Testing the Combination of Targeted Radiotherapy With Anti-Cancer Drugs, Venetoclax and ASTX-727, to Improve Outcomes for Adults With Newly Diagnosed Acute Myeloid Leukemia

Inclusion Criteria

• •Patients must have histologically or cytologically confirmed diagnosis of acute myeloid leukemia (AML) according to 2022 World Health Organization (WHO) criteria
• •Evidence of CD33 expression in more than 25% of bone marrow blasts by flow cytometry determined by local assessment
• •Patients must be considered ineligible for induction therapy defined by the following
• •* ≥ 75 years of age; OR
• •* \<75 years of age with at least one of the following co-morbidities or high-risk genetic features. Geriatric assessment and other tools to assess frailty have not been validated in patients with AML, and therefore will not be used to assess eligibility
• •* Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 or 3;
• •* Cardiac history of congestive heart failure (CHF) requiring treatment or Ejection Fraction ≤ 50% or chronic stable angina;
• •* Diffusion capacity of lung for carbon monoxide (DLCO) ≤ 65% or forced expiratory volume in 1 second (FEV1) ≤ 65%;
• •* Moderate hepatic impairment with total bilirubin \> 1.5 to ≤ 3.0 × upper limit of normal (ULN)
• •* Patents with high risk genetic features based on local testing
• •* inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)
• •* t(3q26.2;v)
• •* -5 or del(5q); -7; -17/abnormal(17p)
• •* Complex karyotype or monosomal karyotype as defined by ELN 2022
• •* Mutated TP53
• •Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of linituzumab-Ac-225 in combination with venetoclax and ASTX-727 in patients \< 18 years of age, children are excluded from this study
• •ECOG performance status 0-3 (Karnofsky ≥ 60%). For patients with ECOG performance status of 3, the decline in status should be due to AML per investigator's determination
• •Total bilirubin ≤ 3.0x institutional ULN unless considered due to Gilbert syndrome
• •Aspartate aminotransferase (AST)(serum gluatmic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 x institutional ULN
• •Creatinine clearance ≥ 60 ml/min
• •Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• •For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• •Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• •Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association (NYHA) Functional Classification. Patients with heart failure must have NYHA functional class congestive heart failure (CHF) II or below to be eligible
• •Hydroxyurea, cytarabine or leukopheresis are allowed for management of hyperleukocytosis, before initiation of study therapy. All-trans retinoic acid (ATRA) given emergently for suspected acute promyelocytic leukemia (APL) is also allowed. White blood cell (WBC) count must be \< 25 x 10\^9/L to start on study therapy per venetoclax label. Hydroxyurea and ATRA may be administered up to one day prior to start of study treatment
• •Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants