Internal tandem duplication of fms-like tyrosine kinase 3 is associated with poor outcome in patients with myelodysplastic syndrome.
BACKGROUND
The prognostic significance of internal tandem duplication (ITD) of the fms-like tyrosine kinase 3 gene (FLT3) for patients with myelodysplastic syndrome (MDS) is not clearly defined. In the current study, the authors sought to assess the value of FLT3/ITD mutation status as a prognostic genetic marker for patients with MDS.


METHODS
FLT3/ITD mutation status was evaluated by performing DNA polymerase chain reaction assays on 198 bone marrow samples obtained from patients with MDS at initial diagnosis. All aberrant products were sequenced, and GeneScan analysis was performed to measure FLT3/ITD mutant levels.


RESULTS
Five patients (2.5%)--2 of the 99 patients who had refractory anemia with excess blasts and 3 of the 51 patients who had chronic myelomonocytic leukemia--had FLT3/ITD mutations. FLT3/ITD was not observed in any of the 48 patients who had refractory anemia (with or without ringed sideroblasts). There was no significant difference in clinicohematologic characteristics, cytogenetic characteristics, or International Prognostic Scoring System score between the FLT3/ITD-positive group and the FLT3/ITD-negative group. Four of the 5 patients carrying the FLT3/ITD mutation experienced progression of disease to acute myeloid leukemia (AML), compared with 70 of the 193 patients who did not have FLT3/ITD (P = 0.066). In addition, progression to AML was more rapid in patients with FLT3/ITD-positive disease than in patients with FLT3/ITD-negative disease (mean +/- standard error, 3.0 +/- 0.5 months vs. 62.8 +/- 5.6 months; P < 0.0001). Patients with FLT3/ITD-positive disease also had significantly shorter survival compared with patients who had FLT3/ITD-negative disease (mean +/- standard error, 5.2 +/- 1.4 months vs. 33.7 +/- 3.1 months; P < 0.0001). On multivariate analysis, FLT3/ITD was identified as an independent predictor of reduced time to development of AML (P = 0.0001) and reduced overall survival (P = 0.002).


CONCLUSIONS
The results of the current study demonstrate that FLT3/ITD is associated with a high risk of transformation to AML, rapid progression of AML, and poor survival in patients with MDS.
Shih
Lee-Yung
LY
Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan. sly7012@adm.cgmh.org.tw
Lin
Tung-Liang
TL
Wang
Po-Nan
PN
Wu
Jin-Hou
JH
Dunn
Po
P
Kuo
Ming-Chung
MC
Huang
Chein-Fuang
CF
D000328:Adult; D000368:Aged; D001853:Bone Marrow / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D018450:Disease Progression; D005260:Female; D020440:Gene Duplication; D006801:Humans; D015479:Leukemia, Myelomonocytic, Acute / Q000175:diagnosis / Q000235:genetics*; D015477:Leukemia, Myelomonocytic, Chronic / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000235:genetics*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics; D012307:Risk Factors; D015996:Survival Rate; D020080:Tandem Repeat Sequences; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3
D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3