Extended experience with a non‐cytotoxic DNMT1‐targeting regimen of decitabine to treat myeloid malignancies. (17th November 2019)

• Record Type: Journal Article
• Authors: Awada, Hassan; Mahfouz, Reda Z.; Kishtagari, Ashwin; Kuzmanovic, Teodora; Durrani, Jibran; Kerr, Cassandra M.; Patel, Bhumika J.; Visconte, Valeria; Radivoyevitch, Tomas; Lichtin, Alan; Carraway, Hetty E.; Maciejewski, Jaroslaw P.; Saunthararajah, Yogen
• Is Part Of: British journal of haematology. Volume 188:Number 6(2020)
• Page Start: 924
• Page End: 929
• Publication Date: 2019-11-17
• Subjects: myeloid neoplasms -- decitabine -- noncytotoxic DNMT1 depletion; Hematology -- Periodicals; Blood -- Diseases -- Periodicals; 616.15
• DOI: 10.1111/bjh.16281
• Languages: English
• ISSNs: 0007-1048

Abstract

Summary: 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.