title: Prognostic significance of NPM1 mutations in the absence of FLT3-internal tandem duplication in older patients with acute myeloid leukemia: a SWOG and UK National Cancer Research Institute/Medical Research Council report.
abstract: OBJECTIVE
  Younger patients with acute myeloid leukemia (AML) harboring NPM1 mutations without FLT3-internal tandem duplications (ITDs; NPM1-positive/FLT3-ITD-negative genotype) are classified as better risk; however, it remains uncertain whether this favorable classification can be applied to older patients with AML with this genotype. Therefore, we examined the impact of age on the prognostic significance of NPM1-positive/FLT3-ITD-negative status in older patients with AML.
  
  
  METHODS
  Patients with AML age ≥ 55 years treated with intensive chemotherapy as part of Southwest Oncology Group (SWOG) and UK National Cancer Research Institute/Medical Research Council (NCRI/MRC) trials were evaluated. A comprehensive analysis first examined 156 patients treated in SWOG trials. Validation analyses then examined 1,258 patients treated in MRC/NCRI trials. Univariable and multivariable analyses were used to determine the impact of age on the prognostic significance of NPM1 mutations, FLT3-ITDs, and the NPM1-positive/FLT3-ITD-negative genotype.
  
  
  RESULTS
  Patients with AML age 55 to 65 years with NPM1-positive/FLT3-ITD-negative genotype treated in SWOG trials had a significantly improved 2-year overall survival (OS) as compared with those without this genotype (70% v 32%; P < .001). Moreover, patients age 55 to 65 years with NPM1-positive/FLT3-ITD-negative genotype had a significantly improved 2-year OS as compared with those age > 65 years with this genotype (70% v 27%; P < .001); any potential survival benefit of this genotype in patients age > 65 years was marginal (27% v 16%; P = .33). In multivariable analysis, NPM1-positive/FLT3-ITD-negative genotype remained independently associated with an improved OS in patients age 55 to 65 years (P = .002) but not in those age > 65 years (P = .82). These results were confirmed in validation analyses examining the NCRI/MRC patients.
  
  
  CONCLUSIONS
  NPM1-positive/FLT3-ITD-negative genotype remains a relatively favorable prognostic factor for patients with AML age 55 to 65 years but not in those age > 65 years.
authors.affiliation: Fabiana Ostronoff, Megan Othus, Elihu Estey, Frederick R. Appelbaum, Kenneth J. Kopecky, Min Fang, Vivian G. Oehler, Era L. Pogosova-Agadjanyan, Jerald P. Radich, Soheil Meshinchi, and Derek L. Stirewalt, Fred Hutchinson Cancer Research Center; Fabiana Ostronoff, Elihu Estey, Frederick R. Appelbaum, Min Fang, Vivian G. Oehler, Jerald P. Radich, and Derek L. Stirewalt, University of Washington; Stephen H. Petersdorf, Seattle Genetics, Seattle, WA; Michelle Lazenby, Anna Evans, Amanda Gilkes, and Alan Burnett, Cardiff University School of Medicine, Cardiff, United Kingdom; John Godwin, Providence Cancer Center Group and Earle A. Chiles Research Institute, Portland, OR; Alan F. List, H. Lee Moffitt Cancer Center, Tampa, FL; and Cheryl L. Willman, University of New Mexico, Albuquerque, NM. fostrono@fhcrc.org.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Ostronoff
authors.affiliation: Fabiana Ostronoff, Megan Othus, Elihu Estey, Frederick R. Appelbaum, Kenneth J. Kopecky, Min Fang, Vivian G. Oehler, Era L. Pogosova-Agadjanyan, Jerald P. Radich, Soheil Meshinchi, and Derek L. Stirewalt, Fred Hutchinson Cancer Research Center; Fabiana Ostronoff, Elihu Estey, Frederick R. Appelbaum, Min Fang, Vivian G. Oehler, Jerald P. Radich, and Derek L. Stirewalt, University of Washington; Stephen H. Petersdorf, Seattle Genetics, Seattle, WA; Michelle Lazenby, Anna Evans, Amanda Gilkes, and Alan Burnett, Cardiff University School of Medicine, Cardiff, United Kingdom; John Godwin, Providence Cancer Center Group and Earle A. Chiles Research Institute, Portland, OR; Alan F. List, H. Lee Moffitt Cancer Center, Tampa, FL; and Cheryl L. Willman, University of New Mexico, Albuquerque, NM.
