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. 2020 Mar;188(6):924-929.
doi: 10.1111/bjh.16281. Epub 2019 Nov 17.

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

Hassan Awada  1 , Reda Z Mahfouz  1 , Ashwin Kishtagari  1   2 , Teodora Kuzmanovic  1 , Jibran Durrani  1 , Cassandra M Kerr  1 , Bhumika J Patel  1   2 , Valeria Visconte  1 , Tomas Radivoyevitch  3 , Alan Lichtin  2 , Hetty E Carraway  2 , Jaroslaw P Maciejewski  1   2 , Yogen Saunthararajah  1   2
Affiliations

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

Hassan Awada et al. Br J Haematol. 2020 Mar.

Abstract

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.

Keywords: decitabine; myeloid neoplasms; noncytotoxic DNMT1 depletion.

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Conflict of interest statement

YS is a Board member and consultant for, and has equity and royalty rights with, EpiDestiny.

Figures

Figure 1
Figure 1
(A) Response (haematologic improvement or complete remission [HI/CR]) versus non‐response [stable disease or progressive disease (SD/PD)] in patients grouped by myeloid malignancy sub‐type and previous 5‐azacytidine (5Aza), lenalidomide or cytarabine (AraC) therapy. (B) Change in abnormal metaphases on therapy [(abnormal metaphases on treatment − pretreatment)/pretreatment ×100]. Only cases with both on‐treatment and pretreatment karyotype analyses shown. (C) Change in the bone marrow myeloblast percentage on therapy (best response myeloblasts% on‐treatment − pretreatment myeloblasts%). Only cases with pretreatment (with this decitabine regimen) myeloblasts ≥5% together with on‐treatment bone marrow myeloblast data available shown. (D) Overall survival, stratified by responders and non‐responders. (E) Pretreatment bone marrow cellularity. Lines, Median ± interquartile range (IQR); P‐value, Wilcoxon test, two‐sided, HI/CR versus SD/PD. (F) Pretreatment absolute neutrophil counts (ANC;×109/l) by response versus non‐response within each disease subtype. Lines, Median ± IQR; P‐value, Wilcoxon test, two‐sided, HI/CR versus SD/PD
See this image and copyright information in PMC

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