| The FMS-like tyrosine kinase-3(FLT3) is a member of the receptor tyrosine kinase superfamily, specifically the type III family[1]. FLT3 is expressed in hematopoietic stem and progenitor cells, where it functions in cell differentiation, proliferation and survival. FLT3 expression is normally limited to CD34+ stem cells and progenitor cells in human bone marrow. Upon interaction with various cytoplasmic proteins, FLT3 regulates cell proliferation and differentiation via intracellular signal transduction[1]. In recent years, many studies on larger populations confirmed that the activating mutations of FLT3 play a vital role in the occurrence and progression of acute myeloid leukemia(AML); of the known mutations, the FLT3 internal tandem duplications(FLT3-ITD) have a high correlation with the occurrence, development and poor prognosis of AML[2,3]. Therefore, studying FLT3-ITD could provide new approaches for the future clinical treatment of refractory AML.FLT3-ITD+ AML usually have unique clinical features of high peripheral white blood cells and bone marrow blast count, poor prognosis and high relapse rate, which as an independent prognostic factor has been recognized by the majority of clinicians. At present, chemotherapy, targeted therapy and hematopoietic cell transplantation are the 3 primary therapeutic methods available to acute myeloid leukemia patients. Although allo-HSCT is more effective than standard chemotherapy in AML, it still remains controversial whether allogeneic transplantation can improved the outcomes in FLT3-ITD+ AML. Many researches reported that allogeneic transplantation early in the first complete remission(CR1) can improve the long-term outcomes for FLT3-ITD+ AML[4-7]. However, other investigators argued that there was insufficient evidence supporting this approach, and they concluded that the poor prognosis remained even after early allo-HSCT in patients with FLT3-ITD+ AML[8-11]. Exploring the new treatment methods of FLT3-ITD+ AML have became the focus of clinical researchers in recent years. Based on the above mentioned, we applied summary of clinical data, Meta analysis and experimental drug intervention to explore the effective clinical treatment for FLT3-ITD+ AML.Method:1. Observed the distribution of FLT3-ITD and the overlap of FLT3-ITD and WT1 or NPM1 or other mutations in 67 cases of FLT3-ITD+ AML in Chongqing with multiple center, then summarized the and their clinical features, curative effect and the effection of allo-HSCT for prognosis.2. Collected the published clinical case-control study data for meta-analysis, to evaluate the effect of allo-HSCT for FLT3-ITD+ AML.3. Arsenic trioxide(As2O3) intervention in human leukemia MV4-11 cells(FLT3-ITD mutation positive cells) in vitro, to observe the changes of cell proliferation, cell cycle, apoptosis and mRNA expressing of FLT3-ITD.Main results:1. In FLT3-ITD+ AML, the most common immunophenotype is M5, accounting for about 36%, followed by M2,accounting for about 28%. In inducer remission treatment, this group has longer time to get CR, and only 27.5% of those patients reached CR in first times of chemotherapy, and 46.3% patients combined with other mutations. Allogeneic transplantation early in the first complete remission(CR1) can improve the long-term outcomes, to the patients who have no suitable donor, can consider for autologous stem cell transplantation. But transplantation related mortality and higher risk of relapse after transplantation is still an important factor for the prognosis of FLT3-ITD+ AML.2. Meta-analysis showed that compared with chemotherapy, both allo-HSCT and autologous hematopoietic cell transplantation(auto-HSCT) can reduce the relapse rate(RR, P<0. 01), and improve both the overall survival(OS, P<0.01)and disease free survival(DFS, P<0.01). But when compared allo-HSCT with auto-HSCT, no significance was found in OS(P=0.27) and DFS(P=0.19), only the relapse indicator has significant difference, P<0.01. Allogeneic transplantation early in the first complete remission(CR1) can improve the long-term outcomes for FLT3-ITD+ AML. The FLT3 mutation allelic ratio has an important effect on the prognosis.3. The optimal reaction time of As2O3 effect on human leukemia MV4-11 cells’ proliferation was 48 H, the IC50 was 0.9829 umol/L(95%C:0.9124-1.059umol/L). And with the increase of drug concentration and time, the survival rate of MV4-11 cells decreased gradually(P<0.01). The cell apoptosis increased(P<0.05) and FLT3-ITD mRNA expression decreased simultaneously(P<0.01).Main conclusion:FLT3-ITD was frequently found in cytogenetically normal acute myeloid leukemia(AML), most of FLT3-ITD+ AML have the clinical features of high peripheral white blood cells and bone marrow blast count, poor prognosis and high relapse rate, and lots of those patients combined with other mutations. Allogeneic transplantation after CR1 can effectively improve the poor prognosis of FLT3-ITD+ AML; to the patients who have no suitable donor, can consider for autologous stem cell transplantation; As2O3 can obviouly inhibit proliferation and promote apoptosis in MV4-11 cells, which may be closely related to the downregulation of PI3K/AKT signal pathway. |
PDF Full Text Request