Ascorbate in Myelodysplastic Syndrome

This Phase II clinical trial investigates the combination of high-dose intravenous ascorbate (vitamin C) with azacitidine in adults with higher-risk myelodysplastic syndrome (MDS). The study includes a small safety run-in followed by an efficacy phase, enrolling a total of 38 participants. It aims to determine whether adding high-dose ascorbate can safely enhance the therapeutic response to azacitidine, a standard hypomethylating agent used in MDS treatment.

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).