Favorable prognostic impact of NPM1 mutations in older patients with cytogenetically normal de novo acute myeloid leukemia and associated gene- and microRNA-expression signatures: a Cancer and Leukemia Group B study.
OBJECTIVE
To analyze the prognostic significance of NPM1 mutations, and the associated gene- and microRNA-expression signatures in older patients with de novo, cytogenetically normal acute myeloid leukemia (CN-AML) treated with intensive chemotherapy.


METHODS
One hundred forty-eight adults age >or= 60 years with de novo CN-AML, enrolled onto Cancer and Leukemia Group B protocols 9720 and 10201, were studied at diagnosis for NPM1, FLT3, CEBPA, and WT1 mutations, and gene- and microRNA-expression profiles.


RESULTS
Patients with NPM1 mutations (56%) had higher complete remission (CR) rates (84% v 48%; P < .001) and longer disease-free survival (DFS; P = .047; 3-year rates, 23% v 10%) and overall survival (OS; P < .001; 3-year rates, 35% v 8%) than NPM1 wild-type patients. In multivariable analyses, NPM1 mutations remained independent predictors for higher CR rates (P < .001) and longer DFS (P = .004) and OS (P < .001), after adjustment for other prognostic clinical and molecular variables. Unexpectedly, the prognostic impact of NPM1 mutations was mainly observed in patients >or= 70 years. Gene- and microRNA-expression profiles associated with NPM1 mutations were similar across older patient age groups and similar to those in younger (< 60 years) patients with CN-AML. These profiles were characterized by upregulation of HOX genes and their embedded microRNAs and downregulation of the prognostically adverse MN1, BAALC, and ERG genes.


CONCLUSIONS
NPM1 mutations have favorable prognostic impact in older patients with CN-AML, especially those age >or= 70 years. The gene- and microRNA-expression profiles suggest that NPM1 mutations constitute a marker defining a biologically homogeneous entity in CN-AML that might be treated with specific and/or targeted therapies across age groups.
Becker
Heiko
H
Division of Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
Marcucci
Guido
G
Maharry
Kati
K
Radmacher
Michael D
MD
Mrózek
Krzysztof
K
Margeson
Dean
D
Whitman
Susan P
SP
Wu
Yue-Zhong
YZ
Schwind
Sebastian
S
Paschka
Peter
P
Powell
Bayard L
BL
Carter
Thomas H
TH
Kolitz
Jonathan E
JE
Wetzler
Meir
M
Carroll
Andrew J
AJ
Baer
Maria R
MR
Caligiuri
Michael A
MA
Larson
Richard A
RA
Bloomfield
Clara D
CD
D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D008297:Male; D035683:MicroRNAs / Q000502:physiology*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012074:Remission Induction; D015996:Survival Rate; D016896:Treatment Outcome; D025721:WT1 Proteins / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
D014408:Biomarkers, Tumor; D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D035683:MicroRNAs; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D025721:WT1 Proteins; D000090243:Nucleophosmin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3