title: Monitoring of minimal residual disease in NPM1-mutated acute myeloid leukemia: a study from the German-Austrian acute myeloid leukemia study group.
abstract: OBJECTIVE
  To evaluate the prognostic value of minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) with NPM1 mutation (NPM1(mut)).
  
  
  METHODS
  RNA-based real-time quantitative polymerase chain reaction (RQ-PCR) specific for the detection of six different NPM1(mut) types was applied to 1,682 samples (bone marrow, n = 1,272; blood, n = 410) serially obtained from 245 intensively treated younger adult patients who were 16 to 60 years old.
  
  
  RESULTS
  NPM1(mut) transcript levels as a continuous variable were significantly associated with prognosis after each treatment cycle. Achievement of RQ-PCR negativity after double induction therapy identified patients with a low cumulative incidence of relapse (CIR; 6.5% after 4 years) compared with RQ-PCR-positive patients (53.0%; P < .001); this translated into significant differences in overall survival (90% v 51%, respectively; P = .001). After completion of therapy, CIR was 15.7% in RQ-PCR-negative patients compared with 66.5% in RQ-PCR-positive patients (P < .001). Multivariable analyses after double induction and after completion of consolidation therapy revealed higher NPM1(mut) transcript levels as a significant factor for a higher risk of relapse and death. Serial post-treatment assessment of MRD allowed early detection of relapse in patients exceeding more than 200 NPM1(mut)/10(4) ABL copies.
  
  
  CONCLUSIONS
  We defined clinically relevant time points for NPM1(mut) MRD assessment that allow for the identification of patients with AML who are at high risk of relapse. Monitoring of NPM1(mut) transcript levels should be incorporated in future clinical trials to guide therapeutic decisions.
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Krönke
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.forename: Kai-Ole
authors.initials: KO
authors.lastname: Jensen
authors.forename: Florian
authors.initials: F
authors.lastname: Tschürtz
authors.forename: Andrea
authors.initials: A
authors.lastname: Corbacioglu
authors.forename: Verena I
authors.initials: VI
authors.lastname: Gaidzik
authors.forename: Peter
authors.initials: P
authors.lastname: Paschka
authors.forename: Shiva
authors.initials: S
authors.lastname: Onken
authors.forename: Karina
authors.initials: K
authors.lastname: Eiwen
authors.forename: Marianne
authors.initials: M
authors.lastname: Habdank
authors.forename: Daniela
authors.initials: D
authors.lastname: Späth
authors.forename: Michael
authors.initials: M
authors.lastname: Lübbert
authors.forename: Mohammed
authors.initials: M
authors.lastname: Wattad
authors.forename: Thomas
authors.initials: T
authors.lastname: Kindler
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Salih
authors.forename: Gerhard
authors.initials: G
authors.lastname: Held
authors.forename: David
authors.initials: D
authors.lastname: Nachbaur
authors.forename: Marie
authors.initials: M
authors.lastname: von Lilienfeld-Toal
authors.forename: Ulrich
authors.initials: U
authors.lastname: Germing
authors.forename: Detlef
authors.initials: D
authors.lastname: Haase
authors.forename: Hans-Günther
authors.initials: HG
authors.lastname: Mergenthaler
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krauter
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Gudrun
authors.initials: G
authors.lastname: Göhring
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
mesh_terms: D000293:Adolescent; D000328:Adult; D001317:Austria; D001853:Bone Marrow / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D005858:Germany; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D018365:Neoplasm, Residual / Q000235:genetics* / Q000628:therapy; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D011379:Prognosis; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin