title: DNMT3A R882 Mutation with FLT3-ITD Positivity Is an Extremely Poor Prognostic Factor in Patients with Normal-Karyotype Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation.
abstract: The prognostic relevance of epigenetic modifying genes (DNMT3A, TET2, and IDH1/2) in patients with acute myeloid leukemia (AML) has been investigated extensively. However, the prognostic implications of these mutations after allogeneic hematopoietic cell transplantation (HCT) have not been evaluated comprehensively in patients with normal-karyotype (NK)-AML. A total of 115 patients who received allogeneic HCT for NK-AML were retrospectively evaluated for the FLT3-ITD, NPM1, CEBPA, DNMT3A, TET2, IDH1/2, WT1, NRAS, ASXL2, FAT1, DNAH11, and GATA2 mutations in diagnostic samples and analyzed for long-term outcomes after allogeneic HCT. The prevalence rates for the mutations were as follows: FLT3-ITD positivity (FLT3-ITD(pos)) (32.2%), NPM1 mutation (43.5%), CEBPA mutation (double) (24.6%), DNMT3A mutation (DNMT3A(mut)) (31.3%), DNMT3A R882(mut) (18.3%), TET2 mutation (8.7%), and IDH1/2 mutation (16.5%). The 5-year overall survival (OS) and event-free survival (EFS) rates were 57.3% and 58.1%, respectively. A multivariate analysis revealed that FLT3-ITD(pos) (hazard ratio, [HR], 2.23; P = .006) and DNMT3A R882(mut) (HR, 2.74; P = .002) were unfavorable prognostic factors for OS. In addition, both mutations were significant risk factors for EFS and relapse. People with DNMT3A R882(mut) accompanied by FLT3-ITD(pos) had worse OS and EFS, and higher relapse rates than those with the other mutations, which were confirmed in a propensity score 1:2 matching analysis. These results suggest that DNMT3A R882(mut), particularly when accompanied by FLT3-ITD(pos), is a significant prognostic factor for inferior transplantation survival outcome by increasing relapse risk, even after allogeneic HCT.
authors.affiliation: Hematology-Oncology, Chonnam National University Hwasun Hospital, Jeollanam-do, Korea.
authors.forename: Jae-Sook
authors.initials: JS
authors.lastname: Ahn
authors.affiliation: Hematology-Oncology, Chonnam National University Hwasun Hospital, Jeollanam-do, Korea. Electronic address: hjoonk@chonnam.ac.kr.
authors.forename: Hyeoung-Joon
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Hematology-Oncology, Chonnam National University Hwasun Hospital, Jeollanam-do, Korea.
authors.forename: Yeo-Kyeoung
authors.initials: YK
authors.lastname: Kim
authors.affiliation: Hematology-Oncology, Chonnam National University Hwasun Hospital, Jeollanam-do, Korea.
authors.forename: Seun-Shin
authors.initials: SS
authors.lastname: Lee
authors.affiliation: Hematology-Oncology, Chonnam National University Hwasun Hospital, Jeollanam-do, Korea.
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Jung
authors.affiliation: Hematology-Oncology, Chonnam National University Hwasun Hospital, Jeollanam-do, Korea.
authors.forename: Deok-Hwan
authors.initials: DH
authors.lastname: Yang
authors.affiliation: Hematology-Oncology, Chonnam National University Hwasun Hospital, Jeollanam-do, Korea.
authors.forename: Je-Jung
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Genomic Research Center for Hematopoietic Diseases, Chonnam National University Hwasun Hospital, Jeollanam-do, Korea.
authors.forename: Nan Young
authors.initials: NY
authors.lastname: Kim
authors.affiliation: Genomic Research Center for Hematopoietic Diseases, Chonnam National University Hwasun Hospital, Jeollanam-do, Korea.
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Division of Hematology-Oncology, Samsung Medical Center, Seoul, Korea.
authors.forename: Chul Won
authors.initials: CW
authors.lastname: Jung
authors.affiliation: Division of Hematology-Oncology, Samsung Medical Center, Seoul, Korea.
authors.forename: Jun-Ho
authors.initials: JH
authors.lastname: Jang
authors.affiliation: Department of Hematology, The Catholic University of Korea, Seoul, Korea.
authors.forename: Hee Je
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Hematology-Oncology, Kyungpook National University Hospital, Daegu, Korea.
authors.forename: Joon Ho
authors.initials: JH
authors.lastname: Moon
authors.affiliation: Department of Hematology-Oncology, Kyungpook National University Hospital, Daegu, Korea.
authors.forename: Sang Kyun
authors.initials: SK
authors.lastname: Sohn
authors.affiliation: Department of Hematology-Oncology, Soon Chun Hyang University Hospital, Seoul, Korea.
authors.forename: Jong-Ho
authors.initials: JH
authors.lastname: Won
authors.affiliation: Department of Hematology-Oncology, Dong-A University College of Medicine, Busan, Korea.
authors.forename: Sung-Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada.
authors.forename: Dennis Dong Hwan
authors.initials: DD
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D064591:Allografts; D019943:Amino Acid Substitution; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D018572:Disease-Free Survival; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D000090243:Nucleophosmin; D015996:Survival Rate; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: C000717967:DNMT3A protein, human; C000716967:NPM1 protein, human; D000090243:Nucleophosmin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
keywords: Acute myeloid leukemia; Allogeneic hematopoietic cell transplantation; DNMT3A; IDH1/2; Normal karyotype; TET2