Inclusion Criteria:
* 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
Exclusion Criteria:
* Symptomatic central nervous system involvement with AML
* Prior treatment for AML, with the exception of cytoreduction for proliferative disease (per institutional protocol) with any of the following: Hydroxyurea, hematopoietic growth factors, leukapheresis
* Another active malignancy within the previous 5 years of C1D1
* Investigational therapy within 28 days of C1D1, or within 5 half-lives or longer, if known
* Recent and significant medical interventions, such as major surgery within 28 days or stem cell transplant within 100 days (and without active treatment for graft versus host disease \[GVHD\]) of C1D1. Standard of care procedures for patients with hematologic malignancies, such as biopsies and lumbar punctures, are not exclusionary
* Hypersensitivity to any of the components of the investigational regimen (i.e., cladribine, cytarabine, venetoclax, azacitidine) or any excipients in the formulations
* Treatment based on agents targeting or inhibiting BCL-2 (for other, prior indication/malignancy) within the previous 5 years
* History of dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally
* Use of drugs with documented drug-drug interaction toxicities with the study drugs
* Strong or moderate CYP3A4 inducers or inhibitors within 2 days or 3 half lives whichever is longer, prior to C1D1 are exclusionary. Dose adjustments and other modifications may be considered if the wash-out period has not been met, with the approval of the investigator and the research pharmacy
* Uncontrolled infection. Participants with controlled infection must be afebrile and hemodynamically stable for at least 72 hours prior to C1D1 and must be amenable to alternate treatment if current treatment will interact with investigational regimen
* Active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Enrollment of individuals with evidence of chronic HBV or HCV infection will be considered on a case-by-case basis by the principal investigator
* Individuals with serology positive for human immunodeficiency virus (HIV) and under active treatment with highly active antiretroviral therapy (HAART) (or another therapy that may interfere with metabolism of study agents)
* Pregnancy at enrollment or unwillingness to stop breastfeeding. Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with the chemotherapy agents, breastfeeding be discontinued from start of treatment until 1 week after the final dose of any study drug
* Uncontrolled intercurrent illness including, but not limited to ongoing or active uncontrolled infection, unstable cardiac or pulmonary function or acute insufficiency (e.g., symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia), or psychiatric illness or social situation that could limit compliance with study requirements
