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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References
Fenaux P, Mufti GJ, Hellström-Lindberg E et al (2010) Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 28:562–569
Kantarjian HM, Thomas XG, Dmoszynska A et al (2012) Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol 30:2670–2677
Dombret H, Seymour JF, Butrym A et al (2015) International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 126:291–299
National Comprehensive Cancer Network: NCCN clinical practice guidelines in oncology (2015). Acute myeloid leukemia v 1. http://www.nccn.org/professionals/physician_gls/pdf/aml.pdf
Döhner H, Estey EH, Amadori S et al (2010) Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European leukemia net. Blood 2010(115):453–474
Cashen AF, Schiller GJ, O’Donnell MR et al (2010) Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol 28:556–561
Lübbert M, Rüter BH, Claus R et al (2012) A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy. Haematologica 97:393–401
Itzykson R, Thépot S, Quesnel B et al (2011) Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine. Blood 117:403–411
Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B et al (2006) Phase 1/2 study of the combination of 5-aza-2’-deoxycytidine with valproic acid in patients with leukemia. Blood 108:3271–3279
Ramos F, Thépot S, Pleyer L et al (2015) Azacitidine frontline therapy for unfit acute myeloid leukemia patients: clinical use and outcome prediction. Leuk Res 39:296–306
Yan P, Frankhouser D, Murphy M et al (2012) Genome-wide methylation profiling in decitabine-treated patients with acute myeloid leukemia. Blood 120:2466–2474
Shen L, Kantarjian H, Guo Y et al (2010) DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. J Clin Oncol 28:605–613
Emadi A, Faramand R, Carter-Cooper B et al (2015) Presence of isocitrate dehydrogenase mutations may predict clinical response to hypomethylating agents in patients with acute myeloid leukemia. Am J Hematol 90:77–79
Metzeler KH, Walker A, Geyer S et al (2012) DNMT3A mutations and response to the hypomethylating agent decitabine in acute myeloid leukemia. Leukemia 26:1106–1107
DiNardo CD, Patel KP, Garcia-Manero G et al (2014) Lack of association of IDH1, IDH2 and DNMT3A mutations with outcome in older patients with acute myeloid leukemia treated with hypomethylating agents. Leuk Lymphoma 55:1925–1929
Coombs CC, Sallman DA, Devlin SM, et al. (2016) Mutational correlates of response to hypomethylating agent therapy in acute myeloid leukemia. Haematologica (Epub ahead of print)
Hackanson B, Bennett KL, Brena RM et al (2008) Epigenetic modification of CCAAT/enhancer binding protein alpha expression in acute myeloid leukemia. Cancer Res 68:3142–3151
Gaidzik VI, Schlenk RF, Paschka P et al (2013) Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML study group (AMLSG). Blood 121:4769–4777
Fröhling S, Schlenk RF, Breitruck J et al (2005) Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML study group Ulm. Blood 100:4372–4380
Döhner K, Schlenk RF, Habdank M et al (2005) Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood 106:3740–3746
Yalcin A, Kreutz C, Pfeifer D et al (2013) MeDIP coupled with a promoter tiling array as a platform to investigate global DNA methylation patterns in AML cells. Leuk Res 37:102–111
Marcucci G, Metzeler KH, Schwind S et al (2012) Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia. J Clin Oncol 30:742–750
Ferreira HJ, Heyn H, Vizoso M et al (2016) DNMT3A mutations mediate the epigenetic reactivation of the leukemogenic factor MEIS1 in acute myeloid leukemia. Oncogene 35:3079–3082
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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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