Randomization for the Identification of Best Treatment Intensity for Less Fit Adults With Acute Myeloid Leukemia and Myeloid Neoplasms

Inclusion Criteria:

* Age ≥ 18 years
* Diagnosis of high grade myeloid neoplasm (\> 10% blasts in blood or marrow), other than acute promyelocytic leukemia (APL) according to the 2022 International Consensus Classification (ICC) classification. Patients with acute leukemias of ambiguous lineage are eligible
* The use of cytoreductive therapy before treatment is permitted. Patients with symptoms/signs of leukostasis, white blood cell (WBC) \> 100,000/μL, or acute symptoms that in the opinion of the treating physician are likely related to their high-grade myeloid neoplasm may receive up to 2 doses of cytarabine (up to 500 mg/m\^2 each) prior to study day 1
* Patients may have received treatment for antecedent low-grade myeloid neoplasm (\< 10% myeloid blasts on blood or bone marrow)
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 3 (for patients aged \< 75 years) or ECOG performance status of 0 - 2 (for patients aged ≥ 75 years)
* The presence of one or more of the following criteria for 'unfitness'. (Patients without respiratory symptoms at rest are eligible and should only complete spirometry/diffusion capacity of the lung for carbon monoxide \[DLCO\] measurements as clinically indicated):

  * ECOG Performance Status of 2 or 3
  * Cardiac history of congestive heart failure (CHF) requiring treatment or ejection fraction ≤ 50% or chronic stable angina
  * Documented DLCO ≤ 65% or forced expiratory volume in 1 second (FEV1) ≤ 65%; or dyspnea at rest, or requiring supplemental oxygen
  * Creatinine clearance ≥ 30 mL/min to \< 45 ml/min
  * Moderate hepatic impairment with total bilirubin \> 1.5 to ≤ 3.0 × upper limit of normal (ULN)
  * Any other comorbidity that the physician judges to be incompatible with intensive chemotherapy
* Adequate cardiac function:

  * Patients aged ≤ 60 years without a history of cardiac disease or evidence of heart failure are eligible if they also exhibit the following:

    * Chest x-ray (CXR) without evidence of moderate or severe pulmonary edema or pleural effusion, and a normal cardio-mediastinal silhouette
    * Electrocardiogram (ECG) without evidence of atrial or ventricular chamber enlargement
    * Note that patients with either abnormal CXR or ECG should have a structural heart assessment (echocardiogram, multigated acquisition scan \[MUGA\] or similar) and are eligible if left ventricular ejection fraction (LVEF) \> 40% and the abnormalities in the CXR/ECG do not preclude safe administration of intensive chemotherapy
  * Patients with a documented left ventricular ejection fraction (LVEF) ≥ 40%, assessed within 3 months prior to registration, e.g. by MUGA scan or echocardiography, or another appropriate diagnostic modality are eligible
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3x ULN, unless judged due to leukemic organ involvement
* Total bilirubin ≤ 3 x ULN unless judged due to leukemic organ involvement, Gilbert's syndrome, or hemolysis
* Women of childbearing potential and men must agree to use adequate contraception for an appropriate period of time during and after the completion of study treatment
* HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
* Ability to understand and the willingness to provide informed consent

Exclusion Criteria:

* Known hypersensitivity to cytarabine, anthracycline, hypomethylating agents, or venetoclax
* Cardiovascular disability status of New York Heart Association class ≥ 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain
* Subject has chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or any other medical condition that in the opinion of the investigator would adversely affect his/her participating in this study
* Subject exhibits evidence of other clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial or fungal)
* Concomitant illness associated with a likely survival of \< 1 year
* Active pregnancy or breast feeding