Study of ADI-PEG 20, Venetoclax and Azacitidine in Acute Myeloid Leukemia

Inclusion Criteria: * Cohort 1: Previously treated (relapsed/recurrent) or refractory AML based on the 2022 revision to the World Health Organization (WHO) criteria (Arber 2022) * Cohort 2: Untreated AML per 2022 WHO (Arber 2022) criteria with high-risk features and not a candidate for intensive chemotherapy because of age 60 years or older, age-related comorbidities, cardiac disease, prior anthracycline use, high probability of treatment-related mortality, or otherwise would not benefit from intensive chemotherapy treatment. * Age ≥ 18 years * Life expectancy reasonably adequate for evaluating the treatment * White blood cell (WBC) count of 10 × 109/L or less. (Use of hydroxyurea to control WBC is allowed till 48 hours prior to protocol treatment) * Adequate renal function: Creatinine ≤ 1.5 x upper limit of normal (ULN) or creatinine clearance \> 40 mL/minute (measured or calculated according to the Cockcroft-Gault formula) * Adequate liver function * Total bilirubin ≤ 1.5 x ULN * ALT and AST both ≤ 2.5 x institutional ULN or ≤ 5 times the ULN for patients with leukemic involvement of liver Exclusion Criteria: * Prior treatments as follows: 1. Cohort 1: \>2 cycles of prior combination treatment with venetoclax+hypomethelating agent (i.e. azacitidine, decitabine) is exclusionary. All other prior treatment for antecedent hematological disorders and/or for AML is permitted. 2. Cohort 2: Prior treatment for antecedent hematological disorders with venetoclax or chemotherapy or any prior treatment for their AML is exclusionary. However, treatment with other agents, including hydroxyurea or ≤2 cycles of hypomethylating agent (i.e. azacitidine, decitabine), for MDS or myeloproliferative neoplasm is permitted. * Cohort 2: Favorable risk AML per European LeukemiaNet (ELN) 2022 criteria (Döhner 2022) * Known active CNS involvement by leukemia