Tagraxofusp and Azacitidine for Maintenance Treatment in Patients With CD123 Positive AML and MDS Following Donor Hematopoietic Cell Transplant

Inclusion Criteria: * Documented informed consent of the participant and/or legally authorized representative * Agreement to allow the use of archival tissue from diagnostic tumor biopsies. * If unavailable, exceptions may be granted with study principal investigator (PI) approval * Age: 18-75 years old * Eastern Cooperative Oncology Group (ECOG) ≤ 2 * First or second allogeneic HCT-eligible patients with AML or MDS with high-risk cytogenetics per European LeukemiaNet (ELN) (AML) or Revised International Prognostic Scoring System (R-IPSS) (MDS); or by having active (morphological) or minimal residual disease (MRD)+ status at the time of HCT (by multicolor flowcytometry, cytogenetics or molecular testing) OR patients who underwent HCT for AML or MDS with high-risk cytogenetics per ELN (AML) or R-IPSS (MDS) * Positive for CD123 by flow cytometry of either peripheral blood or bone marrow aspirates at the time of diagnosis at any time-point prior to HCT. (Note: CD123 measurement will be conducted using the 10-color Beckman Coulter Navios XL flow cytometer. We will use CD123 PE \[Beckman Coulter #A32535\] to gate the abnormal population of interest. This population will be compared to the internal negative control population \[e.g., T-cells\]. If more than 20% of the abnormal population is positive relative to this control, it will be classified as positive.) * Any conditioning regiment or GVHD prophylaxis is allowed * Any donor (i.e., match related/unrelated, mismatched, haploidentical, etc.) or graft source (i.e., bone marrow, mobilized peripheral blood stem cells, etc.) is allowed * Prior treatment with CD123-therapy is allowed if no progression is documented on therapy * Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of protocol therapy * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only) * STUDY MAINTENANCE TREATMENT: Complete response (CR) or MRD-positive on day 30 bone marrow biopsy (BMB) for disease assessment * STUDY MAINTENANCE TREATMENT: Patients must be fully engrafted after HCT before starting the first cycle of maintenance. Full engraftment is defined as absolute neutrophil count (ANC) of 500 or above for 3 days and platelet count of more than 20,000 without transfusion for 7 consecutive days * STUDY MAINTENANCE TREATMENT: ECOG ≤ 2 * STUDY MAINTENANCE TREATMENT: No treatment with anti-CD123 therapy after allogeneic HCT * STUDY MAINTENANCE TREATMENT: No evidence of active or uncontrolled infection * STUDY MAINTENANCE TREATMENT: No active GVHD; prednisone dose of ≤ 10 mg/daily is allowed * STUDY MAINTENANCE TREATMENT: ANC ≥ 1.5 (within 7 days of day 1 of the cycle 1) * NOTE: Transfusion (red blood cells \[RBC\] or platelet) to achieve the above-mentioned counts is allowed * STUDY MAINTENANCE TREATMENT: Hemoglobin (HbG) ≥ 7 (within 7 days of day 1 of the cycle 1) * NOTE: Transfusion (RBC or platelet) to achieve the above-mentioned counts is allowed * STUDY MAINTENANCE TREATMENT: Platelet count ≥ 20K (within 7 days of day 1 of the cycle 1) * NOTE: Transfusion (RBC or platelet) to achieve the above-mentioned counts is allowed * STUDY MAINTENANCE TREATMENT: Total bilirubin ≤ 2 x upper limit of normal (ULN) (unless has Gilbert's disease) (within 7 days of day 1 of the cycle 1) * STUDY MAINTENANCE TREATMENT: Aspartate aminotransferase (AST) ≤ 2.5 x ULN (within 7 days of day 1 of the cycle 1) * STUDY MAINTENANCE TREATMENT: Alanine aminotransferase (ALT) ≤ 2.5 x ULN (within 7 days of day 1 of the cycle 1) * STUDY MAINTENANCE TREATMENT: Serum albumin \> 3.2 (within 7 days of day 1 of the cycle 1) (note that albumin infusions are not permitted in order to enable eligibility but can be given after treatment starts) * STUDY MAINTENANCE TREATMENT: Creatinine clearance of ≥ 30 mL/min per 24 hour urine test or the Cockcroft-Gault formula (within 7 days of day 1 of the cycle 1) * STUDY MAINTENANCE TREATMENT: If not receiving anticoagulants: International normalized ratio (INR) or prothrombin (PT) ≤ 1.5 x ULN (within 7 days of day 1 of the cycle 1) * If on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants * STUDY MAINTENANCE TREATMENT: Women of childbearing potential (WOCBP): negative urine or serum pregnancy test (within 7 days of day 1 of the cycle 1) * If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * STUDY MAINTENANCE TREATMENT: The Patient should agree to use acceptable contraceptive methods for the duration of the time in the study, and to continue to use contraceptive methods for 6 months following the end of study therapy * STUDY MAINTENANCE TREATMENT: The patient may not have persistent clinically significant toxicities grade ≥ 1 from previous therapies, including cytotoxic chemotherapy, targeted therapies, biological therapies, or immunotherapies, not readily controlled by supportive measures (excluding alopecia, nausea, and fatigue) * STUDY MAINTENANCE TREATMENT: The patient has not received treatment with another investigational agent within 14 days of study entry * STUDY MAINTENANCE TREATMENT: The patient does not have clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina, or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication) * STUDY MAINTENANCE TREATMENT: The patient does not have uncontrolled, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease, pulmonary hypertension) that in the opinion of the Investigator would put the patient at significant risk for pulmonary complications during the study * STUDY MAINTENANCE TREATMENT: The patient does not have known active or suspected central nervous system (CNS) disease. If suspected, CNS disease should be ruled out with relevant imaging and/or examination of cerebrospinal fluid * STUDY MAINTENANCE TREATMENT: The patient does not have uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, disseminated intravascular coagulation, or psychiatric illness/social situations that would limit compliance with study requirements * STUDY MAINTENANCE TREATMENT: The patient does not have any condition which, in the opinion of the Investigator, places the patient at an unacceptably high risk for toxicities Exclusion Criteria: * History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agents (tagraxofusp and azacitidine) * Females only: Pregnant or breastfeeding * Any other condition including, but not limited to, uncontrolled infection, disseminated intravascular coagulation, or psychiatric illness, that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures * The patient has an active malignancy and/or cancer history that may confound the assessment of the study endpoints. Patients with a past cancer history (within 2 years of entry) with substantial potential for recurrence and/or ongoing active malignancy must be discussed with the sponsor before study entry. Patients with the following neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ, cervical intraepithelial neoplasia, organ-confined prostate cancer with no evidence of progressive disease * The patient has clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina, or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication) * The patient has uncontrolled, clinically significant pulmonary disease (e.g. chronic obstructive pulmonary disease, pulmonary hypertension) that in the opinion of the Investigator would put the patient at significant risk for pulmonary complications during the study * The patient has known active or suspected central nervous system (CNS) disease. If suspected, CNS disease should be ruled out with relevant imaging and/or examination of cerebrospinal fluid * Active hepatitis B or C or HIV infection * The patient has any condition which, in the opinion of the investigator, places the patient at an unacceptably high risk for toxicities * Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)