Sensitive measurement of quantity dynamics of FLT3 internal tandem duplication at early time points provides prognostic information.
BACKGROUND
The level of minimal residual disease (MRD) in acute myeloid leukemia (AML) at early time points (TPs) may be an important prognostic factor. Although internal tandem duplication of FLT3 (FLT3-ITD) as an MRD marker has been questioned for its instability based on semi-quantitative methods, we hypothesized that FLT3-ITD dynamics measured by sensitive quantitative real-time PCR at early TPs before appearance of instability may provide prognostic information.


METHODS
We measured mutant quantity in 493 serial samples from 55 patients with a median follow-up time of 64.8 months. The FLT3-ITD quantities after induction (TP1) and after the first post-induction chemotherapy (TP2) were analyzed.


RESULTS
We found that lower FLT3-ITD levels at TP2 predicted longer overall survival (OS) and disease-free survival (DFS) regardless of cytogenetic risk. Multivariate analysis showed that ≥3 log reduction of FLT3-ITD at TP2 independently predicted better DFS and a trend toward better OS. FLT3-ITD disappeared at relapse in 16.7% of patients and none in those harboring mutant NPM1 compared with 29.4% in those with wild-type NPM1 (P = 0.032).


CONCLUSIONS
Though the mutation may disappear at relapse in a few patients, FLT3-ITD levels at early TPs after chemotherapy provide prognostic information. FLT3-ITD is significantly more stable in those with mutant NPM1.
Chou
W-C
WC
Department of Laboratory Medicine; Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei.
Hou
H-A
HA
Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei.
Liu
C-Y
CY
Department of Nursing, Biostatistics Consulting Laboratory, National Taipei College of Nursing, Taipei.
Chen
C-Y
CY
Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei.
Lin
L-I
LI
Graduate Institute of Medical Biotechnology, College of Medicine, National Taiwan University, Taiwan.
Huang
Y-N
YN
Department of Laboratory Medicine.
Chao
Y-C
YC
Department of Laboratory Medicine.
Hsu
C-A
CA
Department of Laboratory Medicine.
Huang
C-F
CF
Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei.
Tien
H-F
HF
Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei. Electronic address: hftien@ntu.edu.tw.
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D018572:Disease-Free Survival; D005260:Female; D056726:Genetic Association Studies; D005819:Genetic Markers; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D015999:Multivariate Analysis; D016254:Mutagenesis, Insertional; D018365:Neoplasm, Residual / Q000175:diagnosis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D000090243:Nucleophosmin; D011379:Prognosis; D017422:Sequence Analysis, DNA; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
D005819:Genetic Markers; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3