title: DNMT3A Mutational Status Affects the Results of Dose-Escalated Induction Therapy in Acute Myelogenous Leukemia.
abstract: OBJECTIVE
  DNA methyltransferase 3A (DNMT3A) is one of the commonly mutated genes in acute myelogenous leukemia (AML). Reports on the prognostic significance of DNMT3A mutations have been inconsistent, and most of the data are available only for patients 60 years of age or younger. We hypothesized that this inconsistency is due to an interaction between the dose of anthracycline used in induction therapy and DNMT3A status. We studied whether patients with DNMT3A-mutated AML treated with standard dose anthracyclines had an inferior survival compared with patients with other mutation profiles or those who received high-dose therapy.
  
  
  METHODS
  A total of 152 patients in this retrospective cohort study (median age, 54 years) with de novo AML underwent induction therapy and next-generation sequencing of 33 commonly mutated genes in hematologic malignancies, including DNMT3A, FLT3-ITD, NPM1, and IDH1/2. Cox regression was used to know whether those with DNMT3A mutations who were treated with standard dose anthracycline had inferior survival.
  
  
  RESULTS
  DNMT3A mutations, found in 32% of patients, were not associated with an inferior survival. Dose escalation of anthracycline in the induction regimen was associated with improved survival in those with DNMT3A mutations but not those with wild-type DNMT3A. Patients with DNMT3A mutations who received standard dose induction had shorter survival time than other patient groups (10.1 months vs. 19.8 months, P = 0.0129). This relationship remained significant (HR, 1.90; P = 0.006) controlling for multiple variables.
  
  
  CONCLUSIONS
  Patients with DNMT3A-mutated AML have an inferior survival when treated with standard-dose anthracycline induction therapy. This group should be considered for high-dose induction therapy.
authors.affiliation: Division of Hematology and Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Alison R
authors.initials: AR
authors.lastname: Sehgal
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Gimotty
authors.affiliation: Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jing-Mei
authors.initials: JM
authors.lastname: Hsu
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Robert
authors.initials: R
authors.lastname: Daber
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Morrissette
authors.affiliation: Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Selina
authors.initials: S
authors.lastname: Luger
authors.affiliation: Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Alison W
authors.initials: AW
authors.lastname: Loren
authors.affiliation: Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, Pennsylvania. carroll2@mail.med.upenn.edu.
authors.forename: Martin
authors.initials: M
authors.lastname: Carroll
mesh_terms: D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D015331:Cohort Studies; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D004252:DNA Mutational Analysis; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D060828:Induction Chemotherapy / Q000379:methods*; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D000090243:Nucleophosmin; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; C000717967:DNMT3A protein, human; C000716967:NPM1 protein, human; D000090243:Nucleophosmin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A