title: Persistence of DNMT3A R882 mutations during remission does not adversely affect outcomes of patients with acute myeloid leukaemia.
abstract: Somatic mutation of the DNMT3A gene at the arginine R882 site is common in acute myeloid leukaemia (AML). The prognostic significance of DNMT3A R882 mutation clearance, using traditional diagnostic next generation sequencing (NGS) methods, during complete remission (CR) in AML patients is controversial. We examined the impact of clearing DNMT3A R882 mutations at diagnosis to the detectable threshold of ˂3% during CR on outcome in 56 adult AML patients. Mutational remission, defined as clearance of pre-treatment DNMT3A R882 and all other AML-associated mutations to a variant allele frequency ˂3%, occurred in 14 patients whereas persistent DNMT3A R882 mutations were observed in 42 patients. There were no significant differences in disease-free or overall survival between patients with and without DNMT3A R882 mutation clearance. Patients with persistent DNMT3A R882 who cleared all other AML mutations and did not acquire new mutations (n = 30), trended towards longer disease-free survival (1·6 vs. 0·6 years, P = 0·06) than patients with persistence of DNMT3A R882, in addition to other mutations or acquisition of new AML-associated mutations, such as those in TET2, JAK2, ASXL1 and TP53 (n = 12). These data demonstrate that DNMT3A R882 mutations, as assessed by traditional NGS methods, persist in the majority of AML patients in CR.
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA. Bhavana.Bhatnagar@osumc.edu.|The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA. Bhavana.Bhatnagar@osumc.edu.
authors.forename: Bhavana
authors.initials: B
authors.lastname: Bhatnagar
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Eisfeld
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.|Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.
authors.forename: Deedra
authors.initials: D
authors.lastname: Nicolet
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Mrózek
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Blachly
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.|The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: Shelley
authors.initials: S
authors.lastname: Orwick
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Lucas
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.|Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Kohlschmidt
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: William
authors.initials: W
authors.lastname: Blum
authors.affiliation: Monter Cancer Center, Hofstra North Shore-Long Island Jewish School of Medicine, Lake Success, NY, USA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Kolitz
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.|The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA. john.byrd@osumc.edu.|The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA. john.byrd@osumc.edu.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D001853:Bone Marrow / Q000473:pathology; D003062:Codon; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D011379:Prognosis; D012074:Remission Induction; D016896:Treatment Outcome
chemical_list: D003062:Codon; C000717967:DNMT3A protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
keywords: DNA (cytosine-5)-methyltransferase 3 alpha; acute myeloid leukaemia; mutation clearance; prognosis; survival