authors.forename: Megan
authors.initials: M
authors.lastname: Othus
authors.affiliation: Fabiana Ostronoff, Megan Othus, Elihu Estey, Frederick R. Appelbaum, Kenneth J. Kopecky, Min Fang, Vivian G. Oehler, Era L. Pogosova-Agadjanyan, Jerald P. Radich, Soheil Meshinchi, and Derek L. Stirewalt, Fred Hutchinson Cancer Research Center; Fabiana Ostronoff, Elihu Estey, Frederick R. Appelbaum, Min Fang, Vivian G. Oehler, Jerald P. Radich, and Derek L. Stirewalt, University of Washington; Stephen H. Petersdorf, Seattle Genetics, Seattle, WA; Michelle Lazenby, Anna Evans, Amanda Gilkes, and Alan Burnett, Cardiff University School of Medicine, Cardiff, United Kingdom; John Godwin, Providence Cancer Center Group and Earle A. Chiles Research Institute, Portland, OR; Alan F. List, H. Lee Moffitt Cancer Center, Tampa, FL; and Cheryl L. Willman, University of New Mexico, Albuquerque, NM.
authors.forename: Michelle
authors.initials: M
authors.lastname: Lazenby
authors.affiliation: Fabiana Ostronoff, Megan Othus, Elihu Estey, Frederick R. Appelbaum, Kenneth J. Kopecky, Min Fang, Vivian G. Oehler, Era L. Pogosova-Agadjanyan, Jerald P. Radich, Soheil Meshinchi, and Derek L. Stirewalt, Fred Hutchinson Cancer Research Center; Fabiana Ostronoff, Elihu Estey, Frederick R. Appelbaum, Min Fang, Vivian G. Oehler, Jerald P. Radich, and Derek L. Stirewalt, University of Washington; Stephen H. Petersdorf, Seattle Genetics, Seattle, WA; Michelle Lazenby, Anna Evans, Amanda Gilkes, and Alan Burnett, Cardiff University School of Medicine, Cardiff, United Kingdom; John Godwin, Providence Cancer Center Group and Earle A. Chiles Research Institute, Portland, OR; Alan F. List, H. Lee Moffitt Cancer Center, Tampa, FL; and Cheryl L. Willman, University of New Mexico, Albuquerque, NM.
authors.forename: Elihu
authors.initials: E
authors.lastname: Estey
authors.affiliation: Fabiana Ostronoff, Megan Othus, Elihu Estey, Frederick R. Appelbaum, Kenneth J. Kopecky, Min Fang, Vivian G. Oehler, Era L. Pogosova-Agadjanyan, Jerald P. Radich, Soheil Meshinchi, and Derek L. Stirewalt, Fred Hutchinson Cancer Research Center; Fabiana Ostronoff, Elihu Estey, Frederick R. Appelbaum, Min Fang, Vivian G. Oehler, Jerald P. Radich, and Derek L. Stirewalt, University of Washington; Stephen H. Petersdorf, Seattle Genetics, Seattle, WA; Michelle Lazenby, Anna Evans, Amanda Gilkes, and Alan Burnett, Cardiff University School of Medicine, Cardiff, United Kingdom; John Godwin, Providence Cancer Center Group and Earle A. Chiles Research Institute, Portland, OR; Alan F. List, H. Lee Moffitt Cancer Center, Tampa, FL; and Cheryl L. Willman, University of New Mexico, Albuquerque, NM.
