FLT3 internal tandem duplication associates with adverse outcome and gene- and microRNA-expression signatures in patients 60 years of age or older with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study.
The clinical impact of FLT3-internal tandem duplications (ITDs), an adverse prognostic marker in adults aged < 60 years with primary cytogenetically normal acute myeloid leukemia (CN-AML), requires further investigation in older patients. In CN-AML patients aged ≥ 60 years treated on Cancer and Leukemia Group B frontline trials, we found that FLT3-ITD remained associated with shorter disease-free survival (P < .001; hazard ratio = 2.10) and overall survival (P < .001; hazard ratio = 1.97) in multivariable analyses. This impact on shorter disease-free survival and overall survival was in patients aged 60-69 (P < .001, each) rather than in those aged ≥ 70 years. An FLT3-ITD-associated gene-expression signature revealed overexpression of FLT3, homeobox genes (MEIS1, PBX3, HOXB3), and immunotherapeutic tar-gets (WT1, CD33) and underexpression of leukemia-associated (MLLT3, TAL1) and erythropoiesis-associated (GATA3, EPOR, ANK1, HEMGN) genes. An FLT3-ITD-associated microRNA-expression signature included overexpressed miR-155 and underexpressed miR-144 and miR-451. FLT3-ITD identifies older CN-AML patients with molecular high risk and is associated with gene- and microRNA-expression signatures that provide biologic insights for novel therapeutic approaches.
Whitman
Susan P
SP
The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
Maharry
Kati
K
Radmacher
Michael D
MD
Becker
Heiko
H
Mrózek
Krzysztof
K
Margeson
Dean
D
Holland
Kelsi B
KB
Wu
Yue-Zhong
YZ
Schwind
Sebastian
S
Metzeler
Klaus H
KH
Wen
Jing
J
Baer
Maria R
MR
Powell
Bayard L
BL
Carter
Thomas H
TH
Kolitz
Jonathan E
JE
Wetzler
Meir
M
Moore
Joseph O
JO
Stone
Richard M
RM
Carroll
Andrew J
AJ
Larson
Richard A
RA
Caligiuri
Michael A
MA
Marcucci
Guido
G
Bloomfield
Clara D
CD
D000367:Age Factors; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003582:Cytogenetics; D005260:Female; D020440:Gene Duplication; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D011379:Prognosis; D016019:Survival Analysis; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
D035683:MicroRNAs; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3