| Background Acute myeloid leukemia is a highly heterogeneous and malignant clonal disease of the hematopoietic system. The diagnosis of AML depends on the findings of morphology, immunology, cytogenetics and molecular. The comprehensive and complete laboratory data will be helpful in assessing the prognosis and providing guidance to the therapy of AML patients. With the intensive researches on the characteristics of molecular biology, the researchers revealed that AML patients are highly heterogeneous on the genetic level, and a series of abnormal gene expressions and mutations related to the prognosis of AML were found. Fms like tyrosine kinase 3(FLT3) gene, one of the family members of type Ⅲ receptor of tyrosine kinase which predicts poor prognosis of AML, is one of the most common genes that was found recent years. The mutations of FLT3 gene play an important role in the development and prognosis of AML. Internal tandem duplication of FLT3(FLT3-ITD) is the main form of FLT3 gene mutation, with an incidence of 13%~31% in AML cases. The FLT3-ITD mutated AML patients usually experience high WBC counts and bone marrow blasts, low remission rate, high relapse rate and short overall survival time.Objective To analyze the incidence of FLT3-ITD mutation in AML cases and the correlations with clinical and laboratory characteristics, treatment response and prognosis assessment in AML patients with FLT3-ITD mutation.Materials and methods Collect the clinical and laboratory data of 347 AML patients who were newly-diagnosed in the First Affiliated Hospital of Zhengzhou University from October 2012 to December 2014. According to the detection result of FLT3-ITD mutation, cases were divided into FLT3-ITDm+AML group and FLT3-ITDm-AML group. The FLT3-ITD mutation was detected by PCR and DNA sequencing method. Bone marrow were stained by GIEMSA and histo-chemistry staining, and the morphology of bone marrow cells and the blasts counts were observed under a microscope. Flow Cytometry was applied to detect the immunophenotypic characteristics of leukemia cells, and the number of positive cells and antigen positive rate were analyzed by a software, respectively. Bone marrow cells were cultured for 24 hours and G banding technique was used to analyze the chromosome karyotype. According to the karyotype performance, patients were classified into better-risk, intermediate-risk and poor-risk groups. All cases were diagnosed according to the FAB and WHO criteria, then received induction therpy and post-remission therapy. Patients were followed up until January 31, 2015 or the date of death. The event-free survival rate and overall survival rate were analyzed by SPSS software.Results 1. The clinical characteristics of FLT3-ITDm+AML: The incidence of FLT3-ITD mutation in AML patients was 17.3 percent. No significant difference was found in sex or age between 60 FLT3-ITDm+AML cases and 287 cases with FLT3-ITDm-AML. Compared with FLT3-ITDm-AML patients, FLT3-ITDm+AML patients had a higher WBC counts and bone marrow blasts(P<0.05).2. The immunophenotypic features of FLT3-ITDm+AML: In a series of 22 antigens observed, 9 antigens were significant different between the two groups: the positive cell numbers of CD33, CD11 b, CD4 and CD7 were higher,while CD16, CD15, CD56, CD117 and CD34 were lower in FLT3-ITDm+AML(P<0.05). 7 antigens were significant different between the two groups: the positive rate of CD33, CD4 and CD7 were higher, while CD16, CD15, CD117 and CD34 were lower in FLT3-ITDm+AML(P<0.05).3. The subtype distribution of FLT3-ITDm+AML: According to the FAB classification, there were 22(36.7%) cases of AML-M2 and 31(51.7%) cases of AML-M5 in FLT3-ITDm+AML group, and there were 163(56.8%) cases of AML-M2 and 76(26.5%) cases of AML-M5 in FLT3-ITDm-AML group. AML-M5 accounted for a higher proportion than other subtypes in FLT3-ITDm+AML.4. The cytogenetic characteristics of FLT3-ITDm+AML: 73.1 percent of FLT3-ITDm+AML patients were carrying a normal karyotype. FLT3-ITDm+AML had a lower percentage in better-risk karyotype group than FLT3-ITDm-AML had(7.7% vs 20.3%; χ2=4.163, P=0.041). +5. The treatment response: The CR rate in FLT3-ITDm+AML was significantly lower than in FLT3-ITDm-AML after the first cycle of induction therapy(39.6% vs 69.6%; χ2=17.132, P=0.000). The median follow-up time of FLT3-ITDm+AML and FLT3-ITDm-AML patients were 5.6(0.07~25.1) months and 7.3(0.03~28.4) months, respectively. For FLT3-ITDm+AML patients, the 1 year EFS rate(33.1% vs 66.4%; Z=-3.021, P=0.001) and 1 year OS rate(41.8% vs 70.6%; Z=-2.876, P=0.002) were significantly lower than these in FLT3-ITDm-AML patients.6. The correlation of FLT3-ITD mutation with NPM1 mutation: FLT3-ITDm+AML had a significant higher chance in the co-occurrence of NPM1 mutation than FLT3-ITDm-AML(44.6% vs 14.8%; χ2=24.826, P=0.000). Compared with FLT3-ITDm+/NPM1m-AML, FLT3-ITDm+/NPM1m+AML were significantly older and with more cases of older than 60 years old(P<0.05). The median follow-up time of FLT3-ITDm+/NPM1m+AML and FLT3-ITDm+/NPM1m-AML were 4.7(0.07~22.1) months and 6.1(1.3~25.1) months, respectively. No significant differences were found in the 1 year EFS rate(36.7% vs 27.3%; Z=-1.233, P=0.109)and 1 year OS rate(38.9% vs 42.7%; Z =-0.923, P=0.176) between the two groups.Conclusion 1. FLT3-ITDm+AML patients are associated with higher WBC counts and bone marrow blasts, characteristic aberrant surface antigens expression in the leukemia cells, and lower induced CR rate and 1 year OS rate, indicate that FLT3-ITD mutation is an adverse prognostic factor in AML.2. FLT3-ITD mutation is more common in AML with normal karyotype, and has a higher incidence in AML-M5.3. FLT3-ITDm+AML has a higher chance in the co-occurrence of NPM1 mutation. FLT3-ITDm+/NPM1m+AML patients are older and with more elderly cases, the long-term prognosis of them requires further observation. |
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