Extended experience with a non‐cytotoxic DNMT1‐targeting regimen of decitabine to treat myeloid malignancies

The nucleoside analogue decitabine can deplete the epigenetic regulator DNA methyltransferase 1 (DNMT1), an effect that occurs, and is saturated at, low concentrations/doses. A reason to pursue this molecular‐targeted effect instead of the DNA damage/cytotoxicity produced with high concentrations/doses, is that non‐cytotoxic DNMT1‐depletion can cytoreduce even p53‐null myeloid malignancies while sparing normal haematopoiesis. We thus identified minimum doses of decitabine (0·1–0·2 mg/kg) that deplete DNMT1 without off‐target anti‐metabolite effects/cytotoxicity, and then administered these well‐tolerated doses frequently 1–2X/week to increase S‐phase dependent DNMT1‐depletion, and used a Myeloid Malignancy Registry to evaluate long‐term outcomes in 69 patients treated this way. Consistent with the scientific rationale, treatment was well‐tolerated and durable responses were produced (~40%) in genetically heterogeneous disease and the very elderly.