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Evaluating the impact of genetic and epigenetic aberrations on survival and response in acute myeloid leukemia patients receiving epigenetic therapy

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Abstract

Treatment with hypomethylating agents such as decitabine, which results in overall response rates of up to 50%, has become standard of care in older patients with acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy. However, there still exists a lack of prognostic and predictive molecular biomarkers that enable selection of patients who are likely to benefit from epigenetic therapy. Here, we investigated distinct genetic (FLT3-ITD, NPM1, DNMT3A) and epigenetic (estrogen receptor alpha (ERα), C/EBPα, and OLIG2) aberrations in 87 AML patients from the recently published phase II decitabine trial (AML00331) to identify potential biomarkers for patients receiving hypomethylating therapy. While FLT3-ITD and NPM1 mutational status were not associated with survival or response to therapy, patients harboring DNMT3A R882 mutations showed a non-significant association towards shorter overall survival (hazard ratio (HR) 2.15, 95% confidence interval (CI) 0.91–5.12, p = 0.08). Promoter DNA methylation analyses using pyrosequencing also revealed a non-significant association towards shorter overall survival of patients with higher levels of methylation of ERα (HR 1.50, CI 0.97–2.32, p = 0.07) and OLIG2 CpG4 (HR 1.52, CI 0.96–2.41, p = 0.08), while DNA methylation of C/EBPα showed no association with outcome. Importantly, in multivariate analyses adjusted for clinical baseline parameters, the impact of ERα and OLIG2 CpG4 methylation was conserved (HR 1.76, CI 1.01–3.06, p = 0.05 and HR 1.67, CI 0.91–3.08, p = 0.10, respectively). In contrast, none of the investigated genetic and epigenetic markers was associated with response to treatment. Additional to the previously reported adverse prognostic clinical parameters such as patients’ age, reduced performance status, and elevated lactate dehydrogenase levels, DNMT3A R882 mutation status, as well as ERα and OLIG2 CpG4 DNA methylation status, may prove to be molecular markers in older AML patients prior to hypomethylating therapy.

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Acknowledgements

This work was supported by grants from the German Cancer Aid (BH 110213) and the German Research Foundation (DFG; SPP 1463, ML 429/8-1 and CRC 992 MEDEP, C4).

Authors’ contribution

JKH, VIG, CSS, AY, MA, and NBD performed the experiments, analyzed the data, and revised the manuscript. CS performed the statistical analyses, analyzed the data, and drafted/revised the manuscript. KD and LB analyzed the data and drafted/revised the manuscript. JD was involved in the design of the study and revised the manuscript. ML and BH designed the study and drafted/revised the manuscript. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Department of Hematology/Oncology and Stem Cell Transplantation, University Medical Center, Hugstetterstr. 55, 79106, Freiburg, Germany

    Jan K. Hiller, Charlotte Schmidt-Salzmann, Arzu Yalcin, Mahmoud Abdelkarim, Nadja Blagitko-Dorfs, Justus Duyster, Michael Lübbert & Björn Hackanson

  2. Center for Clinical Trials and Biostatistics, University Medical Center, Freiburg, Germany

    Claudia Schmoor

  3. Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany

    Verena I. Gaidzik, Konstanze Döhner & Lars Bullinger

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  1. Jan K. Hiller
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Correspondence to Björn Hackanson.

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JKH and CS contributed equally to the manuscript.

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Hiller, J.K., Schmoor, C., Gaidzik, V.I. et al. Evaluating the impact of genetic and epigenetic aberrations on survival and response in acute myeloid leukemia patients receiving epigenetic therapy. Ann Hematol 96, 559–565 (2017). https://doi.org/10.1007/s00277-016-2912-7

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  • DOI: https://doi.org/10.1007/s00277-016-2912-7

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