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Genomic and epigenomic predictors of response to guadecitabine in relapsed/refractory acute myelogenous leukemia.


ABSTRACT: BACKGROUND:Guadecitabine is a novel DNA methyltransferase (DNMT) inhibitor with improved pharmacokinetics and clinical activity in a subset of patients with relapsed/refractory acute myeloid leukemia (r/r AML), but identification of this subset remains difficult. METHODS:To search for biomarkers of response, we measured genome-wide DNA methylation, mutations of 54 genes, and expression of a panel of 7 genes in pre-treatment samples from 128 patients treated at therapeutic doses in a phase I/II study. RESULTS:Response rate to guadecitabine was 17% (2 complete remission (CR), 3 CR with incomplete blood count recovery (CRi), or CR with incomplete platelets recovery (CRp)) in the phase I component and 23% (14 CR, 9 CRi/CRp) in phase II. There were no strong mutation or methylation predictors of response. Gene expression clustering defined a subset of patients (~?20%) that had (i) high DNMT3B and low CDKN2B, CTCF, and CDA expression; (ii) enrichment for KRAS/NRAS mutations; (iii) frequent CpG island hypermethylation; (iv) low long interspersed nuclear element 1 (LINE-1) hypomethylation after treatment; and (v) resistance to guadecitabine in both phase I (response rate 0% vs. 33%, p?=?0.07) and phase II components of the study (response rate 5% vs. 30%, p?=?0.02). Multivariate analysis identified peripheral blood (PB) blasts and hemoglobin as predictors of response and cytogenetics, gene expression, RAS mutations, and hemoglobin as predictors of survival. CONCLUSIONS:A subset of patients (~?20%) with r/r AML is unlikely to benefit from guadecitabine as a single agent. In the remaining 80%, guadecitabine is a viable option with a median survival of 8?months and a 2-year survival rate of 21%. TRIAL REGISTRATION:NCT01261312 .

SUBMITTER: Chung W 

PROVIDER: S-EPMC6647096 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Genomic and epigenomic predictors of response to guadecitabine in relapsed/refractory acute myelogenous leukemia.

Chung Woonbok W   Kelly Andrew D AD   Kropf Patricia P   Fung Henry H   Jelinek Jaroslav J   Su Xiang Yao XY   Roboz Gail J GJ   Kantarjian Hagop M HM   Azab Mohammad M   Issa Jean-Pierre J JJ  

Clinical epigenetics 20190722 1


<h4>Background</h4>Guadecitabine is a novel DNA methyltransferase (DNMT) inhibitor with improved pharmacokinetics and clinical activity in a subset of patients with relapsed/refractory acute myeloid leukemia (r/r AML), but identification of this subset remains difficult.<h4>Methods</h4>To search for biomarkers of response, we measured genome-wide DNA methylation, mutations of 54 genes, and expression of a panel of 7 genes in pre-treatment samples from 128 patients treated at therapeutic doses in  ...[more]

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