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

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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
Issue number1
StatePublished - Jul 22 2019


  • 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


Dive into the research topics of 'Genomic and epigenomic predictors of response to guadecitabine in relapsed/refractory acute myelogenous leukemia'. Together they form a unique fingerprint.

Cite this