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 history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
* 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

Exclusion Criteria:

* Acute promyelocytic leukemia (APL)
* Patients with favorable risk AML per the European LeukemiaNet (ELN) 2022 criteria
* Active central nervous system (CNS) involvement of AML requiring therapy
* Prior therapy with radiopharmaceuticals or external beam radiation therapy (EBRT)
* Previous therapy with venetoclax or other BCL-2 directed therapy
* Patients with Fridericia-corrected QT interval (QTcF) \> 450ms at screening. QTcF will be calculated as the mean of the QTcF value from three separate electrocardiography (EKGs)
* Receiving any other investigational agents
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to venetoclax or ASTX-727
* Uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous per investigators opinion
* Pregnant women are excluded from this study because lintuzumab-Ac225 is a radiotherapy agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with lintuzumab-Ac225, breastfeeding should be discontinued if the mother is treated with lintuzumab-Ac225. These potential risks may also apply to other agents used in this study

  * Women of child-bearing potential must agree to use adequate contraception (hormonal birth control or abstinence) prior to study entry and for the duration of study participation, and for 6 months following completion of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception (latex or synthetic condom or abstinence) prior to the study, for the duration of study participation, and 3 months after completion of the study
* Patients unable to swallow tablets/capsules and patients with malabsorption syndrome or other conditions that may interfere with the oral administration of medications are not eligible
* Patients who have had chemotherapy, targeted small molecule therapy (aside from imatinib, dasatinib, or nilotinib, hydroxyurea, cytarabine or ATRA),within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study are not eligible
* Prior allogenic stem cell transplant
* Patients who received a live vaccine within 30 days of planned start of study therapy

  * NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist, registered trademark) are live attenuated vaccines, and are not allowed
* Patients who have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit within 3 days prior to the initiation of study treatment and are unwilling to discontinue consumption of these throughout the receipt of study drugs
* Patients who are unable to take spironolactone or eplerenone due to intolerance, allergy, drug-drug interactions, or for any other reason