The Clinical Research Of Acute Myloid Leukemia Patients With FLT3-ITD Mutation

Part I The clinical characteristics and molecular genetics profile of373acute myloid leukemia patientsObjective: To analyze the genetic profile of FLT3-ITD and other recurrence geneticmutation such as NPM1, N-RAS, DNMT3A, c-KIT, CEBPα in acute myeloid leukemia(AML) patients. To explore correlations between FLT3-ITD and other mutations andcompare the clinical charatoristics between FLT3-ITD (+) patients and wtFLT3patients.Methods: A total of373AML patients in our center were retrospectively analyzedfrom October2006to October2012. Genomic DNA was extracted from patients’bonemarrow sample at diagnosis. We assesed following mutation including FLT3-ITD、FLT3-TKD、N-RAS、IDH1、DNMT3、c-KIT、NPM1、IDH2in these patients with PCRand sequencing. Futhermore, we compared the clinical charateristic of patients carryingdifferent mutation.Results: According to FAB classification, there are2patients with M0subtype,59patients with M1subtype,96patients with M2subtype,49patients with M4subtype,58patients with M5subtype,17patients with M6subtype,1patient with M7subtype and91patients unclassified. According to risk stratification by kayrotype, there are36pateints inlow-risk group, there are249pateints in medium-risk group (188patients are normalkayrotype), there are47pateints in high-risk group, and41pateints unclassified. Themedian WBC at diagnosis are31.9(1.12-490)×109/L, the median count of HGB are81(38-152)g/L, and the median platlet count are35.0(5.3-530.0)×109/L. the median blastcount in bone marrow at diagnosis are76.4%(20-99.4%).290of373patients had at least one mutation. FLT3-ITD mutation was found in total81patients that accounted for21.71%of the cohort. FLT3-ITD was mostly seen in M1and M5subtype, particularly the patientswith normal karyotype (P=0.034) and rare in low or high risk group. FLT3-ITD (+)patients usually presented with higher white blood cell counts. NPM1was found in43patients (11.52%), N-RAS was found in39patients(10.64%)，DNMT3A was found in33patients(8.5%)， IDH2was found in33patients(8.84%)，CEBPα was found in24patients(6.34%), IDH1was found in20patients(5.36%)，FLT3-TKD was found in15patients(4.02%)。 FLT3-ITD (+) patients with NPM1mutation have similar clinicalcharateristic with FLT3-ITD (+) only patients.Conclusion: FLT3-ITD mutation was mostly common among acute myloid leukemiapatients, which was frequently seen in M1and M5subtype and normal kayrotype.FLT3-ITD (+) patients usually presented with higher white blood cell counts. FLT3-ITD (+)patients with other mutation had similar clinical characteristic to FLT3-ITD (+) patients. Part II Clinical outcome of acute myeloid leukemia patients withFLT3-ITD mutation followed allogeneic hematopoietic stem celltransplantationObjective: To study clinical outcome of FLT3-ITD (+) acute myeloid leukemia(AML) patients treated with allogeneic hematopoietic stem cell transplantation(allo-HSCT), and to explore the prognosis based on the different origins and disease status.Methods: we retrospectively analyzed399AML hospitalized patients from October2006to June2013, including314patients received allo-HSCT and85patients receivedhigh dose chemotherpy. The median follow-up time was39.5months. There are80FLT3-ITD (+) pateints,54of them received allo-HSCT and26of them received high dosechemotherpy. Results: The five-year overall survival (OS) of all FLT3-ITD (+) pateints were21%,with median survival at21months (95%CI13.909-28.901). The five-year leukemia-freesurvival (LFS) of all FLT3-ITD (+) pateints were15%, with median leukemia-free survivalat18months (95%CI9.411-26.589).In54FLT3-ITD (+) patients receivd allo-HSCT, thefive-years overall survival (5-OS) rate was56%and five-years leukemia-free survival(5-LFS) rate was47%, the five year cumulative rate of relapse was29.6%,and the five yearcumulative rate of treatment-related mortality was11.1%. Comparing to FLT3-ITD (+)patinets received allo-HSCT, the five-year OS and five-year LFS of FLT3-ITD (+) patientsreceived high dose chemotherpy were significantly lower (7%and3%, P<0.001andP=0.003). Comparing to FLT3-ITD (+) patinets received allo-HSCT, the five-year OS andfive-year LFS of wtFLT3patients received high dose chemotherpy were similar(61%and49%, P>0.05), and the five year cumulative rate of relapse and treatment-related mortalitywas similar (17.9%and18.4, P=0.345and P=0.103).In FLT3-ITD AML patients received allo-HSCT, haplo-identical HSCT had similarcurative effect with the mached sibling donors HSCT (three year OS:60%vs54%; threeyear LFS:54%vs45%). The three year OS and LFS were not significantly different (P=0.786, P=0.941). The multiple variable analyses of patients receiving allo-HSCT showedthe independent risk factors of OS are disease recurrence (HR=9.508，P<0.001), diseasestatus before allo-HSCT (HR=0.625，P=0.052), and conditioning regimen (HR=0.174，P<0.001).Conclusion: Allo-HSCT significantly improves the clinical outcome of FLT3-ITD (+)AML patients, and haplo-identical HSCT had similar curative effect with the sibling donor.Disease relapse was most strong prognostic factor for FLT3-ITD (+) AML patient treatedwith allo-HSCT.