Clinical Characteristics Of Acute Myeloid Leukemia With FLT3 Mutation(non-M3 Type) And The Effect Of Concomitant Mutation On Prognosis

BackgroundAcute myeloid leukemia(AML)is a genetically heterogeneous disease with different genetic and molecular mechanisms of alteration resulting in differences in clinical features,pathogenesis,treatment outcomes and prognosis.FMS-like tyrosine kinase 3(FLT3)mutations are one of the most common genetic abnormalities in AML and can be detected in 25%-30%of new-onset patients.Previous studies have demonstrated that FLT3 mutations are associated with poor prognosis in AML patients and are valuable as a guide for selecting treatment options and assessing prognosis.However,the prognosis of FLT3 mutation in AML patients is not completely consistent,because these patients often have other kinds of genetic abnormalities,and these concomitant genes also play an important role in the characteristics of the disease.Therefore,it is necessary to further study the clinical characteristics of FLT3 mutation-positive AML patients and the influence of co-existing gene mutations on the therapeutic effect and prognosis of the disease,so as to provide a basis for accurate clinical treatment.ObjectiveTo detect gene mutations and gene fusions in primary AML patients,to analyze the clinical characteristics of FLT3 mutation patients,to observe the distribution of concomitant mutation genes in FLT3 mutation-positive patients,and to analyze the impact of different concomitant mutations on treatment outcome and prognosis,with a view to developing a more refined risk stratification system for clinical purposes.Methods1.Participants:109 newly diagnosed AML patients admitted to Zhongshan People’s Hospital from August 2017 to March 2020.All patients were diagnosed according to WHO(2016)hematopoietic and lymphoid tissue tumor classification and Chinese guidelines for diagnosis and treatment of Adult Acute Myeloid Leukemia(non-Acute Promyelocytic Leukemia)(2017 Edition).There were 34 patients with positive FLT3mutation and 75 patients with negative FLT3 mutation.2.Method:The medical records of enrolled AML patients were collected,bone marrow specimens from enrolled patients were collected by bone marrow aspiration,and 30 of common genetic mutations to AML were detected using generation sequencing,25 fusion genes were detected using real-time quantitative RT-PCR,and karyotype analysis was performed by applying the 24-h culture method and R revealed banding technique to analyze mid-division cells.To analyze the clinical characteristics of FLT3 mutation-positive patients,the distribution of concomitant mutation genes,and the effects of concomitant gene mutations on treatment effect and prognosis.3.Statistical Analysis:SPSS 20.0 statistical software was applied to analyze the data.T-test was used for measurement data conforming to normal distribution,and rank sum test was used for measurement data without conforming to normal distribution;counting data was analyzed by chi-square test or Fisher’s exact probability method;Kaplan-Meier method was used for survival analysis.p<0.05 indicated that the difference was statistically significant.Results1.Clinical characteristics of patients with positive FLT3 mutation:1.1 Clinical manifestations:Compared with FLT3 mutation-negative patients,the patients with positive FLT3 mutation were significantly older(55 vs 46 years,P<0.05),and the number of white blood cells and platelets were significantly higher(34.47×10~9/L vs 11.48×10~9/L,60×10~9/L vs 41×10~9/L,P<0.05).1.2 Characteristics of genetics:32.4%of FLT3 mutation-positive patients were accompanied with abnormal chromosome karyotype,which was not different from that of FLT3 mutation negative patients.The positive rate of fusion gene in FLT3 mutation-positive patients was significantly lower than that in FLT3 mutation-negative patients(11.8%vs 38.7%,P<0.05).Compared with FLT3 mutation-negative patients,FLT3mutation-positive patients were more likely to have NPM1 mutations or DNMT3A mutations(44.1%vs 8%,41.2%vs 14.7%,P<0.05).1.3 Characteristics of therapeutic effect and prognosis:The rate of complete response(CR)at one course and two courses in the FLT3 mutation-positive group was significantly lower than that in the FLT3 mutation-negative group(44.1%vs 66.7%,58.8%vs 77.3%,P<0.05),and the one-year OS rate was slightly lower in the FLT3mutation-positive patients than in FLT3 mutation-negative patients(66.7%vs 83.6%,P>0.05).2.Distribution of concomitant gene mutations in FLT3 mutation positive patients:88.2%of patients with FLT3 mutations were accompanied with other types of mutations.Among them,the highest positive rate was NPM1 mutation,accounting for44.1%,followed by DNMT3A mutation,accounting for 41.2%.3.Effect of NPM1 gene on therapeutic effect and prognosis of AML patients with FLT3 mutation:44.1%of patients with FLT3 mutations were also combined with NPM1 mutations.The one-course CR rate in the FLT3~+/NPM1~+group was not significantly different from that in FLT3 mutation-negative patients,but was significantly higher than that in FLT3~+/NPM1~-patients(73.3%vs 66.7%vs 21.1%,P<0.05).The CR rate of two courses in the FLT3~+/NPM1~+group was also significantly higher than that in the FLT3~+/NPM1~-group(80%vs 42.1%,P<0.05).Compared with FLT3~+/NPM1~-group and FLT3 mutation-negative group,the one-year OS rate of FLT3~+/NPM1~+group was higher(P>0.05)and the survival time was significantly longer(P<0.05).4.Effect of DNMT3A gene on therapeutic effect and prognosis of AML patients withFLT3 mutation:41.2%of FLT3 mutation-positive patients also had DNMT3A gene mutation.There was no significant difference in one-course CR rate and two-course CR rate among FLT3~+/DNMT3A~+group,FLT3~+/DNMT3A~-group and FLT3 mutation negative group(P>0.05).Follow-up after two courses of chemotherapy showed that compared with FLT3 mutation negative group and FLT3~+/DNMT3A~-group,the one-year OS rate of FLT3~+/DNMT3A~+group was significantly lower(P=0.044)and the overall survival time was significantly shorter(P<0.05).ConclusionAML patients with FLT3 mutations often have co-mutations of other types of genes,among which NPM1 and DNMT3A mutations are the most common.Different concomitant mutations will have a certain impact on the prognosis of patients,and more detailed risk stratification should be conducted for FLT3-mutation-positive AML patients according to different concomitant mutations.