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.

Epigenetic modifier gene mutations‐positive AML patients with intermediate‐risk karyotypes benefit from decitabine with CAG regimen

“…The leading reason might be the different combinations with decitabine in the two studies. The previous study included HMAs alone or a combination with valproic acid/vorinostat/ATRA + valproic acid/low‐dose cytarabine, without any regimen containing anthracyclines, thereby causing the prognostic discrepancies, confirmed in another study unsuccessfully exploring epigenetic biomarkers in AML patients receiving only decitabine . The reason why EMM (+) patients benefit from DCAG in our study rather than from HMAs alone or standard induction regimens might be derived from the complementation between decitabine and CAG regimen.…”

“…The previous study included HMAs alone or a combination with valproic acid/vorinostat/ATRA + valproic acid/low-dose cytarabine, without any regimen containing anthracyclines, thereby causing the prognostic discrepancies, confirmed in another study unsuccessfully exploring epigenetic biomarkers in AML patients receiving only decitabine. 9 The reason why EMM (+) patients benefit from DCAG in our study rather than from HMAs alone or standard induction regimens might be derived from the complementation between decitabine and CAG regimen. The abnormal level of epigenetics from EMMs probably can be altered by decitabine, which, however, might not be enough to achieve better prognosis when we use decitabine alone, because of the coexistence of other high-risk factors without direct connection with abnormal epigenetic level (e.g., high WBC, RUNX1 mutation, thrombocytopenia, etc.).…”

“…[16][17][18] However, as shown in our published review, the biomarkers for HMAs remained controversial 19 due to differential combinations with decitabine. [7][8][9] Previous reports 20 illustrated AML patients treated with only decitabine responded poorly. Most of the patients required ≥2 monthly cycles to achieve remissions and even required ≥3 cycles.…”

“…However, there is a lack of prognostic and predictive biomarkers for selecting patients who would probably benefit from HMAs better. There have been several controversial reports on the prognostic effects of EMMs when AML patients received HMAs . However, these groups were limited to cohorts only receiving HMAs or HMAs in combination with drugs excluding anthracyclines, and there are almost no studies comparing therapeutic discrepancies between HMAs and standard induction chemotherapies in AML cohorts with EMMs.…”

“…There have been several controversial reports on the prognostic effects of EMMs when AML patients received HMAs. [7][8][9] However, these groups were limited to cohorts only receiving HMAs or HMAs in combination with drugs excluding anthracyclines, and there are almost no studies comparing therapeutic discrepancies between HMAs and standard induction chemotherapies in AML cohorts with EMMs. In our study, we aimed at exploring whether IR-AML patients with EMMs could benefit from decitabine plus cytarabine, aclarubicin and granulocyte colony-stimulating factor (DCAG).…”