To determine the efficacy of the combination of tagraxofusp, cladribine, and cytarabine.

Inclusion Criteria

• Documented diagnosis of relapsed or refractory acute myeloid leukemia (AML) according to World Health Organization (WHO) 2022 criteria
• Expression of CD123 by either flow cytometry or immunohistochemical staining with no minimum threshold for positivity
• Must have received initial therapy with venetoclax in combination with a hypomethylating agent (either azacitidine or decitabine) with no subsequent therapy unless mutations in the IDH or FLT3 genes.

If mutations in the IDH or FLT3 genes, treatment with IDH or FLT3 inhibitors after initial failure of venetoclax plus HMA is allowed, but not required.

• Age ≥ 18 years of age
• ECOG ≤ 2
• Albumin ≥ 3.2 g/dL at time of screening (note that albumin supplementation is not permitted to enable eligibility)
• Left ventricular ejection fraction ≥ 50%
• No clinically significant abnormalities on 12-lead electrocardiogram (ECG) including: complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval >250ms, or QTcF (Friderica's method) >450ms in 3 successive measurements
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Females of reproductive potential need to either commit to true abstinence from heterosexual contact or agree to use, and be able to comply with highly effective contraception without interruption prior to starting treatment, during the study therapy, and for 30 days after last dose of study therapy
• For males of reproductive potential: agreement to use of condoms
• Adequate hepatic/renal function defined as:

Hepatic function: total bilirubin ≤ 1.5 x ULN (unless attributable to Gilbert's disease or leukemic involvement) AND AST or ALT ≤ 3 x ULN

Renal function: creatinine clearance > 30 mL/minute, calculated by Cockcroft Gault formula

• Women of childbearing potential must have a negative urine or serum pregnancy test
• Ability to understand and the willingness to provide written informed consent.

Exclusion Criteria:

• Prior therapy apart from Venetoclax in combination with a hypomethylating agent, or Venetoclax in combination with a hypomethylating agent followed by monotherapy with IDH or FLT3 inhibitors
• Patients who received systemic anti-cancer therapy <14 days prior to their first day of study drug administration.
• Patients who received systemic anti-cancer therapy <14 days prior to their first day of study drug administration. Concurrent hydroxyurea will be allowed. Hydroxyurea use will be allowed only during the first cycle if needed for disease control.
• Significant cardiac disease (any NYHA Class 3 or 4 CHF, uncontrolled angina, history of MI, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension, or clinically significant arrhythmias not controlled by medication)
• Any uncontrolled bacterial, fungal, viral or other infection.
• Known HIV+ or active hepatitis B or C infection, defined as positive viral load for HBV or HCV or a positive surface antigen (HBsAg) test for hepatitis B.
• The patient has persistent clinically significant toxicities Grade >/= 2 from previous therapies not readily controlled by supportive measures (excluding alopecia, nausea, and fatigue).
• 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 study entry) with substantial potential for recurrence and/or ongoing active malignancy must be discussed with study team 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 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 CNS disease. If suspected, CNS disease should be ruled out with relevant imaging and/or examination of cerebrospinal fluid.
• The patient is receiving immunosuppressive therapy - with the exception of low-dose prednisone (\