1. Extended experience with a non‐cytotoxic DNMT1‐targeting regimen of decitabine to treat myeloid malignancies
- Author
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Alan E. Lichtin, Hetty E. Carraway, Ashwin Kishtagari, Yogen Saunthararajah, Jibran Durrani, Tomas Radivoyevitch, Cassandra M Kerr, Bhumika J. Patel, Valeria Visconte, Hassan Awada, Reda Z. Mahfouz, Teodora Kuzmanovic, and Jaroslaw P. Maciejewski
- Subjects
Male ,Antimetabolites, Antineoplastic ,Myeloid ,DNA damage ,Short Report ,Decitabine ,03 medical and health sciences ,0302 clinical medicine ,Short Reports ,Humans ,Cytotoxic T cell ,Medicine ,noncytotoxic DNMT1 depletion ,Cytotoxicity ,Aged ,Aged, 80 and over ,Myeloproliferative Disorders ,Nucleoside analogue ,business.industry ,Hematology ,myeloid neoplasms ,Haematological Malignancy – Clinical ,Regimen ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,DNMT1 ,Cancer research ,Female ,business ,030215 immunology ,medicine.drug - 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.
- Published
- 2019