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This investigational combination therapy, consisting of high-dose intravenous ascorbate (vitamin C), azacitidine, and venetoclax, is being evaluated for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients ineligible for intensive chemotherapy. The regimen is the subject of a Phase I clinical trial led by Dr. Kittika Poonsombudlert at the University of Iowa. The biological rationale involves ascorbate's role as a cofactor for TET2 and other 2-oxoglutarate-dependent dioxygenases, which are often mutated or downregulated in AML; by restoring TET2 function, ascorbate may enhance the epigenetic effects of the hypomethylating agent azacitidine. Additionally, pharmacological doses of ascorbate generate reactive oxygen species that selectively target leukemic cells. Venetoclax complements this by inhibiting BCL-2, an anti-apoptotic protein frequently overexpressed in AML, thereby lowering the threshold for programmed cell death.
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