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Appelbaum
authors.affiliation: Fabiana Ostronoff, Megan Othus, Elihu Estey, Frederick R. Appelbaum, Kenneth J. Kopecky, Min Fang, Vivian G. Oehler, Era L. Pogosova-Agadjanyan, Jerald P. Radich, Soheil Meshinchi, and Derek L. Stirewalt, Fred Hutchinson Cancer Research Center; Fabiana Ostronoff, Elihu Estey, Frederick R. Appelbaum, Min Fang, Vivian G. Oehler, Jerald P. Radich, and Derek L. Stirewalt, University of Washington; Stephen H. Petersdorf, Seattle Genetics, Seattle, WA; Michelle Lazenby, Anna Evans, Amanda Gilkes, and Alan Burnett, Cardiff University School of Medicine, Cardiff, United Kingdom; John Godwin, Providence Cancer Center Group and Earle A. Chiles Research Institute, Portland, OR; Alan F. List, H. Lee Moffitt Cancer Center, Tampa, FL; and Cheryl L. Willman, University of New Mexico, Albuquerque, NM.
authors.forename: Anna
authors.initials: A
authors.lastname: Evans
authors.affiliation: Fabiana Ostronoff, Megan Othus, Elihu Estey, Frederick R. Appelbaum, Kenneth J. Kopecky, Min Fang, Vivian G. Oehler, Era L. Pogosova-Agadjanyan, Jerald P. Radich, Soheil Meshinchi, and Derek L. Stirewalt, Fred Hutchinson Cancer Research Center; Fabiana Ostronoff, Elihu Estey, Frederick R. Appelbaum, Min Fang, Vivian G. Oehler, Jerald P. Radich, and Derek L. Stirewalt, University of Washington; Stephen H. Petersdorf, Seattle Genetics, Seattle, WA; Michelle Lazenby, Anna Evans, Amanda Gilkes, and Alan Burnett, Cardiff University School of Medicine, Cardiff, United Kingdom; John Godwin, Providence Cancer Center Group and Earle A. Chiles Research Institute, Portland, OR; Alan F. List, H. Lee Moffitt Cancer Center, Tampa, FL; and Cheryl L. Willman, University of New Mexico, Albuquerque, NM.
authors.forename: John
authors.initials: J
authors.lastname: Godwin
authors.affiliation: Fabiana Ostronoff, Megan Othus, Elihu Estey, Frederick R. Appelbaum, Kenneth J. Kopecky, Min Fang, Vivian G. Oehler, Era L. Pogosova-Agadjanyan, Jerald P. Radich, Soheil Meshinchi, and Derek L. Stirewalt, Fred Hutchinson Cancer Research Center; Fabiana Ostronoff, Elihu Estey, Frederick R. Appelbaum, Min Fang, Vivian G. Oehler, Jerald P. Radich, and Derek L. Stirewalt, University of Washington; Stephen H. Petersdorf, Seattle Genetics, Seattle, WA; Michelle Lazenby, Anna Evans, Amanda Gilkes, and Alan Burnett, Cardiff University School of Medicine, Cardiff, United Kingdom; John Godwin, Providence Cancer Center Group and Earle A. Chiles Research Institute, Portland, OR; Alan F. List, H. Lee Moffitt Cancer Center, Tampa, FL; and Cheryl L. Willman, University of New Mexico, Albuquerque, NM.
