Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples.
In acute myeloid leukemia (AML), activating mutations in the fms-like tyrosine kinase 3 (FLT3) gene predict poor prognosis. We determined FLT3 internal tandem duplications (FLT3/ITD) and D835 point mutations in paired initial and relapse samples from 80 pediatric and adult AML patients. One D835 point mutation was found in an initial pediatric AML sample. Fms-like tyrosine kinase 3/ITDs were present in 21 initial and 22 relapse samples (26.3 and 27.5%, respectively). Interestingly, FLT3/ITD positivity was related to a significantly shorter time to relapse, most pronounced when the ITD-positive status was found at relapse (P<0.001). However, FLT3/ITD status changed between diagnosis and relapse in 14 cases. In four patients, the FLT3/ITD became undetectable at relapse in five patients FLT3/ITDs were only detected at relapse, and in five patients the length or number of FLT3/ITDs changed. Gain of FLT3/ITDs may suggest oligoclonality with selective outgrowth of the FLT3/ITD-positive clone, whereas losses may reflect ITDs in the more mature leukemic cells rather than in the leukemic stem cell, or, alternatively, that other genetic aberrations provided a greater selective advantage. Studying FLT3/ITD kinetics in minimal residual disease setting may provide some answers for the changes we observed. Fms-like tyrosine kinase 3/ITD is a relevant marker for prognosis, and remains an important target for therapeutic inhibition.
Cloos
J
J
Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands. j.cloos@vumc.nl
Goemans
B F
BF
Hess
C J
CJ
van Oostveen
J W
JW
Waisfisz
Q
Q
Corthals
S
S
de Lange
D
D
Boeckx
N
N
Hählen
K
K
Reinhardt
D
D
Creutzig
U
U
Schuurhuis
G J
GJ
Zwaan
Ch M
ChM
Kaspers
G J L
GJ
D000293:Adolescent; D000328:Adult; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics; D007947:Leukemia, Megakaryoblastic, Acute / Q000235:genetics; D007948:Leukemia, Monocytic, Acute / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000453:epidemiology* / Q000235:genetics*; D015479:Leukemia, Myelomonocytic, Acute / Q000235:genetics; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics; D008297:Male; D018365:Neoplasm, Residual / Q000453:epidemiology / Q000235:genetics; D017354:Point Mutation; D011379:Prognosis; D012008:Recurrence; D012307:Risk Factors; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
D005819:Genetic Markers; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3