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 . Electronic supplementary material The online version of this article (10.1186/s13148-019-0704-3) contains supplementary material, which is available to authorized users.

DNA Methyltransferases in Cancer: Biology, Paradox, Aberrations, and Targeted Therapy

“…On the one hand, clinical trials and clinically approved DNMTis are mostly applicable to hematological tumors. In addition to decitabine, which is often mentioned above, there is guadecitabine for the treatment of relapsed/refractory AML [ 125 ], and the combination of DNMTi CC-486 and HDACi romidepsin for the treatment of advanced solid tumors [ 126 ]. These drugs are also very promising in clinical applications.…”

Clinical implications of recurrent gene mutations in acute myeloid leukemia

“…This suggested the need for age-tailored targeted therapies for the treatment of pediatric AML [98]. Furthermore, a novel DNMT inhibitor, guadecitabine demonstrated improved pharmacokinetics and clinical activity in a subset of R/R AML patients [5].…”

“…Six genes, including FMSlike tyrosine kinase 3 (FLT3), nucleophosmin 1 (NPM1), CCAAT/enhancer binding protein alpha (CEBPA), Runtrelated transcription factor 1 (RUNX1), additional sex combs-like 1 (ASXL1), and tumor protein p53 (TP53), have already been incorporated into the risk categories proposed by the European Leukemia Net (ELN) [2]. Other recurrent gene mutations have been reported in AML patients [3][4][5][6][7][8]. Furthermore, the important roles of recurrent gene mutation in AML pathogenesis had been explored and gene mutation-targeted therapies had been developed [8][9][10][11][12][13][14][15].…”

Identification of Two DNMT3A Mutations Compromising Protein Stability and Methylation Capacity in Acute Myeloid Leukemia

“…Nowadays, no predictive marker of response to guadecitabine has been defined for newly diagnosed AML. However, Chung et al reported no significant association between gene mutations and complete remission in a cohort of 128 relapsed/refractory AML [27]. Trends were observed for TET2 -mutated cases (higher CR rate) and IDH1/2 -mutated and TP53 -mutated AML (resistance).…”