Inclusion Criteria:
* Men and women ≥18 years old
* Must sign an informed consent form (ICF) indicating that he or she understands the purpose of, and procedures required for the study and is willing to participate in the study
* Diagnosis of AML according to ICC 2022 (with the exclusion of MDS/AML with 10-19% blasts)
* Previously untreated AML except may have received emergency leukapheresis, hydroxyurea before study entry to control hyperleukocytosis
* Deemed unfit for intensive chemotherapy by meeting at least 1 of the following criteria:
1. Participant is ≥75 years of age with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 OR
2. Participant is ≥18 to 74 years of age and has any of the following comorbidities:
1. ECOG performance status of 2 or 3
2. Cardiac status including any one of the following: congestive heart failure requiring treatment or ejection fraction ≤50% or chronic stable angina
3. Known history of diffusion capacity of lung for carbon monoxide (DLCO) ≤65% of forced expiratory volume in the first second (FEV1) ≤65%
4. Creatinine clearance (CrCl) ≥15 mL/min to \<45 mL/min
5. Hepatic disorder with total bilirubin \>1.5 to 3x the upper limit of normal (ULN)
6. Any other comorbidity that the investigators determine to be incompatible with conventional intensive chemotherapy
* Adequate liver and renal function defined as:
1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<3xULN; for participants with leukemic infiltration of the liver (documented by biopsy or imaging), AST and ALT \<5xULN is permitted
2. Total bilirubin ≤1.5xULN, unless bilirubin rise is due to Gilbert's syndrome or of nonhepatic origin. Participants who are \<75 years of age may have a bilirubin up to 3xULN.
3. Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 (by the Modification of Diet in Renal Disease \[MDRD\] formula). Participants who are \<75 years of age may have an eGFR ≥15 mL/min/1.73 m2.
* Women of childbearing potential (WOCBP), defined as fertile women between menarche and post menopause unless permanently sterile, must have a negative highly sensitive serum β-human chorionic gonadotropin (β-hCG) or urine pregnancy test at screening
* Must be willing to use contraception as consistent with institutional guidelines regarding the use of contraceptive methods for participants participating in clinical studies
1. WOCBP must agree to adhere to the following birth control measures while receiving study treatment continuing to 3 months after the last dose of study drug:
1. Must be practicing a highly effective method of birth control (failure rate of \<1% per year when used consistently and correctly) as determined by institutional standards
2. Must agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction
3. Must not be breastfeeding and not planning to become pregnant
2. Male participants who are sexually active with WOCBP, and male partners of study participants who are WOCBP, and who are not surgically or otherwise sterile must agree to adhere to the following birth control measures while receiving study treatment and for 3 months after the last dose of study drug:
1. Must agree to use a barrier method of birth control (e.g., either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap \[diaphragm or cervical/vault caps\] with spermicidal foam, gel, film, cream, or suppository)
2. Must not donate sperm
3. Must no plan to father a child
* Participants with HIV infection are eligible for the trial if the following criteria are met:
1. CD4+ T-cell count ≥200 cells/μL
2. No prior history of AIDS-defining opportunistic infection within the past 12 months
3. Receiving treatment with antiretroviral therapy
4. Undetectable viral load within 6 months of screening
Exclusion Criteria:
* Any prior treatment for AML (except those outlined in inclusion criterion #4)
* Participant has received a hypomethylating agent (HMA) or venetoclax for MDS or myeloproliferative neoplasm
* Leukemic involvement in the central nervous system
* Participants with acute promyelocytic leukemia (APL)
* ECOG performance status of 4 for participants 18 to 74 years of age and ECOG performance status of 3 or 4 for participants ≥75 years of age
* Use of immune suppressive agents ≤4 weeks before the first administration of cusatuzumab. Participants may be included if free of systemic corticosteroids \>5 days before the first administration of cusatuzumab with the exception of corticosteroids at physiologic replacement doses.
* Received a live, attenuated vaccine within 4 weeks prior to initiation of study drug
* Active malignancies (i.e., progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. Exceptions to this exclusion criterion include the following:
1. Nonmelanoma skin cancer treated within the last 24 months that is considered completely cured
2. Adequately treated breast lobular carcinoma in situ and breast ductal carcinoma in situ
3. Adequately treated cervical carcinoma in situ and breast ductal carcinoma in situ
4. History of localized breast cancer and receiving anti-hormonal agents, or history of localized prostate cancer (N0M0) and receiving androgen depravation therapy
5. A malignancy that is considered cured with minimal risk of recurrence
* Any active systemic infection
* History of prior HSCT (allogeneic or autologous transplants)
* Active hepatitis B or C infection or other clinically active liver diseases ad defined below:
1. Seropositivity for hepatitis B is defined by a positive test for hepatitis B surface antigen (HBsAg)
2. Participants with resolved infection (i.e., participants who are HBsAg negative with antibodies to total hepatitis B core antigen \[anti-HBc\] with or without the presence of hepatitis B surface antibody \[anti-HBs\]) must be screened using PCR measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded.
* Participants with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR
3. Active hepatitis C infection as defined by being positive for a nucleic acid test for hepatitis C virus (HCV) RNA
* Congestive hear failure severity that is New York Heart Association Class III or IV
* Unstable angina
* Known allergies, hypersensitivity, or intolerance to cusatuzumab, venetoclax, or azacitidine or their excipients (e.g., mannitol, an excipient of azacitidine)
* Inability or difficulty swallowing capsules/tablets, malabsorption syndrome, or any disease or medical condition significantly affecting gastrointestinal function
* Any condition for which, in the investigator's opinion, participation would not be in the best interest of the participant (e.g., compromise the well-being) or physical limitations that could prevent, limit, or confound the protocol-specified assessments
* Major surgery (e.g., requiring general anesthesia) ≤4 weeks prior to initiation of study treatment
