Wilms' tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study.
OBJECTIVE
To analyze the prognostic impact of Wilms' tumor 1 (WT1) gene mutations in cytogenetically normal acute myeloid leukemia (CN-AML). PATIENTS AND METHODS We studied 196 adults younger than 60 years with newly diagnosed primary CN-AML, who were treated similarly on Cancer and Leukemia Group B (CALGB) protocols 9621 and 19808, for WT1 mutations in exons 7 and 9. The patients also were assessed for the presence of FLT3 internal tandem duplications (FLT3-ITD), FLT3 tyrosine kinase domain mutations (FLT3-TKD), MLL partial tandem duplications (MLL-PTD), NPM1 and CEBPA mutations, and for the expression levels of ERG and BAALC.


RESULTS
Twenty-one patients (10.7%) harbored WT1 mutations. Complete remission rates were not significantly different between patients with WT1 mutations and those with unmutated WT1 (P = .36; 76% v 84%). Patients with WT1 mutations had worse disease-free survival (DFS; P < .001; 3-year rates, 13% v 50%) and overall survival (OS; P < .001; 3-year rates, 10% v 56%) than patients with unmutated WT1. In multivariable analyses, WT1 mutations independently predicted worse DFS (P = .009; hazard ratio [HR] = 2.7) when controlling for CEBPA mutational status, ERG expression level, and FLT3-ITD/NPM1 molecular-risk group (ie, FLT3-ITD(negative)/NPM1(mutated) as low risk v FLT3-ITD(positive) and/or NPM1(wild-type) as high risk). WT1 mutations also independently predicted worse OS (P < .001; HR = 3.2) when controlling for CEBPA mutational status, FLT3-ITD/NPM1 molecular-risk group, and white blood cell count.


CONCLUSIONS
We report the first evidence that WT1 mutations independently predict extremely poor outcome in intensively treated, younger patients with CN-AML. Future trials should include testing for WT1 mutations as part of molecularly based risk assessment and risk-adapted treatment stratification of patients with CN-AML.
Paschka
Peter
P
Division of Hematology and Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
Marcucci
Guido
G
Ruppert
Amy S
AS
Whitman
Susan P
SP
Mrózek
Krzysztof
K
Maharry
Kati
K
Langer
Christian
C
Baldus
Claudia D
CD
Zhao
Weiqiang
W
Powell
Bayard L
BL
Baer
Maria R
MR
Carroll
Andrew J
AJ
Caligiuri
Michael A
MA
Kolitz
Jonathan E
JE
Larson
Richard A
RA
Bloomfield
Clara D
CD
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis; D002066:Busulfan / Q000008:administration & dosage; D003561:Cytarabine / Q000008:administration & dosage; D003630:Daunorubicin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D016162:Genes, Wilms Tumor; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D000090243:Nucleophosmin; D011379:Prognosis; D016016:Proportional Hazards Models; D018709:Statistics, Nonparametric; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
D014408:Biomarkers, Tumor; C000716967:NPM1 protein, human; D003561:Cytarabine; D000090243:Nucleophosmin; D005047:Etoposide; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D002066:Busulfan; D003630:Daunorubicin