• Ability to comprehend the investigational nature of the study and provide informed consent (i.e., participant or legally authorized representative \[LAR\]). Written informed consent must be obtained prior to any study-specific procedures or interventions

• • Sign informed consent for the #4422 Biorepository prior to any study-specific procedures of interventions

• Eligible AML patients of all races and ethnic groups will be considered for participation, irrespective of gender identity

• Newly diagnosed, histologically confirmed monocytic AML, as defined by World Health Organization (WHO), or active signaling mutated AML defined as AML with mutation(s) to N/KRAS, FLT3 ITD/TKD, NF1, PTPN11 or CBL

• Ineligible for standard of care induction therapy using intensive chemotherapy (IC) or unwilling to undergo IC induction therapy. Ineligible for IC is defined as

‣ ≥ 75 yrs of age; OR

⁃ 18-74 yrs of age with one of the following:

• Eastern Cooperative Oncology Group (ECOG) performance status of ≥ 2 at screening

∙ Severe cardiac disorder (e.g., congestive heart failure requiring treatment, ejection fraction ≤ 50%, or chronic stable angina)

∙ Severe pulmonary disorder (e.g., diffuse capacity of the lung for carbon monoxide \[DLCO\] ≤ 65% or forced expiratory volume in 1 second \[FEV1\] ≤ 65%)

∙ Creatinine clearance \< 45 ml/min (calculated by the Cockcroft-Gault equation)

∙ Hepatic disorder with total bilirubin \> 1.5 x upper limit of normal (ULN)

∙ Any other comorbidity that the treating physician judges to be incompatible with IC

• If ≥ 75 yrs of age, the following organ function values must be met and ECOG must be 0 to 2 at screening:

‣ Creatinine clearance (calculated with the Cockcroft-Gault equation) ≥ 30 ml/min

⁃ Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (Unless due to leukemic infiltration)

⁃ Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) or alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 x ULN (Unless due to leukemic infiltration) (With the exception of documented Gilbert's syndrome or similar conditions. Liver function testing (LFT) and timepoints may be added, as clinically indicated, in such cases)

• Note: In cases of confirmed leukemic organ involvement, exceptions may be made

• Willing and able to provide bone marrow (BM) samples, including BM samples for research use only analysis

• Willing and able to accept supportive and prophylactic care for hematologic toxicities, infection, and immediate sequalae

• Willingness to adhere to (a) study schedule of activities; (b) requirements for bio samples collections; and (b) lifestyle restrictions while on-treatment

• Negative urine pregnancy test at screening and within 24 hours of cycle 1 day 1 (C1D1) for persons of childbearing potential (PCBP). Serum pregnancy testing will be used for confirmation in cases of equivocal results. Pregnancy is exclusionary because the agents used in this study have the potential for teratogenic or abortifacient effects

• Willingness to comply with study requirements for contraception within the specified timeframe, as follows:

‣ Sperm producing participants who are active with PCBP must use approved contraception from C1D1 to 30 days, 3 months, or 6 months, after the last dose of venetoclax (30 days), azacitidine (3 months), cladribine (6 months), or cytarabine (6 months), whichever is later in time

⁃ PCBP who are sexually active with sperm-producing persons must use contraception from C1D1 to 30 days after the last dose of venetoclax or to 6 months after the last dose of azacitidine, cladribine, or cytarabine, whichever is later in time