointestinal toxicity * Patients may not have abnormal coagulation parameters (PT \>15 seconds, PTT\>40 seconds, and/or INR \>1.5). Patients with chronic anticoagulation can be considered for inclusion after discussion with the PI * Patients may not have known or suspected hypersensitivity to azacitidine or mannitol * Patients may not have any significant medical, surgical, or mental health problem that would prevent appropriate patient participation in the study * Patients may not have any conditions including, but not limited to, laboratory abnormalities which put patients at unacceptable risk as per evaluation of treating physician * Patients may not have a history of idiopathic thrombocytopenic purpura, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS)