A treatment cycle is 28 days. Tagraxofusp will be administered at 9 mcg/kg IV over 15 minutes (-5 or +15 minutes) daily for 3 consecutive days (or 3 doses over a period not to exceed 10 days if postponement is required to allow for toxicity resolution), followed by azacitidine administered at 75 mg/m2 SQ or IV daily on Day 4 through Day 10. Venetoclax will begin on Day 4 and continue through Day 24 (21 consecutive days). A bone marrow biopsy (BM Bx) will be performed on Day 24 (+3 days) of Cycle 1.

Subjects who do not achieve a CRm will proceed with the next cycle of Induction Phase study treatment, irrespective of hematologic laboratory values. Cycle 2+ will consist of tagraxofusp 9 mcg/kg IV over 15 minutes daily for 3 consecutive days (Day 1-3 or 3 doses over a period not to exceed 10 days if postponement is required to allow for toxicity resolution), azacitidine 75 mg/m2 SQ or IV on Day 1 through Day 7 or Days 1-7 or 1-5, 8-9 and venetoclax 400 mg daily Day 1 through Day 21.

A bone marrow biopsy (BM Bx) will be performed on Day 21 (+3 days) of Cycle 2. If a CRm is obtained or maintained, the subject will move to or remain on the Continuation Phase. Subjects who do not achieve a marrow CR (CRm) after Cycle 2 will proceed with the next cycle of Induction Phase study treatment as described above, irrespective of hematologic laboratory values. If a CRm is obtained after Cycle 3 or 4, the subject will move to the Continuation Phase .

If a CRm is not obtained after Cycle 4, study treatment will be discontinued and the subject will move to follow up. If per the investigator, the subject is receiving clinical benefit, study treatment may continue until toxicity or completion of 12 total cycles. A BM Bx will be performed at least every 3 cycles for these subjects.

Inclusion Criteria:

Subject must meet all of the following applicable inclusion criteria to participate in this study:

• Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• Subjects must have newly diagnosed, untreated AML, as defined by ≥ 20% blasts in peripheral blood or bone marrow by manual aspirate differential, immunohistochemistry staining, or flow cytometry, as defined by standard WHO 2016 diagnostic criteria.
• Subjects must have documented CD123 positivity on leukemia cells by a centralized flow cytometry assay (Hematologics).
• Documented diagnosis of prior MDS, CMML, MDS/MPN overlap syndromes, or MPN's according to WHO criteria. Subjects must have received at least 2 cycles of hypomethylating agents (azacitidine or decitabine or oral decitabine/cedazuridine) for the management of MDS, CMML, MDS/MPN overlap syndromes, or MPN's. NOTE: Subjects who have enrolled on clinical trials with investigational agents in combination with HMA's will still be eligible. Investigational agents must have been discontinued >14 days prior to study treatment initiation. Subjects who have enrolled on clinical trials with investigational agents in combination with HMA's will still be eligible. Investigational agents must have been discontinued > 21 days prior to study treatment initiation.
• WBC < 30 x 109 /µL- subjects with WBC ≥ 30 x 109 /µL may still be eligible after receiving cytoreduction measures such as hydroxyurea, and/or leukapheresis, if WBC < 30 x 109 /µL prior to study treatment initiation. Cytoreduction with hydroxyurea, leukapheresis and/or cyclophosphamide is allowed prior to treatment. Hydroxyurea must be discontinued ≥ 12 hours prior to study treatment initiation. Cyclophosphamide must be discontinued ≥ 5 days prior to study treatment initiation.
• Age ≥ 18 years at the time of consent.
• ECOG Performance Status of 0-2.
• Demonstrate adequate organ function within 28 days prior to registration.
• Left ventricular ejection fraction (LVEF) ≥ 45%.
• Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to registration. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.
• Females of childbearing potential and male participants must be willing to use effective contraception as outlined in the protocol.
• Known HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial.
• Patients with known evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, the HCV viral load must be undetectable to be eligible for this trial.
• As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.

