Ruxolitinib With Azacitidine Maintenance for the Treatment of Patients With Acute Myeloid Leukemia Undergoing Reduced Intensity Allogeneic Stem Cell Transplantation

Inclusion Criteria: * PART A: Willingness to provide written informed consent before any study-specific procedures or interventions are performed. For participants unable to independently provide consent, a legally authorized representative (LAR) must provide consent * PART A: Age ≥ 18 years, at the time of consent * PART A: All types and categories of AML, as defined by World Health Organization (WHO) 2022, excluding acute promyelocytic leukemia (APL) * PART A: In complete remission (CR) or complete remission with incomplete blood count recovery (CRi) after induction of remission for transition to transplant by European LeukemiaNet 2022 Risk Stratification (ELN 2022) * PART A: Planned alloHSCT with granulocyte colony-stimulating factor mobilized peripheral blood stem cells (PBSCs) and pre transplant conditioning disease status assessment of CR or CRi, as defined by ELN 2022 criteria * PART A: Patient is at high risk for relapse based on cytogenetics, MRD by next generation sequencing (NGS), and/or ELN 2022 definition of adverse risk disease per the opinion of the treating physician * PART A: Patients must have an unrelated PBSC donor meeting study donor selection requirements * PART A: Only RIC or NMA conditioning must be plan and patient is not a candidate for myeloablative conditioning (MAC). Post-transplant cyclophosphamide / tacrolimus / mycophenolate mofetil (PTCy/Tac/MMF) GVHD prophylaxis is planned with PTCy at 25 mg/kg/day on Day +3 and Day +4 post-HSCT * Permitted conditioning regimens (per institutional protocol) * Reduced-intensity conditioning: * Fludarabine/ melphalan * Dose reduction of melphalan to 100 rather than 140 are permitted at discretion of treating physician * Non-Myeloablative Conditioning: * Fludarabine/ busulfan/ total-body irradiation (TBI) * Fludarabine/ TBI * PART A: Backup graft donor (meeting study donor selection requirements) identified and ready for cases of graft failure * PART A: Karnofsky performance status (KPS) ≥ 50% * PART A: Direct bilirubin ≤ 3 × upper limit of normal (ULN) within 7 days prior to start of conditioning. Patients with leukemic involvement or Gilbert's Syndrome must have a direct bilirubin of ≤ 2 x ULN within 7 days of start of conditioning * PART A: Creatinine clearance \> 30 mL/min, calculated by the Cockcroft-Gault formula or measured by 24-hour urine collection * PART A: Willingness to receive infusion of SOC blood products * PART A: Evidence of chronic hepatitis B virus (HBV) infection (i.e., hepatitis B virus surface antigen \[HBsAg\]-positive with undetectable or low HBV deoxyribonucleic acid \[DNA\]) in the absence of HBV therapy, or serologic evidence of a resolved prior HBV infection (i.e., HBsAg-negative and hepatitis B virus core antibody \[anti-HBc-positive\]) is permitted but patient must agree to appropriate institutional guideline prophylaxis * PART A: History of hepatitis C virus (HCV) infection is permitted given prior curative treatment or undetectable HCV viral load by serology or polymerase chain reaction (PCR) testing * Patients who are HCV antibody (Ab) seropositive but HCV ribonucleic acid (RNA) negative due to prior treatment or natural resolution are eligible * PART A: For persons of child-bearing potential (PCBP), a negative pregnancy test within ≤ 7 days of start of conditioning * PART A: Ruxolitinib may have adverse effects on a fetus in utero. Furthermore, it is not known if either drug agent has transient adverse effects on the composition of sperm. PCBP and participants who produce viable sperm must be willing to comply with study requirements for contraception starting at start of conditioning through 120 days after discontinuation of study treatment. Should a participant or participant's sexual partner become pregnant or suspect a pregnancy while participating in this study, the individual should inform their treating physician immediately * PART A: It is unknown whether ruxolitinib, or its metabolites, are excreted in human milk. Since many drugs are excreted in human milk, and because of the potential for serious adverse reactions in the nursing infant, patients must agree to not breast-feed for the entire 2 years of the study to be eligible for enrollment * PART B: Absolute neutrophil count (ANC) ≥ 1,000/μL, measured twice approximately 48 hours apart, within 7 days prior to C2D1, in the absence of granulocyte colony-stimulating factor (G-CSF) treatment during this 7-day period * PART B: Platelet count ≥ 50,000/μL, measured twice approximately 48 hours apart, within 7 days prior to C2D1, in the absence of platelet transfusions or growth factor therapies that increase platelet counts during this 7 day period * PART B: Hemoglobin \> 8 g/L within the 7 days prior to C2D1, regardless of transfusion support * PART B: Day +30 (+/- 5 days) chimerism of ≥ 70% donor CD3+ cells and 100% donor CD33+ cells * PART B: For PCBP, a negative pregnancy test within 72 hours prior to C2D1 * DONOR: Donor is willing and able to donate * DONOR: Unrelated donor with a 7/8 or 8/8 match at human leukocyte antigen (HLA)-A, -B, -C and -DRB1 at high resolution using DNA-based typing. Unrelated donor must be willing to donate peripheral blood stem cells * DONOR: Age 18-35 at the time of workup request for PBSC donation * DONOR: Meet the donor registries' medical suitability requirements for PBSC donation * DONOR: Must undergo screening, testing, and determination of eligibility according to current Food and Drug Administration (FDA) requirements as defined in 21 Code of Federal Regulations (CFR) 1271 Subpart C and applicable guidance documents. Donors will be tested using kits that are FDA licensed, approved, or cleared for human cell and tissue/tissue-product donor screening. Sample testing will be performed at Clinical Laboratory Improvement Amendments (CLIA) certified laboratories * DONOR: Must agree to donate PBSC * DONOR: Must have the ability to give informed consent according