Inclusion Criteria
- Age ≥ 18 years.
- Diagnosis of myelodysplastic syndrome (MDS) requiring treatment with a hypomethylating agent (HMA).
- Higher-risk MDS per the Molecular International Prognostic Scoring System (IPSS-M) - Moderate High, High, or Very High risk categories.
- No prior MDS-directed therapy, except:
≤ 1 prior cycle of azacitidine, decitabine, or oral decitabine-cedazuridine; or prior use of ESA, luspatercept, or imetelstat. Prior hydroxyurea use is allowed but continuation beyond Cycle 1 requires PI approval.
- ECOG performance status 0-2.
- Adequate organ function: Creatinine clearance >45 mL/min; total bilirubin ≤1.5 × ULN; ALT and AST ≤3 × ULN.
- Ability to provide written informed consent.
- Willingness to comply with study visits, treatment, and contraception requirements.
- Negative pregnancy test for women of childbearing potential at screening.
Exclusion Criteria
- MDS with isolated del(5q) eligible for lenalidomide therapy.
- MDS/MPN overlap syndromes other than MDS.
- Known hypersensitivity or allergy to ascorbate or azacitidine.
- Pregnant or nursing individuals.
- Inability or unwillingness to use adequate contraception.
- Uncontrolled intercurrent illness including active infection, recent myocardial infarction (≤6 months), uncontrolled heart failure or arrhythmia, pulmonary edema, unstable angina, or significant psychiatric illness.
- Renal disease requiring dialysis, diabetic nephropathy, renal transplant recipients, or history of oxalate nephropathy.
- Paroxysmal nocturnal hemoglobinuria.
- Uncontrolled HIV infection (patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible).
- G6PD deficiency.
- Use of warfarin (due to potential interaction with high-dose ascorbate).
- Diabetic patients using fingerstick or continuous glucose monitors to adjust insulin doses (ascorbate can cause false readings).
- Concurrent active malignancy, except adequately treated nonmelanoma skin cancer or curatively treated in situ cancers with >2 years disease-free.
- Systemic immunosuppressive therapy with prednisone ≥20 mg/day (or equivalent), except for inhaled or topical steroids.
- Primary hemochromatosis or transfusion-related iron overload (ferritin >1000 ng/mL).