Clinical Study On Newly Diagnosed AML Treated By Decitabine Plus Ia Regimen And The Ability Of BTG1 To Predict The Response

Objective:Hypomethylating agents have showed promising efficiency in elderly acute myeloid leukemia（AML）patients.The clinical data of response to hypomethylating agents in newly diagnosed non-elderly AML patients,however,is lacking.As AML is a highly heterogeneous disease,how variant allelic frequency and mutation sites of mutated genes affected the response of decitabine has not been reported.Additionally,no maker could be used to predict the response of decitabine in AML.This study focused on the efficiency of decitabine in non-elderly AML patients based on retrospective study,clinical trial and experimental study.The aim of this study is to find clinical characteristics and molecular makers that can be applied in response prediction,and to optimize the induction regime for non-elderly AML patients.Methods:464 AML cases from a single center were retrospectively analyzed.In different subgroups,the clinical efficiency of cases treated with decitabine-containing regime and without decitabine regime were compared.Subsequently,a multi-center,prospective and randomized clinical trial of newly diagnosed non-elderly AML patients treated with decitabine plus IA regime were conducted（Chinese Clinical Trial Registry,Chi CTR2000037928）.The complete remission（CR）,measurable residual disease（MRD）,prognosis and safety between patients treated with decitabine plus IA regime and IA regime were compared.Finally,in vitro experiments of decitabine were performed in three types of AML cell lines.A marker which was closely associated with the efficiency of decitabine was screened using a combination of epigenetic and transcriptomic analysis.This maker was confirmed for sensitivity and specificity in clinical samples.Results:（1）For non-elderly AML patients accompanied with FLT3-ITD^high mutation（OR=2.636,95%CI 1.478-3.543;P=0.009）and C-KIT D816 mutation（OR=2.133,95%CI 1.135-3.473;P=0.002）,MRD negativity was more frequently achieved with decitabine-containing regime than without decitabine regime（P for interaction<0.05）.（2）77 cases with full evaluation have been enrolled in clinical trial（phase results）,including39 cases treated with decitabine plus IA regime and 38 cases treated with IA regime.The CR/CRi rate was 84.6%in decitabine plus IA regime group,a little higher than IA regime group（76.3%）（P=0.358）.The MRD negative rate was achieved in 71.8%of decitabine plus IA regime,significantly higher than that of IA regime（47.4%）（P=0.029）.No difference in one-year RFS（77.1%vs.61.5%,P=0.295）or one-year OS（85.4%vs.83.3%,P=0.369）was observed between the two groups.No prolonged duration of neutropenia（P=0.683）or thrombocytopenia（P=0.166）was observed in decitabine plus IA regime.（3）In vitro experiment showed that the changes of methylation and expression level of BTG1varied in three types of AML cell lines,and were closely associated with the IC50 of decitabine.In AML patients treated with decitabine plus IA regime,the ability to predict CR could be assigned with a sensitivity of 84.0%and a specificity of 100.0%when BTG1expression was<0.318,area under the curve（AUC）=0.944,P=0.002.The ability to predict MRD negativity could be assigned with a sensitivity of 76.5%and a specificity of84.6%when BTG1 expression was<0.194,AUC=0.805,P=0.005。Conclusion:（1）Decitabine-containing regime showed more effective in non-elderly AML patients with FLT3-ITD^highmutation and C-KIT D816 mutation.（2）Non-elderly AML patients could achieve higher MRD negative rate with decitabine plus IA regime compared with IA regime,but CR rate and prognosis were not significantly improved（phase results）.Increased adverse events were not observed in decitabine plus IA regime compared with IA regime.（3）Low expression of BTG1 in newly diagnosed AML patients treated with decitabine-containing regime was associated with CR and MRD negativity.Detection of the expression level of BTG1 potentially predict whether AML patients could benefit from decitabine-containing regime.