authors.forename: Amanda
authors.initials: A
authors.lastname: Gilkes
authors.affiliation: Fabiana Ostronoff, Megan Othus, Elihu Estey, Frederick R. Appelbaum, Kenneth J. Kopecky, Min Fang, Vivian G. Oehler, Era L. Pogosova-Agadjanyan, Jerald P. Radich, Soheil Meshinchi, and Derek L. Stirewalt, Fred Hutchinson Cancer Research Center; Fabiana Ostronoff, Elihu Estey, Frederick R. Appelbaum, Min Fang, Vivian G. Oehler, Jerald P. Radich, and Derek L. Stirewalt, University of Washington; Stephen H. Petersdorf, Seattle Genetics, Seattle, WA; Michelle Lazenby, Anna Evans, Amanda Gilkes, and Alan Burnett, Cardiff University School of Medicine, Cardiff, United Kingdom; John Godwin, Providence Cancer Center Group and Earle A. Chiles Research Institute, Portland, OR; Alan F. List, H. Lee Moffitt Cancer Center, Tampa, FL; and Cheryl L. Willman, University of New Mexico, Albuquerque, NM.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Kopecky
authors.affiliation: Fabiana Ostronoff, Megan Othus, Elihu Estey, Frederick R. Appelbaum, Kenneth J. Kopecky, Min Fang, Vivian G. Oehler, Era L. Pogosova-Agadjanyan, Jerald P. Radich, Soheil Meshinchi, and Derek L. Stirewalt, Fred Hutchinson Cancer Research Center; Fabiana Ostronoff, Elihu Estey, Frederick R. Appelbaum, Min Fang, Vivian G. Oehler, Jerald P. Radich, and Derek L. Stirewalt, University of Washington; Stephen H. Petersdorf, Seattle Genetics, Seattle, WA; Michelle Lazenby, Anna Evans, Amanda Gilkes, and Alan Burnett, Cardiff University School of Medicine, Cardiff, United Kingdom; John Godwin, Providence Cancer Center Group and Earle A. Chiles Research Institute, Portland, OR; Alan F. List, H. Lee Moffitt Cancer Center, Tampa, FL; and Cheryl L. Willman, University of New Mexico, Albuquerque, NM.
authors.forename: Alan
authors.initials: A
authors.lastname: Burnett
authors.affiliation: Fabiana Ostronoff, Megan Othus, Elihu Estey, Frederick R. Appelbaum, Kenneth J. Kopecky, Min Fang, Vivian G. Oehler, Era L. Pogosova-Agadjanyan, Jerald P. Radich, Soheil Meshinchi, and Derek L. Stirewalt, Fred Hutchinson Cancer Research Center; Fabiana Ostronoff, Elihu Estey, Frederick R. Appelbaum, Min Fang, Vivian G. Oehler, Jerald P. Radich, and Derek L. Stirewalt, University of Washington; Stephen H. Petersdorf, Seattle Genetics, Seattle, WA; Michelle Lazenby, Anna Evans, Amanda Gilkes, and Alan Burnett, Cardiff University School of Medicine, Cardiff, United Kingdom; John Godwin, Providence Cancer Center Group and Earle A. Chiles Research Institute, Portland, OR; Alan F. List, H. Lee Moffitt Cancer Center, Tampa, FL; and Cheryl L. Willman, University of New Mexico, Albuquerque, NM.
authors.forename: Alan F
authors.initials: AF
authors.lastname: List
authors.affiliation: Fabiana Ostronoff, Megan Othus, Elihu Estey, Frederick R. Appelbaum, Kenneth J. Kopecky, Min Fang, Vivian G. Oehler, Era L. Pogosova-Agadjanyan, Jerald P. Radich, Soheil Meshinchi, and Derek L. Stirewalt, Fred Hutchinson Cancer Research Center; Fabiana Ostronoff, Elihu Estey, Frederick R. Appelbaum, Min Fang, Vivian G. Oehler, Jerald P. Radich, and Derek L. Stirewalt, University of Washington; Stephen H. Petersdorf, Seattle Genetics, Seattle, WA; Michelle Lazenby, Anna Evans, Amanda Gilkes, and Alan Burnett, Cardiff University School of Medicine, Cardiff, United Kingdom; John Godwin, Providence Cancer Center Group and Earle A. Chiles Research Institute, Portland, OR; Alan F. List, H. Lee Moffitt Cancer Center, Tampa, FL; and Cheryl L. Willman, University of New Mexico, Albuquerque, NM.
