Objective:Acute myeloid leukemia(AML)patients with internal tandem duplications in the FMS-like tyrosine kinase 3 receptor gene(FLT3-ITD)receiving tyrosine kinase inhibitors maintenance after allogeneic hematopoietic ...Objective:Acute myeloid leukemia(AML)patients with internal tandem duplications in the FMS-like tyrosine kinase 3 receptor gene(FLT3-ITD)receiving tyrosine kinase inhibitors maintenance after allogeneic hematopoietic stem cell transplantation(allo-HSCT)demonstrated improved survival outcomes,however,some still experienced relapse during the maintenance.This study aimed to explore risk factors which might be indicators for poor survival after allo-HSCT in this population.Methods:We consecutively enrolled FLT3-ITD AML patients undergoing transplantation at three centers.By integrating genetic profiles with clinical information,we assessed their impact on transplant outcomes.Results:A total of 196 patient were eligible in the analysis,among whom 14%harbored myelodysplasia-related(MR)mutations,including ASXL1,BCOR,EZH2,RUNX1,SF3B1,SRSF2,STAG2,U2AF1,and ZRSR2.Co-mutant MR was independently associated with poorer overall survival(OS)[hazard ratio(HR):2.4,95%confidence interval(95%CI):1.1-5.3,P=0.030].DNMT3A co-mutations strongly predicted adverse survival and relapse[OS:HR:2.1,95%CI:1.0-4.3,P=0.045;relapse-free survival(RFS):HR:2.2,95%CI:1.1-4.1,P=0.017;cumulative incidence of relapse(CIR):HR:2.3,95%CI:1.1-4.8,P=0.030].Compared to patients with negative measurable residual disease(MRD)complete remission(CR),no significant differences were observed in CR patients with positive MRD,while those without CR exhibited significantly inferior outcomes(P=0.003).Conclusions:Patients with myelodysplasia-related gene mutations(MRmut)and/or DNMT3A mutations experienced inferior outcomes after transplantation,requiring further exploration.Furthermore,similar prognoses among CR patients highlighted the need for monitoring specific molecular residual lesions.展开更多
FMS-like tyrosine kinase 3(FLT3)is a viable and important therapeutic target for acute myeloid leukemia(AML).FLT3 internal tandem duplication(FLT3-ITD)mutations have been identified in approximately 30%of AML patients...FMS-like tyrosine kinase 3(FLT3)is a viable and important therapeutic target for acute myeloid leukemia(AML).FLT3 internal tandem duplication(FLT3-ITD)mutations have been identified in approximately 30%of AML patients,and are associated with unfavorable prognosis,higher risk of relapse,drug resistance,and poor clinical outcome.Even FLT3 inhibitors have demonstrated promising efficacy,they cannot cure AML or even significantly extend the lives of patients with FLT3-ITD mutations.This is partly because of poor water solubility,insufficient membrane penetration and short half-life of small molecule inhibitors.Besides,the presence of enzymes like CYP3A4 in bone marrow accelerate the elimination and metabolism of FLT3 inhibitors,resulting in low plasma concentrations and side effects.Here we report the erythrocyte membrane-camouflaged FLT3 inhibitor nanoparticles to enhance FLT3-ITD AML treatment.Briefly,we physically coextruded red blood cell(RBC)membrane vesicles with nanoparticles derived from FLT3 inhibitor F30 to obtain F30@RBC-M,which exhibited comparable potent FLT3-ITD inhibitory effects compared to free F30 in vitro,while displaying a higher potent antitumor efficacy in xenograft models due to the prolonged circulation properties.Furthermore,administration of F30@RBC-M significantly extended the survival of mice in a transplanted mouse model than F30 free drug.These findings suggest that RBC membrane-coated nanoparticles derived from FLT3 inhibitors hold promise as a tool to enhance the therapeutic efficacy to treat FLT3-ITD AML.展开更多
基金supported by grants from the National Key Research and Development Program of China(No.2022YFA1103500)the National Natural Science Foundation of China(No.82170210)。
文摘Objective:Acute myeloid leukemia(AML)patients with internal tandem duplications in the FMS-like tyrosine kinase 3 receptor gene(FLT3-ITD)receiving tyrosine kinase inhibitors maintenance after allogeneic hematopoietic stem cell transplantation(allo-HSCT)demonstrated improved survival outcomes,however,some still experienced relapse during the maintenance.This study aimed to explore risk factors which might be indicators for poor survival after allo-HSCT in this population.Methods:We consecutively enrolled FLT3-ITD AML patients undergoing transplantation at three centers.By integrating genetic profiles with clinical information,we assessed their impact on transplant outcomes.Results:A total of 196 patient were eligible in the analysis,among whom 14%harbored myelodysplasia-related(MR)mutations,including ASXL1,BCOR,EZH2,RUNX1,SF3B1,SRSF2,STAG2,U2AF1,and ZRSR2.Co-mutant MR was independently associated with poorer overall survival(OS)[hazard ratio(HR):2.4,95%confidence interval(95%CI):1.1-5.3,P=0.030].DNMT3A co-mutations strongly predicted adverse survival and relapse[OS:HR:2.1,95%CI:1.0-4.3,P=0.045;relapse-free survival(RFS):HR:2.2,95%CI:1.1-4.1,P=0.017;cumulative incidence of relapse(CIR):HR:2.3,95%CI:1.1-4.8,P=0.030].Compared to patients with negative measurable residual disease(MRD)complete remission(CR),no significant differences were observed in CR patients with positive MRD,while those without CR exhibited significantly inferior outcomes(P=0.003).Conclusions:Patients with myelodysplasia-related gene mutations(MRmut)and/or DNMT3A mutations experienced inferior outcomes after transplantation,requiring further exploration.Furthermore,similar prognoses among CR patients highlighted the need for monitoring specific molecular residual lesions.
基金supported by the National Natural Science Foundation of China(No.32222046,China)the Sichuan Science and Technology Program(Nos.2022NSFSC0823,2023NSFSC193,2022NSFSC0793,China)the 1·3·5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(No.ZYJC21022,China).
文摘FMS-like tyrosine kinase 3(FLT3)is a viable and important therapeutic target for acute myeloid leukemia(AML).FLT3 internal tandem duplication(FLT3-ITD)mutations have been identified in approximately 30%of AML patients,and are associated with unfavorable prognosis,higher risk of relapse,drug resistance,and poor clinical outcome.Even FLT3 inhibitors have demonstrated promising efficacy,they cannot cure AML or even significantly extend the lives of patients with FLT3-ITD mutations.This is partly because of poor water solubility,insufficient membrane penetration and short half-life of small molecule inhibitors.Besides,the presence of enzymes like CYP3A4 in bone marrow accelerate the elimination and metabolism of FLT3 inhibitors,resulting in low plasma concentrations and side effects.Here we report the erythrocyte membrane-camouflaged FLT3 inhibitor nanoparticles to enhance FLT3-ITD AML treatment.Briefly,we physically coextruded red blood cell(RBC)membrane vesicles with nanoparticles derived from FLT3 inhibitor F30 to obtain F30@RBC-M,which exhibited comparable potent FLT3-ITD inhibitory effects compared to free F30 in vitro,while displaying a higher potent antitumor efficacy in xenograft models due to the prolonged circulation properties.Furthermore,administration of F30@RBC-M significantly extended the survival of mice in a transplanted mouse model than F30 free drug.These findings suggest that RBC membrane-coated nanoparticles derived from FLT3 inhibitors hold promise as a tool to enhance the therapeutic efficacy to treat FLT3-ITD AML.
