DNMT3A Mutations Associate with Shorter Survival and Modulate the Prognostic Impact of Mutated NPM1: an Analysis Based on Comprehensive Mutational Screening of 660 AML Patients Treated on German AML Cooperative Group (AMLCG) Trials

Background: Mutations in DNA methyltransferase 3A (DNMT3A) are common in acute myeloid leukemia (AML), affecting ~20% of patients (pts) and 30-40% of those with cytogenetically normal (CN-) AML. Although several groups have investigated their prognostic relevance, most studies focused on younger adults (=60 y) AML pts treated on German AML Cooperative Group (AMLCG) protocols, and studied the association between DNMT3A mutations and outcomes. Patients and Methods: We analyzed pretreatment blood or bone marrow specimens from 660 adult AML pts who received intensive induction chemotherapy on two consecutive phase III trials (AMLCG-1999, n=388, and AMLCG-2008, n=272; median age, 57y, range, 18-86y). Sequence variants in DNMT3A exons 7-23 and other genes known to be mutated in myeloid neoplasms were analyzed by multiplexed amplicon resequencing (Agilent Haloplex). Sequencing was performed on an Illumina MiSeq instrument using 2x250bp paired-end reads. Variants were classified as known/putative driver mutations, variants of unknown significance, or known germline polymorphisms based on published data including dbSNP, the Catalogue Of Somatic Mutations In Cancer (COSMIC) and The Cancer Genome Atlas (TCGA). Cytogenetic analyses were performed centrally. Results: We identified 223 DNMT3A mutations in 207/660 pts (31%), including 180/449 pts (40%) with intermediate-risk cytogenetics according to the MRC classification (P 1 type of DNMT3A mutation. DNMT3A mutations tended to be more frequent in older compared to younger pts (35% vs. 28%, P =.08) and were associated with female sex (38% vs 26% in males; P Conclusion: In our cohort of intensively treated AML pts covering a broad age range, we found that DNMT3A mutations associate with inferior survival and modulate the prognostic impact of mutated NPM1, confirming data recently reported by the MRC group (Gale et al., J Clin Oncol 33:2072). In contrast to this and other published reports, we observed no outcome differences between different types of DNMT3A mutations. Information on DNMT3A mutation status further refined the risk stratification of CN-AML based on the NPM1 mutated / FLT3-ITD negative genotype, supporting a role for DNMT3A mutations as a prognostic marker. Figure 1. Figure 1. Disclosures Subklewe: AMGEN Research (Munich): Research Funding. Krug:Boehringer Ingelheim: Research Funding; Novartis; BMS; Roche; Boehringer Ingelheim; Bayer: Honoraria; Sunesis: Speakers Bureau; Sunesis; Clavis Pharma; usa Pharma, Catapult Cell Therapy, Gilead, Roche: Membership on an entity's Board of Directors or advisory committees.