to standard (non study) informed consent according to applicable donor regulatory requirements Exclusion Criteria: * PART A: Patients with active central nervous system (CNS) involvement with AML. Prior diagnosis of CNS involvement of AML will be allowed if curatively treated * PART A: Patients with malabsorption syndrome or other condition that precludes oral route of drug administration * PART A: Patients with prior intolerance to any of the interventional study drugs or component of the formulations * PART A: Patients with prior failure of treatment with ruxolitinib * PART A: Patients with history of any other malignancy within the 5 years prior to screening, with the exception of the following: * Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast; * Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; * Previous non-hematologic malignancy that has been successfully treated with curative intent (i.e., confined and surgically resected or treated with other modalities); * Myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (only allowed if it transformed to AML and AML should be the indication for marrow transplantation) * PART A: Patients with ejection fraction (EF) \< 40% and patients with New York Heart Association (NYHA) grade III or IV heart failure * PART A: Patients with history of pulmonary embolism (PE) or myocardial infarction (MI) within the 6 months prior to cycle 1 day 1 (C1D1). Treated deep vein thromboses (DVTs) are allowed * PART A: Patients with known history of stroke (including intracranial hemorrhage) within 60 days prior to start of conditioning * PART A: Patients administered therapy with an investigational agent, a known JAK1/2 inhibitor (with the exception of ruxolitinib), or a SOC anti-cancer therapy, including chemotherapy and radiotherapy, within 5 half lives prior to C1D1, or per institutional practice * PART A: Patients administered therapy with a biologic agent (e.g., a monoclonal antibody) for anti-neoplastic intent within 30 days prior to C1D1, or per the institutional practice * PART A: Patients with known clinically significant liver disease defined as ongoing drug-induced liver injury, alcoholic liver disease, non alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, portal hypertension, or history of autoimmune hepatitis * PART A: Patients with known human immunodeficiency virus (HIV) infection. HIV infection, even when controlled with combination antiretroviral therapy, is not allowed due to increased risk of lethal infections associated with marrow-suppressive therapy. Studies in participants under combination antiretroviral therapy may be undertaken at a later date * PART A: Patients with history of active tuberculosis (TB) * PART A: Patients with known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection * Subjects with confirmed SARS-CoV-2 infection must be screen failed and may only rescreen after they meet institutional SARS-CoV-2 infection viral clearance criteria * PART A: Patients with evidence of clinically significant systemic infection * PART A: Patients with clinically significant coagulation abnormality defined by international normalized ratio (INR) \> 1.5 * PART A: Patients with recent significant medical interventions, such as major surgery within 28 days of C1D1. Standard of care procedures for patients with hematologic malignancies, such as biopsies and lumbar punctures, are allowed * PART A: Patients with psychiatric illness/social situation that would limit compliance with the study * PART A: Patients with history of clinically significant medical condition(s) (including comorbidities) and no other reason, per the determination of the investigator, which could interfere with the patient's adherence to the study protocol or would make the patient an unsuitable candidate to receive study drugs * PART B: Patients with evidence of primary graft failure (PGF) or secondary graft failure (SGF) while enrolled on Part A or SGF during screening for Part B * PART B: Patients who experienced a dose limiting toxicity (DLT) in Part A * PART B: Patients administered an investigational agent, a known JAK1/2 inhibitor (with the exception of ruxolitinib), or SOC chemotherapy or radiotherapy within 5 half-lives of C2D1, or per institutional practice * PART B: Patients administered a biologic of anti-neoplastic intent within 30 days of C2D1, or per institutional practice * PART B: Patients with a plan for other maintenance therapy outside of this trial, including a FLT3-ITD inhibitor * PART B: Patients with evidence of clinically significant, uncontrolled systemic infection * PART B: Patients with Mount Sinai Acute Graft Versus Host Disease International Consortium (MAGIC) grade II or greater active aGVHD * PART B: Patients with ongoing or planned therapy with prednisone equivalent of ≥ 10 mg daily for GVHD treatment or other illness * PART B: Patients with newly diagnosed psychiatric illness or new social situation that would limit compliance with the study * PART B: Patients with new or recent history of clinically significant medical condition(s) (including comorbidities) or any other reason, per the determination of the investigator, which could interfere with the patient's adherence to the study protocol or would make the patient an unsuitable candidate to receive study drugs * DONOR: Recipient has evidence of donor-specific HLA antibody (DSA). If recipient is positive for HLA antibodies against a mismatched HLA in the selected donor, defined as the presence of DSA to any mismatched HLA allele/antigen at any of the following loci (HLA-A, -B, -C, -DRB1, DRB3, DRB4, DRB5, -DQA1, - DQB1, -DPA1, -DPB1) with mean fluorescence intensity (MFI) \> 3000 by microarray-based single antigen bead testing, the donor will be excluded. In patients receiving red blood cell or platelet transfusions, DSA evaluation should be performed prior to donor mobilization and initiation of recipient preparative regimen whenever possible * DONOR: Donors with positive coronavirus disease 2019 (COVID-19) testing results (confirmed by PCR) within 72 hours (hr) of stem cell collection