Impact of Distinct Genetic and Epigenetic Aberrations on Survival and Response in Acute Myeloid Leukemia Patients Receiving Epigenetic Therapy
Authors: Hiller Jan K. , Schmoor Claudia , Gaidzik Verena I. , Schmidt-Salzmann Charlotte , Yalcin Arzu , Abdelkarim Mahmoud , Blagitko-Dorfs Nadja , Döhner Konstanze , Bullinger Lars , Duyster Justus , Lübbert Michael , Hackanson Björn 
Published: October 2019

Background: Treatment with hypomethylating agents such as decitabine, which results in complete and partial remission rates of up to 50%, has become standard of care in older patients with acute myeloid leukemia (AML) who are no candidates for intensive chemotherapy. While clinical parameters such as reduced performance status, high leukocyte counts, elevated lactate dehydrogenase (LDH) levels as well as poor-risk cytogenetics are associated with lower response rates and shorter overall survival, there exists only limited data on molecular biomarkers that enables for selection of AML patients who are likely to benefit from epigenetic therapy. Shen et al. (JCO 2010) could show that distinct DNA methylation changes are prognostic for overall survival in myelodysplastic syndrome patients, however, response to decitabine therapy could not be predicted. Additionally, mutations in the epigenetic-modifier gene DNMT3A were recently reported to be associated with response and survival in AML patients treated with hypomethylating agents, however, while some of these studies revealed a positive association with outcome, other studies showed no association with response and overall survival (Metzeler et al., Leukemia 2012, DiNardo et al., Leuk Lymph 2014, Coombs et al., Blood 2015).

Results: In order to contribute further knowledge regarding prognosis and response to hypomethylating therapy in AML patients, 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, Lübbert et al. Haematologica 2012) to identify potential molecular biomarkers. While FLT3-ITD and NPM1 mutational status were not associated with survival or response to therapy, in our cohort patients harboring DNMT3A R882 mutations showed 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 revealed 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: 1.74, CI: 1.03-2.96, p=0.04 and HR: 1.61, CI: 0.96-2.71, p=0.07, respectively) whereas the effect of DNMT3A R882 mutations was reduced to HR: 1.94 (CI: 0.79-4.73, p=0.15). In contrast, none of the investigated molecular markers was associated with response to treatment.

Conclusion: In addition to the well established adverse prognostic clinical parameters such as patients' age, reduced performance status and elevated LDH levels, we provide further evidence that pretreatment genetic and especially epigenetic analyses including DNMT3A R882 mutation status, as well as ERα and OLIG2 CpG4 DNA methylation status may be potential molecular biomarkers in AML patients undergoing epigenetic therapy.

Disclosures

Lübbert: Celgene: Other: Travel Funding; Ratiopharm: Other: Study drug valproic acid; Janssen-Cilag: Other: Travel Funding, Research Funding.