Pattern And Prognostic Significance Of FLT3 Gene Mutation In Chinese Adult Patients With Hematologic Malignancies

1、The characteristics and prognosis of FLT3 gene mutations in Chinese de novo adult AML patientsObjectiveTwo distinct forms of FMS-like tyrosine kinase 3(FLT3)mutations,internal tandem duplication(ITD)in the juxtamembrane domain and point mutation within the activation loop of the tyrosine kinase domain(TKD),were frequent in patients with acute myeloid leukemia(AML).This study was aimed to analyze the impacts of these two mutations on clinical outcomes with AML patients.MethodWe have diagnosed 1101 AML patients between July 2010 and October 2015 from the First Affiliated Hospital of Soochow University.Finally,we identified 175 newly diagnosed adult AML patients with positive FLT3 mutation(excluding APL)and evaluated the clinical features and prognostic significance of these two mutations in AML patients.ResultWe found that the characteristics of FLT3-ITD positive patients were not significantly different from FLT3-TKD positive patients,including age,sex,WBC count,hemoglobin level,platelet count,bone marrow blast count and cytogenetic subtype.Patients with ITD mutation had a higher probability of carrying another somatic mutations and occurring disease recurrence than patients with TKD mutation(p=0.050,P<0.001).Furthermore,AML patients with TKD mutation have more favorable overall survival(OS,p=0.064)and relapse-free survival(RFS,p=0.002)than those with ITD mutation.Based on the analysis,FLT3-TKD positive patients still had longer OS and RFS than FLT3-ITD positive patients,no matter for the allo-HSCT therapy subgroup or for the non-allo-HSCT therapy subgroup.We also found that allo-HSCT therapy subgroup achieved longer OS than non-allo-HSCT therapy subgroup for FLT3-ITD positive patients(p<0.001),but not showed in RFS(p=0.185).However,allo-HSCT could not prolonged the OS and RFS for FLT3-TKD positive patients(p=0.188,p=0.77).Meanwhile,ITD positive patients with a high-risk chromosomal abnormalities and DNMT3A gene mutation had a shorter overall survival(P=0.006,P=0.051),and higher risk of disease recurrence(P=0.037,P=0.089).ConclusionFLT3-ITD positive AML patients have a poor prognosis and a higher risk of disease recurrence.FLT3-TKD-mutated AML patients have more favorable clinical outcomes than those with FLT3-ITD mutation.Allo-HSCT therapy subgroup achieved longer OS and RFS than non-allo-HSCT therapy subgroup for FLT3-ITD positive patients.ITD positive patients with high-risk chromosomal abnormalities and DNMT3A gene mutation have a poor prognosis.2、The characteristics of FLT3 gene mutations in Chinese de novo adult ALL patientsObjectiveActivating mutations in FLT3 are frequent in acute myeloid leukemia(AML,about 30%)and have an unfavorable impact on the prognosis of patients with AML.Meanwhile,FLT3 aberrations have been detected in a smaller fraction of acute lymphoblastic leukemia(ALL),and their prognostic value are not well established.Here,we assessed the clinical features and prognosis of FLT3 mutations in ALL patients.MethodWe have examined a cohort of 117 Chinese de novo adult ALL patients enrolled between June 2016 and June 2017 from the First Affiliated Hospital of Soochow University.Of the 117 patients,we detected activating FLT3 gene mutation and evaluate the clinical features and prognostic significance of FLT3 mutations in ALL patients.ResultFLT3 mutations accounted for 6.8%(8/117)in our ALL cohort.Compared with B-line ALL,FLT3 gene mutation was more common in T-line ALL(P=0.049),and occurred more often in early T precursors(ETP)-ALL(P=0.028).FLT3 mutation did not show an obvious unfavorable effect for ALL patients on both overall survival(OS,P=0.338)and relapse free survival(RFS,P=0.726).However,the age of onset(P=0.004),initial platelet counts(P=0.018)and transplant status(P-0.007)were significantly associated with OS for ALL cases.In T-ALL,expression of CD117 were more likely to have FLT3 mutations than those with negative(P=0.053).CD117 expression could be used as a surrogate for FLT3 mutation,with a sensitivity of 50%and specificity of 93%.ConclusionFLT3 mutation was not common in adult ALL from China,and it is frequent in patients with T-ALL.FLT3 mutation has no significant effect on overall survival(OS)and relapse-free survival(RFS)in ALL patients.While age of onset,platelet counts and transplant status was independent prognostic factors for ALL cases.In spite of small sample size,ETP-ALL and CD117+T-ALL may indicate a comparable higher FLT3-mutant rate.3、The role of FLT3-ITD mutation on de novo adult myelodysplastic syndromes in Chinese populationObjectiveFLT3 gene mutation has a higher incidence in acute myeloid leukemia(AML)patients,and the occurrence of FLT3 mutation often indicate poor prognosis,especially FLT3-ITD mutation.However,it was not fully analyzed in other hematologic malignancies,such as myelodysplastic syndromes(MDS).In our study,the aim was to analyse the clinical features and prognostic significance of FLT3-ITD mutations in adult MDS patients.MethodBetween 2010 and 2016,304 de novo adult MDS patients had FLT3 sequence tested on their bone marrow sample.With 279 patients who had follow up information,we also analyzed the impact of clinical and laboratory characteristics as well as FLT3-ITD mutation status and treatment on prognosis.ResultWe found that the transformation rate with FLT3-ITD positive group was higher than that negative patients(P=0.033).The median progression-free survival(PFS)of FLT3-ITD mutated and wild type group were 43 days and 363.5 days,respectively(P<0.001).The median overall survival(OS)of the two groups were 218 days and 410.5 days(P<0.001).We also found that five factors had independent prognostic impact on OS,WBC counts(P=0.017),bone marrow blast percentage(P=0.003),cytogenetics(P<0.001),transplantation status(P=0.007)and FLT3-ITD mutation(P=0.004).Furthermore,compared with transformation group,the non-progression group was younger(P=0.034),possessing a lower platelet count(P=0.022),lower bone marrow blast percentage(P=0.001),lower FLT3-ITD incidence(P=0.007)and longer OS(P<0.001).ConclusionWhen observed at MDS stage,patients harboring FLT3-ITD mutations had higher AML-transformation rate,quicker disease progression and shorter survival than wild type patients.Nevertheless,once MDS progressed to leukemia,the impact of FLT3-ITD mutations on the overall survival was little.Besides,the prognosis of secondary AML was very poor whether there was ITD mutation or not.