title: Evaluating the impact of genetic and epigenetic aberrations on survival and response in acute myeloid leukemia patients receiving epigenetic therapy.
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.
authors.affiliation: Department of Hematology/Oncology and Stem Cell Transplantation, University Medical Center, Hugstetterstr. 55, 79106, Freiburg, Germany.
authors.forename: Jan K
authors.initials: JK
authors.lastname: Hiller
authors.affiliation: Center for Clinical Trials and Biostatistics, University Medical Center, Freiburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schmoor
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
authors.forename: Verena I
authors.initials: VI
authors.lastname: Gaidzik
authors.affiliation: Department of Hematology/Oncology and Stem Cell Transplantation, University Medical Center, Hugstetterstr. 55, 79106, Freiburg, Germany.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Schmidt-Salzmann
authors.affiliation: Department of Hematology/Oncology and Stem Cell Transplantation, University Medical Center, Hugstetterstr. 55, 79106, Freiburg, Germany.
authors.forename: Arzu
authors.initials: A
authors.lastname: Yalcin
authors.affiliation: Department of Hematology/Oncology and Stem Cell Transplantation, University Medical Center, Hugstetterstr. 55, 79106, Freiburg, Germany.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Abdelkarim
authors.affiliation: Department of Hematology/Oncology and Stem Cell Transplantation, University Medical Center, Hugstetterstr. 55, 79106, Freiburg, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Blagitko-Dorfs
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: Department of Hematology/Oncology and Stem Cell Transplantation, University Medical Center, Hugstetterstr. 55, 79106, Freiburg, Germany.
authors.forename: Justus
authors.initials: J
authors.lastname: Duyster
authors.affiliation: Department of Hematology/Oncology and Stem Cell Transplantation, University Medical Center, Hugstetterstr. 55, 79106, Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Lübbert
authors.affiliation: Department of Hematology/Oncology and Stem Cell Transplantation, University Medical Center, Hugstetterstr. 55, 79106, Freiburg, Germany. bjoern.hackanson@klinikum-augsburg.de.
authors.forename: Björn
authors.identifier: http://orcid.org/0000-0001-7242-7503
authors.initials: B
authors.lastname: Hackanson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D000077209:Decitabine; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D000090243:Nucleophosmin; D015996:Survival Rate / Q000639:trends; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; C000717967:DNMT3A protein, human; C000716967:NPM1 protein, human; D000090243:Nucleophosmin; D000077209:Decitabine; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D001374:Azacitidine
keywords: AML; Biomarker; Decitabine; Epigenetics