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

Woonbok Chung, Andrew D. Kelly, Patricia Kropf, Henry Fung, Jaroslav Jelinek, Xiang Yao Su, Gail J. Roboz, Hagop M. Kantarjian, Mohammad Azab, Jean Pierre J. Issa

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20 Scopus citations

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%.

Original languageEnglish
Article number106
Pages (from-to)106
JournalClinical Epigenetics
Volume11
Issue number1
DOIs
StatePublished - Jul 22 2019

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Azacitidine/administration & dosage
  • Biomarkers, Tumor/genetics
  • DNA Methylation
  • Female
  • Genomics/methods
  • Humans
  • Leukemia, Myeloid, Acute/drug therapy
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Recurrence, Local/drug therapy
  • Survival Analysis
  • Treatment Outcome
  • Young Adult

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