title: Association Between Mutation Clearance After Induction Therapy and Outcomes in Acute Myeloid Leukemia.
abstract: OBJECTIVE
  Tests that predict outcomes for patients with acute myeloid leukemia (AML) are imprecise, especially for those with intermediate risk AML.
  
  
  OBJECTIVE
  To determine whether genomic approaches can provide novel prognostic information for adult patients with de novo AML.
  
  
  METHODS
  Whole-genome or exome sequencing was performed on samples obtained at disease presentation from 71 patients with AML (mean age, 50.8 years) treated with standard induction chemotherapy at a single site starting in March 2002, with follow-up through January 2015. In addition, deep digital sequencing was performed on paired diagnosis and remission samples from 50 patients (including 32 with intermediate-risk AML), approximately 30 days after successful induction therapy. Twenty-five of the 50 were from the cohort of 71 patients, and 25 were new, additional cases.
  
  
  METHODS
  Whole-genome or exome sequencing and targeted deep sequencing. Risk of identification based on genetic data.
  
  
  METHODS
  Mutation patterns (including clearance of leukemia-associated variants after chemotherapy) and their association with event-free survival and overall survival.
  
  
  RESULTS
  Analysis of comprehensive genomic data from the 71 patients did not improve outcome assessment over current standard-of-care metrics. In an analysis of 50 patients with both presentation and documented remission samples, 24 (48%) had persistent leukemia-associated mutations in at least 5% of bone marrow cells at remission. The 24 with persistent mutations had significantly reduced event-free and overall survival vs the 26 who cleared all mutations. Patients with intermediate cytogenetic risk profiles had similar findings. [table: see text].
  
  
  CONCLUSIONS
  The detection of persistent leukemia-associated mutations in at least 5% of bone marrow cells in day 30 remission samples was associated with a significantly increased risk of relapse, and reduced overall survival. These data suggest that this genomic approach may improve risk stratification for patients with AML.
authors: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri2Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee.
authors: Jeffery M
authors: JM
authors: Klco
authors: The McDonnell Genome Institute, Washington University, St Louis, Missouri4Division of Genomics and Bioinformatics, Department of Medicine, Washington University in St Louis, St Louis, Missouri.
authors: Christopher A
authors: CA
authors: Miller
authors: The McDonnell Genome Institute, Washington University, St Louis, Missouri5Department of Genetics, Washington University School of Medicine, St Louis, Missouri.
authors: Malachi
authors: M
authors: Griffith
authors: The McDonnell Genome Institute, Washington University, St Louis, Missouri4Division of Genomics and Bioinformatics, Department of Medicine, Washington University in St Louis, St Louis, Missouri.
authors: Allegra
authors: A
authors: Petti
authors: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri.
authors: David H
authors: DH
authors: Spencer
authors: The McDonnell Genome Institute, Washington University, St Louis, Missouri6Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri.
authors: Shamika
authors: S
authors: Ketkar-Kulkarni
authors: Department of Genetics, Washington University School of Medicine, St Louis, Missouri.
authors: Lukas D
authors: LD
authors: Wartman
authors: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri.
authors: Matthew
authors: M
authors: Christopher
authors: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee6Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri.
authors: Tamara L
authors: TL
authors: Lamprecht
authors: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri.
authors: Nicole M
authors: NM
authors: Helton
authors: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri.
authors: Eric J
authors: EJ
authors: Duncavage
authors: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri.
authors: Jacqueline E
authors: JE
authors: Payton
authors: Division of Biostatistics, Washington University School of Medicine, St Louis, Missouri.
authors: Jack
authors: J
authors: Baty
authors: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri.
authors: Sharon E
authors: SE
authors: Heath
authors: The McDonnell Genome Institute, Washington University, St Louis, Missouri6Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri.
authors: Obi L
authors: OL
authors: Griffith
authors: The McDonnell Genome Institute, Washington University, St Louis, Missouri8Medimmune/AstraZeneca, Gaithersburg, Maryland.
authors: Dong
authors: D
authors: Shen
authors: The McDonnell Genome Institute, Washington University, St Louis, Missouri.
authors: Jasreet
authors: J
authors: Hundal
authors: The McDonnell Genome Institute, Washington University, St Louis, Missouri.
authors: Gue Su
authors: GS
authors: Chang
authors: The McDonnell Genome Institute, Washington University, St Louis, Missouri5Department of Genetics, Washington University School of Medicine, St Louis, Missouri.
authors: Robert
authors: R
authors: Fulton
authors: The McDonnell Genome Institute, Washington University, St Louis, Missouri.
authors: Michelle
authors: M
authors: O'Laughlin
authors: The McDonnell Genome Institute, Washington University, St Louis, Missouri.
authors: Catrina
authors: C
authors: Fronick
authors: The McDonnell Genome Institute, Washington University, St Louis, Missouri5Department of Genetics, Washington University School of Medicine, St Louis, Missouri.
authors: Vincent
authors: V
authors: Magrini
authors: The McDonnell Genome Institute, Washington University, St Louis, Missouri.
authors: Ryan T
authors: RT
authors: Demeter
authors: The McDonnell Genome Institute, Washington University, St Louis, Missouri5Department of Genetics, Washington University School of Medicine, St Louis, Missouri.
authors: David E
authors: DE
authors: Larson
authors: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri5Department of Genetics, Washington University School of Medicine, St Louis, Missouri9Division of Hematology/Oncology, Department of Pediatrics, Washington.
authors: Shashikant
authors: S
authors: Kulkarni
authors: The McDonnell Genome Institute, Washington University, St Louis, Missouri6Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri.
authors: Bradley A
authors: BA
authors: Ozenberger
authors: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri.
authors: John S
authors: JS
authors: Welch
authors: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri.
authors: Matthew J
authors: MJ
authors: Walter
authors: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri10Department of Medicine, Massachusetts General Hospital, Boston.
authors: Timothy A
authors: TA
authors: Graubert
authors: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri.
authors: Peter
authors: P
authors: Westervelt
authors: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors: Jerald P
authors: JP
authors: Radich
authors: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri.
authors: Daniel C
authors: DC
authors: Link
authors: The McDonnell Genome Institute, Washington University, St Louis, Missouri4Division of Genomics and Bioinformatics, Department of Medicine, Washington University in St Louis, St Louis, Missouri5Department of Genetics, Washington University School of Medici.
authors: Elaine R
authors: ER
authors: Mardis
authors: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri.
authors: John F
authors: JF
authors: DiPersio
authors: The McDonnell Genome Institute, Washington University, St Louis, Missouri4Division of Genomics and Bioinformatics, Department of Medicine, Washington University in St Louis, St Louis, Missouri5Department of Genetics, Washington University School of Medici.
authors: Richard K
authors: RK
authors: Wilson
authors: The McDonnell Genome Institute, Washington University, St Louis, Missouri5Department of Genetics, Washington University School of Medicine, St Louis, Missouri6Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis.
authors: Timothy J
authors: TJ
authors: Ley
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001853:Bone Marrow; D003561:Cytarabine / Q000008:administration & dosage; D003630:Daunorubicin / Q000008:administration & dosage; D018572:Disease-Free Survival; D005260:Female; D015894:Genome, Human; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage; D060828:Induction Chemotherapy; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D035683:MicroRNAs / Q000032:analysis; D008875:Middle Aged; D009154:Mutation; D017063:Outcome Assessment, Health Care; D011110:Polymorphism, Genetic; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D012008:Recurrence; D017423:Sequence Analysis, RNA / Q000379:methods
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D003561:Cytarabine; D015255:Idarubicin; D003630:Daunorubicin