Pb1859: dnmt3a mutation patterns and clinical features in korean acute myeloid leukemia patients

Topic: 4. Acute myeloid leukemia - Clinical Background: Acute myeloid leukemia (AML) is a complicated disease characterized by heterogeneous and simultaneous variant genetic alterations. Epigenetic dysregulation is one of the most important carcinogenesis mechanisms and frequently discovered aberration in AML. The correlation of DNA methylation with carcinogenesis and progression has been investigated for years. However, genetic alteration status, including locus and allele frequency of genes associated with DNA methylation, especially DNMT3A, the most prevalent genetic alteration in adult AML, has not been sufficiently investigated. Aims: The objective of this study was to determine clinical significance of DNMT3A mutation and the efficacy of hypomethylating agents (HMA) based on detailed mutation patterns. Methods: For the genetic study part, 96 samples from AML patients were analyzed by target sequencing to investigate the DNMT3A mutation status. For the clinical cohort study part, clinical medical records of newly diagnosed AML patients (n = 216) were collected, and DNMT3A mutated Korean AML patients (n = 62, 30.5%) were reviewed and compared to analyze detailed alteration profiles. Results: In the genetic study, 191 variants were detected from 70 analyzable samples after variant filtering. The mutation prevalence of DNMT3A was 34.3%: Point mutation at R882 of the DNMT3A gene was observed at 14.3% in total and 41.7% in DNMT3A mutation. Mutations at non-R882 were observed in 58.3% of DNMT3A mutations. The median variant allele frequency (VAF) of DNMT3A mutation was 43.1%. In the clinical cohort study part, among 216 patients, the median age at diagnosis was 61.3 years old (range, 18-88 years), 47.7% of patients (n = 103) were adverse prognosis group, and 33.8% (n = 73) had more than 4 mutations. DNMT3A mutant group was sorted out to study detailed alteration profiles. The median age was 64.9 years old (range, 37-87 years) and 49.3% (n = 34) was the adverse risk group. The prevalence of DNMT3A mutation was 30.5% (n = 69) and presented less frequent favorable cytogenetics (P = 0.037). DNMT3A WT group was more responsive to intensive chemotherapy (P = 0.014) than the DNMT3A mutant group, while the response to the first line HMA was not different (P = 0.244). The presence of DNMT3A mutation was associated with shorter overall survival (OS, P = 0.0001). Among DNMT3A mutant group, the prevalence of R882 mutation was 47.8%. The mutation prevalence of DNMT3A methyltransferase domain where R882 residue was located was 76.8%. DNMT3A mutated patients were classified into DNMT3A mutation low (VAF ≤ 47.6%, n = 54) and DNMT3A mutation high (VAF > 47.6%, n = 12) except 3 cases with unknown locations of mutations. Low DNMT3A VAF did not present survival benefit. Low VAF of R882 point mutation (P = 0.0015) and methyltransferase domain mutation (P = 0.0284) presented longer OS. Patients with low VAF of total DNMT3A mutation (P = 0.0047) and methyltransferase domain mutation lived longer after initial HMA therapy (P = 0.0268). Summary/Conclusion: This study presented DNMT3A mutation patterns of Korean AML patients. Results of this study suggest that higher allele frequency of DNMT3A methyltransferase domain mutations might be suggested as an adverse prognostic factor for survival and a predictable factor for initial HMA therapy in elderly AML patients.Overall survival according to VAF of MTD mutation in DNMT3A mutant Korean patients. Cases with unknown mutation loci were excluded. Keywords: Acute myeloid leukemia, Mutation status, DNA methylation, Epigenetic