ASXL1 mutations identify a high-risk subgroup of older patients with primary cytogenetically normal AML within the ELN Favorable genetic category.
The associations of mutations in the enhancer of trithorax and polycomb family gene ASXL1 with pretreatment patient characteristics, outcomes, and gene-/microRNA-expression profiles in primary cytogenetically normal acute myeloid leukemia (CN-AML) are unknown. We analyzed 423 adult patients for ASXL1 mutations, other prognostic gene mutations, and gene-/microRNA-expression profiles. ASXL1 mutations were 5 times more common in older (≥ 60 years) patients (16.2%) than those younger than 60 years (3.2%; P < .001). Among older patients, ASXL1 mutations associated with wild-type NPM1 (P < .001), absence of FLT3-internal tandem duplications (P = .002), mutated CEBPA (P = .01), and with inferior complete remission (CR) rate (P = .04), disease-free survival (DFS; P = .03), overall survival (OS; P = .006), and event-free survival (EFS; P = .002). Within the European LeukemiaNet (ELN) genetic categories of older CN-AML, ASXL1 mutations associated with inferior CR rate (P = .02), OS (P < .001), and EFS (P < .001) among ELN Favorable, but not among ELN Intermediate-I patients. Multivariable analyses confirmed associations of ASXL1 mutations with unfavorable CR rate (P = .03), DFS (P < .001), OS (P < .001), and EFS (P < .001) among ELN Favorable patients. We identified an ASXL1 mutation-associated gene-expression signature, but no microRNA-expression signature. This first study of ASXL1 mutations in primary CN-AML demonstrates that ASXL1-mutated older patients, particularly within the ELN Favorable group, have unfavorable outcomes and may be candidates for experimental treatment approaches.
Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, USA.
Klaus H
KH
Metzeler
Heiko
H
Becker
Kati
K
Maharry
Michael D
MD
Radmacher
Jessica
J
Kohlschmidt
Krzysztof
K
Mrózek
Deedra
D
Nicolet
Susan P
SP
Whitman
Yue-Zhong
YZ
Wu
Sebastian
S
Schwind
Bayard L
BL
Powell
Thomas H
TH
Carter
Meir
M
Wetzler
Joseph O
JO
Moore
Jonathan E
JE
Kolitz
Maria R
MR
Baer
Andrew J
AJ
Carroll
Richard A
RA
Larson
Michael A
MA
Caligiuri
Guido
G
Marcucci
Clara D
CD
Bloomfield
D000208:Acute Disease; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D053208:Kaplan-Meier Estimate; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D000090243:Nucleophosmin; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012097:Repressor Proteins / Q000235:genetics*; D012307:Risk Factors; D016896:Treatment Outcome
C473949:ASXL1 protein, human; D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D035683:MicroRNAs; C000716967:NPM1 protein, human; D012097:Repressor Proteins; D000090243:Nucleophosmin