Ascorbate in Myelodysplastic Syndrome

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).