authors.forename: Min
authors.initials: M
authors.lastname: Fang
authors.affiliation: Fabiana Ostronoff, Megan Othus, Elihu Estey, Frederick R. Appelbaum, Kenneth J. Kopecky, Min Fang, Vivian G. Oehler, Era L. Pogosova-Agadjanyan, Jerald P. Radich, Soheil Meshinchi, and Derek L. Stirewalt, Fred Hutchinson Cancer Research Center; Fabiana Ostronoff, Elihu Estey, Frederick R. Appelbaum, Min Fang, Vivian G. Oehler, Jerald P. Radich, and Derek L. Stirewalt, University of Washington; Stephen H. Petersdorf, Seattle Genetics, Seattle, WA; Michelle Lazenby, Anna Evans, Amanda Gilkes, and Alan Burnett, Cardiff University School of Medicine, Cardiff, United Kingdom; John Godwin, Providence Cancer Center Group and Earle A. Chiles Research Institute, Portland, OR; Alan F. List, H. Lee Moffitt Cancer Center, Tampa, FL; and Cheryl L. Willman, University of New Mexico, Albuquerque, NM.
authors.forename: Vivian G
authors.initials: VG
authors.lastname: Oehler
authors.affiliation: Fabiana Ostronoff, Megan Othus, Elihu Estey, Frederick R. Appelbaum, Kenneth J. Kopecky, Min Fang, Vivian G. Oehler, Era L. Pogosova-Agadjanyan, Jerald P. Radich, Soheil Meshinchi, and Derek L. Stirewalt, Fred Hutchinson Cancer Research Center; Fabiana Ostronoff, Elihu Estey, Frederick R. Appelbaum, Min Fang, Vivian G. Oehler, Jerald P. Radich, and Derek L. Stirewalt, University of Washington; Stephen H. Petersdorf, Seattle Genetics, Seattle, WA; Michelle Lazenby, Anna Evans, Amanda Gilkes, and Alan Burnett, Cardiff University School of Medicine, Cardiff, United Kingdom; John Godwin, Providence Cancer Center Group and Earle A. Chiles Research Institute, Portland, OR; Alan F. List, H. Lee Moffitt Cancer Center, Tampa, FL; and Cheryl L. Willman, University of New Mexico, Albuquerque, NM.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Petersdorf
authors.affiliation: Fabiana Ostronoff, Megan Othus, Elihu Estey, Frederick R. Appelbaum, Kenneth J. Kopecky, Min Fang, Vivian G. Oehler, Era L. Pogosova-Agadjanyan, Jerald P. Radich, Soheil Meshinchi, and Derek L. Stirewalt, Fred Hutchinson Cancer Research Center; Fabiana Ostronoff, Elihu Estey, Frederick R. Appelbaum, Min Fang, Vivian G. Oehler, Jerald P. Radich, and Derek L. Stirewalt, University of Washington; Stephen H. Petersdorf, Seattle Genetics, Seattle, WA; Michelle Lazenby, Anna Evans, Amanda Gilkes, and Alan Burnett, Cardiff University School of Medicine, Cardiff, United Kingdom; John Godwin, Providence Cancer Center Group and Earle A. Chiles Research Institute, Portland, OR; Alan F. List, H. Lee Moffitt Cancer Center, Tampa, FL; and Cheryl L. Willman, University of New Mexico, Albuquerque, NM.
authors.forename: Era L
authors.initials: EL
authors.lastname: Pogosova-Agadjanyan
authors.affiliation: Fabiana Ostronoff, Megan Othus, Elihu Estey, Frederick R. Appelbaum, Kenneth J. Kopecky, Min Fang, Vivian G. Oehler, Era L. Pogosova-Agadjanyan, Jerald P. Radich, Soheil Meshinchi, and Derek L. Stirewalt, Fred Hutchinson Cancer Research Center; Fabiana Ostronoff, Elihu Estey, Frederick R. Appelbaum, Min Fang, Vivian G. Oehler, Jerald P. Radich, and Derek L. Stirewalt, University of Washington; Stephen H. Petersdorf, Seattle Genetics, Seattle, WA; Michelle Lazenby, Anna Evans, Amanda Gilkes, and Alan Burnett, Cardiff University School of Medicine, Cardiff, United Kingdom; John Godwin, Providence Cancer Center Group and Earle A. Chiles Research Institute, Portland, OR; Alan F. List, H. Lee Moffitt Cancer Center, Tampa, FL; and Cheryl L. Willman, University of New Mexico, Albuquerque, NM.