Exclusion Criteria:

Subjects meeting any of the criteria below may not participate in the study:

• Subjects who are suitable for and are willing to receive intensive chemotherapy.

• Diagnosis of acute promyelocytic leukemia.

• Known CNS involvement with AML.

• Previous receipt of tagraxofusp.

• Treatment with chemotherapy, wide-field radiation, or biologic therapy within 14 days of registration. NOTE: hydroxyurea, leukapheresis and/or cyclophosphamide are allowed prior to study entry per the protocol.

• Treatment with investigational drug within 21 days of registration.

• Previous allogeneic stem cell transplant within 60 days prior to registration.

• Receiving immunosuppression therapy, with the exception of prednisone ≤ 10mg/d, for the treatment or prophylaxis of GVHD. If the patient has been on immunosuppressant treatment or prophylaxis for GVHD, the treatment must have been discontinued at least 14 days prior to study treatment initiation and there must be no evidence of Grade ≥ 2 GVHD.

• History of other malignancies (excluding MDS, CMML, MDS/MPN, MPN's) within 2 years prior to reigstration, with the exception of: adequately treated in situ carcinoma of the cervix, breast, prostate; basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; previous malignancy confined and surgically resected (or treated with other modalities) with curative intent. Subjects receiving maintenance or adjuvant therapy for organ-confined malignancy such as breast or prostate cancer are eligible. Maintenance and/or adjuvant chemotherapy must be discontinued >72 hours prior to study treatment initiation. Those with substantial potential for recurrence and/or ongoing active malignancy must be discussed with the sponsor-investigator before registration.

• Clinically significant cardiac disease or abnormalities, defined as any of the following:

  • QTcF ≥ 480 ms (using Fridericia's correction; mean of triplicate ECGs at screening).

  • Myocardial infarction, unstable angina, or poorly controlled atrial fibrillation within 12 months prior to registration.

    • Inadequate rate control, defined as either: Resting heart rate > 80 bpm on ≥ 2 twelve-lead ECGs obtained ≥ 24 hours apart; OR Hemodynamic/Clinical Instability: Evidence of tachycardia-mediated cardiomyopathy, decompensated heart failure attributed to atrial fibrillation, or hemodynamic instability (symptomatic hypotension, end-organ hypoperfusion) requiring urgent rate or rhythm intervention.
    • Symptom Burden (modified European Heart Rhythm Association [mEHRA]): mEHRA Class 3 (severe symptoms, normal daily activity affected) or Class 4 (disabling symptoms, normal daily activity discontinued), or any cardiac-related syncope.
    • Treatment-Refractory Status: Persistence of the above criteria despite ≥2 rate-control agents at guideline-recommended doses (e.g., beta-blocker, non-dihydropyridine calcium-channel blocker, or digoxin), or documented intolerance preventing adequate dosing.

  • Stroke within 6 months of registration

  • Any history of:

    • Congenital long QT syndrome
    • Sustained ventricular tachycardia requiring intervention
    • Ventricular fibrillation
    • Torsades de pointes

  • Presence at screening of:

    • Second- or third-degree AV block without a permanent pacemaker
    • Bi-fascicular block (right bundle branch block [RBBB] with left anterior hemiblock)
    • Complete left bundle branch block
    • Uncontrolled CHF
    • Cardiac insufficiency Grade III or IV per New York Heart Association (NYHA) classification
    • Uncontrolled hypertension
    • Clinically significant abnormalities on a 12-lead electrocardiogram

• Uncontrolled significant pulmonary disease (e.g., COPD, pulmonary hypertension) that in the opinion of the investigator would put the patient at significant risk for pulmonary complications during the study.

• Active uncontrolled or severe systemic infection. Enrollment is possible after control of infection, at discretion of the treating physician.

• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).

• Other severe medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results, and in the judgement of the investigator would make the patient inappropriate for enrollment in this study. This may include psychological, familial, sociological, or geographical condition that would preclude study compliance and follow-up.