Patients With Acute Myeloid Leukemia and Concurrent DNMT3A and TET2 Mutations Demonstrate Lower Survival Outcomes

Methylation-related gene mutations are often found in older patients with acute myeloid leukemia (AML). Among these patients, the presence of concurrent DNMT3A and TET2 mutations was associated with significantly inferior clinical outcomes, including lower complete remission (CR) rates and shorter survival, while IDH1 and IDH2 mutations were associated with superior clinical outcomes, according to retrospective findings published in Frontiers in Medicine. However, authors noted, these gene mutations do not significantly influence the choice between standard chemotherapy and an azacitidine plus venetoclax regimen.

Research is limited on the prognostic impact of methylation-related gene mutations among elderly patients with AML. Researchers conducted a retrospective analysis to determine the impact of gene mutations on AML prognosis, as well as the impact on treatment selection between intensive chemotherapy or combination regiments with HMA therapy. The analysis focused on methylation-related gene mutations—specifically DNMT3A, TET2, IDH1, and IDH2. 

Overall, 645 patients with AML who were over the age of 60 years were included. Patients were mostly male (62.9%) and the median age of all patients was 67 years (range, 60 to 98 years). Methylation-related gene mutations identified among patients included DNMT3A (24.0%), TET2 (22.5%), IDH1 (9.1%), and IDH2 (13.8%). Following diagnosis, 41.0% of patients received intensive chemotherapy, 7.4% received HMA monotherapy, 15.6% of patients were treated with a combination of HMA therapy and low dose chemotherapy, 31.3% received a combination of azacitidine and venetoclax, and 4.8% were treated with other regimens. 

Among all patients, the median duration of remission (DOR) was 16.0 months, and the median OS was 21.2 months. The CR rate was 51.2%, the partial remission (PR) rate was 13.3%, the overall response rate (ORR) was 64.5%. 

When compared to patients without mutations, the OS for patients with DNMT3A mutations was lower (22.3 months vs 12.8 months, P = .192). Patients had a CR rate of 53.6% (P = .5868). Additionally, patients with TET2 mutations also demonstrated a lower OS than patients without mutations (13.7 months vs 21.2 months; P = .208). 

These patients had a CR rate of 42.2% (P = .0594). Patients with co-occurring DNMT3A and TET2 mutations had a median OS of 6.2 months and a 2-year OS rate of 23.9%. The CR rate was 35.5%. Conversely, patients with IDH1 mutations had a median survival of 25.2 months while patients with IDH2 mutations did not reach median survival at time of analysis and had a CR rate of 69.6%.  

Treatment comparisons revealed no significant benefit of azacitidine plus venetoclax over intensive chemotherapy among patients with any methylation-related gene mutations.

“Patients with co-occurring DNMT3A and TET2 mutations showed notably poor treatment responses and survival outcomes,” the researchers concluded, adding “These common methylation-related gene mutations do not significantly influence the choice between IC and azacitidine plus venetoclax regimen.”

Source:

Chen Y, Wu Z, Chen Y, et al. Prognostic impact of methylation-related gene mutations in elderly acute myeloid leukemia: a real-world retrospective analysis. Frontiers in Medicine. Published online May 12, 2025. doi:10.3389/fmed.2025.1594784