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 authorizedrepresentative

• 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-riskcytogenetics per European LeukemiaNet (ELN) (AML) or Revised InternationalPrognostic Scoring System (R-IPSS) (MDS); or by having active (morphological) orminimal residual disease (MRD)+ status at the time of HCT (by multicolorflowcytometry, cytogenetics or molecular testing) OR patients who underwent HCT forAML 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 marrowaspirates at the time of diagnosis at any time-point prior to HCT. (Note: CD123measurement will be conducted using the 10-color Beckman Coulter Navios XL flowcytometer. We will use CD123 PE [Beckman Coulter #A32535] to gate the abnormalpopulation of interest. This population will be compared to the internal negativecontrol population [e.g., T-cells]. If more than 20% of the abnormal population ispositive 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 graftsource (i.e., bone marrow, mobilized peripheral blood stem cells, etc.) is allowed

• Prior treatment with CD123-therapy is allowed if no progression is documented ontherapy

• Agreement by females and males of childbearing potential to use an effective methodof birth control or abstain from heterosexual activity for the course of the studythrough at least 6 months after the last dose of protocol therapy

• Childbearing potential defined as not being surgically sterilized (men andwomen) or have not been free from menses for > 1 year (women only)

• STUDY MAINTENANCE TREATMENT: Complete response (CR) or MRD-positive on day 30 bonemarrow biopsy (BMB) for disease assessment

• STUDY MAINTENANCE TREATMENT: Patients must be fully engrafted after HCT beforestarting the first cycle of maintenance. Full engraftment is defined as absoluteneutrophil 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 allogeneicHCT

• STUDY MAINTENANCE TREATMENT: No evidence of active or uncontrolled infection

• STUDY MAINTENANCE TREATMENT: No active GVHD; prednisone dose of ≤ 10 mg/daily isallowed

• 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 theabove-mentioned counts is allowed

• STUDY MAINTENANCE TREATMENT: Hemoglobin (HbG) ≥ 7 (within 7 days of day 1 of thecycle 1)

• NOTE: Transfusion (RBC or platelet) to achieve the above-mentioned counts isallowed

• STUDY MAINTENANCE TREATMENT: Platelet count ≥ 20K (within 7 days of day 1 of thecycle 1)

• NOTE: Transfusion (RBC or platelet) to achieve the above-mentioned counts isallowed

• 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 7days of day 1 of the cycle 1)

• STUDY MAINTENANCE TREATMENT: Alanine aminotransferase (ALT) ≤ 2.5 x ULN (within 7days of day 1 of the cycle 1)

• STUDY MAINTENANCE TREATMENT: Serum albumin > 3.2 (within 7 days of day 1 of thecycle 1) (note that albumin infusions are not permitted in order to enableeligibility but can be given after treatment starts)

• STUDY MAINTENANCE TREATMENT: Creatinine clearance of ≥ 30 mL/min per 24 hour urinetest or the Cockcroft-Gault formula (within 7 days of day 1 of the cycle 1)

• STUDY MAINTENANCE TREATMENT: If not receiving anticoagulants: Internationalnormalized ratio (INR) or prothrombin (PT) ≤ 1.5 x ULN (within 7 days of day 1 ofthe cycle 1)

• If on anticoagulant therapy: PT must be within therapeutic range of intendeduse of anticoagulants

• STUDY MAINTENANCE TREATMENT: Women of childbearing potential (WOCBP): negative urineor 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 serumpregnancy test will be required

• STUDY MAINTENANCE TREATMENT: The Patient should agree to use acceptablecontraceptive methods for the duration of the time in the study, and to continue touse contraceptive methods for 6 months following the end of study therapy

• STUDY MAINTENANCE TREATMENT: The patient may not have persistent clinicallysignificant toxicities grade ≥ 1 from previous therapies, including cytotoxicchemotherapy, targeted therapies, biological therapies, or immunotherapies, notreadily controlled by supportive measures (excluding alopecia, nausea, and fatigue)

• STUDY MAINTENANCE TREATMENT: The patient has not received treatment with anotherinvestigational agent within 14 days of study entry

• STUDY MAINTENANCE TREATMENT: The patient does not have clinically significantcardiovascular disease (e.g., uncontrolled or any New York Heart Association class 3or 4 congestive heart failure, uncontrolled angina, history of myocardialinfarction, unstable angina, or stroke within 6 months prior to study entry,uncontrolled hypertension or clinically significant arrhythmias not controlled bymedication)

• STUDY MAINTENANCE TREATMENT: The patient does not have uncontrolled, clinicallysignificant pulmonary disease (e.g., chronic obstructive pulmonary disease,pulmonary hypertension) that in the opinion of the Investigator would put thepatient at significant risk for pulmonary complications during the study

• STUDY MAINTENANCE TREATMENT: The patient does not have known active or suspectedcentral nervous system (CNS) disease. If suspected, CNS disease should be ruled outwith relevant imaging and/or examination of cerebrospinal fluid

• STUDY MAINTENANCE TREATMENT: The patient does not have uncontrolled intercurrentillness including, but not limited to, uncontrolled infection, disseminatedintravascular coagulation, or psychiatric illness/social situations that would limitcompliance with study requirements

• STUDY MAINTENANCE TREATMENT: The patient does not have any condition which, in theopinion of the Investigator, places the patient at an unacceptably high risk fortoxicities

Exclusion Criteria:

• History of allergic reactions attributed to compounds of similar chemical orbiologic 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 theInvestigator's judgment, contraindicate the patient's participation in the clinicalstudy due to safety concerns with clinical study procedures

• The patient has an active malignancy and/or cancer history that may confound theassessment of the study endpoints. Patients with a past cancer history (within 2years of entry) with substantial potential for recurrence and/or ongoing activemalignancy must be discussed with the sponsor before study entry. Patients with thefollowing neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma insitu, cervical intraepithelial neoplasia, organ-confined prostate cancer with noevidence of progressive disease

• The patient has clinically significant cardiovascular disease (e.g., uncontrolled orany New York Heart Association class 3 or 4 congestive heart failure, uncontrolledangina, history of myocardial infarction, unstable angina, or stroke within 6 monthsprior to study entry, uncontrolled hypertension or clinically significantarrhythmias not controlled by medication)

• The patient has uncontrolled, clinically significant pulmonary disease (e.g. chronicobstructive pulmonary disease, pulmonary hypertension) that in the opinion of theInvestigator would put the patient at significant risk for pulmonary complicationsduring the study

• The patient has known active or suspected central nervous system (CNS) disease. Ifsuspected, CNS disease should be ruled out with relevant imaging and/or examinationof cerebrospinal fluid

• Active hepatitis B or C or HIV infection

• The patient has any condition which, in the opinion of the investigator, places thepatient at an unacceptably high risk for toxicities

• Prospective participants who, in the opinion of the investigator, may not be able tocomply with all study procedures (including compliance issues related tofeasibility/logistics)