authors.forename: Jerald P
authors.initials: JP
authors.lastname: Radich
authors.affiliation: Fabiana Ostronoff, Megan Othus, Elihu Estey, Frederick R. Appelbaum, Kenneth J. Kopecky, Min Fang, Vivian G. Oehler, Era L. Pogosova-Agadjanyan, Jerald P. Radich, Soheil Meshinchi, and Derek L. Stirewalt, Fred Hutchinson Cancer Research Center; Fabiana Ostronoff, Elihu Estey, Frederick R. Appelbaum, Min Fang, Vivian G. Oehler, Jerald P. Radich, and Derek L. Stirewalt, University of Washington; Stephen H. Petersdorf, Seattle Genetics, Seattle, WA; Michelle Lazenby, Anna Evans, Amanda Gilkes, and Alan Burnett, Cardiff University School of Medicine, Cardiff, United Kingdom; John Godwin, Providence Cancer Center Group and Earle A. Chiles Research Institute, Portland, OR; Alan F. List, H. Lee Moffitt Cancer Center, Tampa, FL; and Cheryl L. Willman, University of New Mexico, Albuquerque, NM.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
authors.affiliation: Fabiana Ostronoff, Megan Othus, Elihu Estey, Frederick R. Appelbaum, Kenneth J. Kopecky, Min Fang, Vivian G. Oehler, Era L. Pogosova-Agadjanyan, Jerald P. Radich, Soheil Meshinchi, and Derek L. Stirewalt, Fred Hutchinson Cancer Research Center; Fabiana Ostronoff, Elihu Estey, Frederick R. Appelbaum, Min Fang, Vivian G. Oehler, Jerald P. Radich, and Derek L. Stirewalt, University of Washington; Stephen H. Petersdorf, Seattle Genetics, Seattle, WA; Michelle Lazenby, Anna Evans, Amanda Gilkes, and Alan Burnett, Cardiff University School of Medicine, Cardiff, United Kingdom; John Godwin, Providence Cancer Center Group and Earle A. Chiles Research Institute, Portland, OR; Alan F. List, H. Lee Moffitt Cancer Center, Tampa, FL; and Cheryl L. Willman, University of New Mexico, Albuquerque, NM.
authors.forename: Soheil
authors.initials: S
authors.lastname: Meshinchi
authors.affiliation: Fabiana Ostronoff, Megan Othus, Elihu Estey, Frederick R. Appelbaum, Kenneth J. Kopecky, Min Fang, Vivian G. Oehler, Era L. Pogosova-Agadjanyan, Jerald P. Radich, Soheil Meshinchi, and Derek L. Stirewalt, Fred Hutchinson Cancer Research Center; Fabiana Ostronoff, Elihu Estey, Frederick R. Appelbaum, Min Fang, Vivian G. Oehler, Jerald P. Radich, and Derek L. Stirewalt, University of Washington; Stephen H. Petersdorf, Seattle Genetics, Seattle, WA; Michelle Lazenby, Anna Evans, Amanda Gilkes, and Alan Burnett, Cardiff University School of Medicine, Cardiff, United Kingdom; John Godwin, Providence Cancer Center Group and Earle A. Chiles Research Institute, Portland, OR; Alan F. List, H. Lee Moffitt Cancer Center, Tampa, FL; and Cheryl L. Willman, University of New Mexico, Albuquerque, NM.
authors.forename: Derek L
authors.initials: DL
authors.lastname: Stirewalt
mesh_terms: D000208:Acute Disease; D000367:Age Factors; D000368:Aged; D002986:Clinical Trials as Topic; D005260:Female; D005838:Genotype; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D011379:Prognosis; D016019:Survival Analysis; D020080:Tandem Repeat Sequences / Q000235:genetics*; D016896:Treatment Outcome; D006113:United Kingdom; D014481:United States; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3