High-dose Ascorbate (HDA) in Combination With Standard of Care Azacitidine and Venetoclax in Acute Myeloid Leukemia (AML)

Inclusion Criteria:

* Adults aged ≥ 18 who are deemed unfit for intensive chemotherapy by meeting at least one of the following criteria:

  * age ≥ 75
  * Eastern Cooperative Oncology Group (ECOG) performance of 2-3
  * Severe cardiac disorder (e.g., congestive heart failure requiring treatment, ejection fraction ≤ 50%, or chronic stable angina)
  * Severe pulmonary disorder (e.g., DLCO ≤ 65% or FEV1 ≤ 65%)
  * Calculated Creatinine clearance 25 - 45 mL/min using the Cockcroft-Gault formula
  * Hepatic disorder with total bilirubin \> 1.5 times the upper limit of normal
  * Any other comorbidity that the investigators determine to be incompatible with intensive chemotherapy
* Newly diagnosed (non-APL) acute myeloid leukemia except those with cytogenetic/molecular abnormalities in the exclusion criteria
* Participants must have adequate organ function, defined as:

  * Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 3.0 x upper limit of normal (ULN)
  * International normalized ratio (INR) \< 1.5 x ULN and partial thromboplastin time (PTT) \< 1.5 x ULN (patient could be eligible if they respond appropriately to correction with FFP or cryoprecipitate)
* Patients with a history of antecedent myelodysplasia (MDS) are eligible if they have not had prior chemotherapy/hypomethylating agent (e.g., azacitidine or decitabine). Prior exposure to other investigational agents could be considered at PI's discretion
* Patients who have developed therapy-related AML after prior radiation or chemotherapy for other malignancy(ies) are eligible if they have not been exposed to hypomethylating agent (e.g., azacitidine or decitabine) and/or venetoclax
* Patients presenting with marked leukocytosis (WBC \> 25 k/mm3) should receive cytoreduction with hydroxyurea or cytarabine dose ≤ 1 g/m2 to mitigate the risk of tumor lysis syndrome before initiation of therapy with venetoclax
* For female participants of childbearing potential, a negative serum or urine pregnancy test (sensitivity of at least 25 mIU/mL) at screening
* Ability to understand and the willingness to sign a written informed consent document.
* Both male and female participants of childbearing potential agree to use an adequate method of contraception from screening through 6 months after the last dose of study treatment.
* Patients with evidence of Central Nervous System (CNS) disease involvement or who are at high risk of developing CNS disease at baseline/screening (defined as: presenting WBC \> 200k/mm3, or monocytic differentiation or active CSN symptoms concerning CNS involvement per the treating physician) are eligible for this trial and may continue to receive or initiate intrathecal chemotherapy as treatment or prophylaxis, respectively, per institutional practice

Exclusion Criteria

* Patients who have received prior therapy to treat their AML (except for cytoreductive hydroxyurea or cytarabine dose ≤ 1 g/m2 for hyperleukocytosis)
* Known hypersensitivity or allergy to ascorbate, azacitidine/decitabine, or venetoclax
* AML patients with the following cytogenetic/molecular aberrations are not eligible i. t(8;21)(q22;q22.1)/RUNX1::RUNX1T1 ii. inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/ CBFB::MYH11 iii. bZIP in-frame mutated CEBPA without any adverse mutations iv. KMT2A rearrangement v. NPM1 or IDH1 or IDH2 or FLT3-ITD or FLT3-TKD mutation
* Patients with kidney disease needing dialysis, diabetic nephropathy, renal transplant recipients, and those with history of acute or chronic oxalate nephropathy
* Patients with primary hemochromatosis or transfusional iron overload as defined as persistently elevated Ferritin \> 1000 ng/mL.
* Patients with type I or type II diabetes mellitus on treatment with short acting insulin who need at least a daily blood glucose monitoring test via finger stick
* Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen
* Other major co-morbidities as determined unsuitable per the treating physician
* HIV-infection that is uncontrolled by anti-retroviral therapy. (HIV-infected patients on effective anti- retroviral therapy with undetectable viral load within 6 months are eligible for this study)
* Patients with G6PD (glucose-6-phosphate dehydrogenase) deficiency
* Patients who are on warfarin or other strong CYP3A4 inducer/inhibitor and cannot have a drug substitution or who decline the drug substitution