Alterations Of FLT3 Gene In Acute Lymphoblastic Leukemia:Characteristics And Outcome

BackgroundFms-like tyrosine kinase 3(FLT3)is a class Ⅲ tyrosine kinase receptor expressed on the surface of normal hematopoietic progenitors and blast cells from most cases of acute myeloid leukemia(AML).FLT3/ITDs occur in approximately 25%of cases of AML in younger adults and predict for increased relapse and reduced survival.In contrast,it’s marginally addressed about the incidence,characteristics and outcome of FLT3 gene alterations in acute lymphoblastic leukemia(ALL).MethodsCollect cases of adults with acute lymphoblastic leukemia(ALL)diagnosed at the Nanfang Hospital from January 2017 to November 2019,gather their bone marrow specimens or blood smears both at diagnosis and relapse to extract DNA,and then detect 18 genes alterations including FLT3 by next-generation sequencing(NGS),and IKZF1 deletion by GAP-PCR in order to briefly determine the incidence,distribution and characteristics of FLT3 gene mutation in adult ALL in China and co-mutation between FLT3 and IKZF1.Select cases of B-ALL regularly treated and retrospectively analyze the clinical feature and prognosis in B-ALL patients with FLT3 mutations.At last,determine the dynamics of FLT3 mutations in paired presentation and relapse sample to ascertain the biology of clonal revolution.Result(1)In this study,a total of 224 cases of adults with acute lymphoblastic leukemia were collected.After diagnostic screening for FLT3 gene mutations by NGS FLT3 alterations were identified in 7.1%(16/224)of these patients,including 1(1/46,2.2%)TALL and 15(15/178,8.4%)B-ALL.Five forms of FLT3 gene mutations were recognized,including internal tandem duplication(ITD),tyrosine kinase domain(TKD),juxtamembrane insertion and deletion(JM-INDEL),juxtamembrane point mutation(JM-PM)and ectodomain point mutation(EC-PM),which were respectively identified in 1.79%、2.23%、0.45%、0.45%and 1.34%of first-diagnosed patients.Three of these mutations—D586_V592del(JM-INDEL),T475P(EC-PM)and W495R(EC-PM)-were first reported and predicted to be deleterious by tools on the impact in protein function.(2)A total of 173 cases of adults B-ALL under regular treatment were collected.There were no significant differences observed in flow-MRD-negative rate during and after induction therapy between these two groups.FLT3-mut was association with increased cumulative incidence of relapse(CIR,77.7%vs 32.2%,P=0.118),reduced event-free survival(EFS,40.5%vs 62,3%,P=0.119)and oral survival(OS,76.4%vs 86.2%,P=0.307).Even except the cases of Philadelphia chromosome positive ALL,the outcome of Log-Rank text showed the same.Notably,IKZF1 gene deletion in FLT3-mut was identified much more than in FLT3-wt group.Furthermore,there was only a mild tendency toward EFS and CIR in patients with one mutation,FLT3 mutation or IKZF1 deletion,but co-mutation of these two mutations showed the worse outcome in comparison to wide type(EFS P=0.019,CIR P=0.005).(3)26 primary tumor-relapse pairs of B-ALL were collected totally,Dynamics of FLT3 mutations presented in 15.4%(4/26)of these patients.(4)The incidence of FLT3 mutations in relapsed B-ALL patients was higher than that at diagnosis(23.1%vs 8.4%,P=0.034).Remarkably,FLT3 gene alterations occurred in 37.5%(3/8)of relapsing patients after allo-HSCT,which did not present at diagnosis.ConclusionCollectively,our data demonstrated FLT3 mutation is rare in ALL at diagnosis but frequent at relapse,and varies in mutation types.FLT3-mut B-ALL is associated with increased relapse and reduced survival,especially when co-mutation with IKZF1 deletion.The clonal revolution of FLT3 mutation is an important characteristic in BALL.