目的挖掘和评价国内3种急性髓系白血病靶向治疗药物上市后不良反应信号。方法利用OpenVigil数据平台,从美国FDA不良事件报告系统分别获取维奈克拉、吉瑞替尼、艾伏尼布上市后药物不良反应(adverse drug reaction,ADR)报告。采用比例报...目的挖掘和评价国内3种急性髓系白血病靶向治疗药物上市后不良反应信号。方法利用OpenVigil数据平台,从美国FDA不良事件报告系统分别获取维奈克拉、吉瑞替尼、艾伏尼布上市后药物不良反应(adverse drug reaction,ADR)报告。采用比例报告比法和报告比值比法检测维奈克拉、吉瑞替尼、艾伏尼布ADR信号,并分别按照发生频次和信号强度进行排序。结果共收集以维奈克拉首要怀疑药物的ADR报告14193份,ADR信号219个;吉瑞替尼ADR报告1885份,ADR信号125个;艾伏尼布ADR报告699份,ADR信号41个。从ADR报告的基本情况来看,3种药物的患者人群均为男性比例高于女性,患者的年龄分布均集中在60~74岁。维奈克拉、吉瑞替尼、艾伏尼布发生频次最高ADR分别为“死亡”“血小板计数减少”“疲乏”;信号强度最高ADR分别为“FLT3基因突变”“原始粒细胞计数增加”“分化综合征”。3种药物发生频次前20的ADR信号共累及系统器官10个,包括各类检查、血液及淋巴系统疾病、感染及侵染类疾病等。维奈克拉与吉瑞替尼发生频次前20的ADR占比最高的系统器官为“血液及淋巴系统疾病”,艾伏尼布发生频次前20的ADR占比最高的系统器官为“各类检查”。结论建议临床应对维奈克拉致心房颤动,吉瑞替尼致脓毒症等ADR给予关注。展开更多
Modern therapy of acute myeloid leukemia(AML)began in 1973 with the first report of the successful combination of daunorubicin and cytarabine,which led to complete remission in approximately 45%of patients.Accurate AM...Modern therapy of acute myeloid leukemia(AML)began in 1973 with the first report of the successful combination of daunorubicin and cytarabine,which led to complete remission in approximately 45%of patients.Accurate AML diagnosis was dependent on morphology,aided initially only by cytochemistry.Unlike acute lymphoblastic leukemia(ALL),immunophenotyping offered little in the diagnosis of AML,at least during the 1970s and 1980s.The advent of reliable cytogenetics changed the entire prognostic outlook of AML.With karyotypic analysis,different groups of AML could be classified and stratified for various therapies.Unique mutational profiling was a major advance in further categorizing AML patients,aided by the immunophenotypic identification of antigenic markers on the cells.All these advances were occurring as the understanding of the importance of the tumor burden—known as minimal residual disease(MRD)—became crucial for the management of AML patients.The efficacy of MRD has rapidly progressed in the past decade,from a specificity of 103 with immunophenotyping to 104 with polymerase chain reaction(PCR),which is only appropriate for some patients with AML,and finally to 105 or even 106 cells with the extraordinary sensitivity of next-generation sequencing(NGS).All of these advances have promoted the concept of personalized medicine,which has led to the advent of targeted agents that can accurately be used for specific diagnostic subtypes.Responses can be predicted and measured accurately.Such targeted agents have now become a cornerstone in the management of AML,increasing effi-cacy and dramatically reducing toxicity.The focus of this review is on one of the most well-studied targeted agents in AML:the FMS-like tyrosine kinase 3(FLT3)inhibitors,which have impacted the prognostication and therapeutics of AML.This review selectively discusses the FLT3 inhibitors in detail,as a model for the other burgeoning targeted agents that have already been approved,as well as those that are currently in development.展开更多
FMS-related tyrosine kinase 3(FLT3)mutations,present in about 25%-30%of acute myeloid leukemia(AML)patients,constitute one of the most frequently detected mutations in these patients.The binding of FLT3L to FLT3 activ...FMS-related tyrosine kinase 3(FLT3)mutations,present in about 25%-30%of acute myeloid leukemia(AML)patients,constitute one of the most frequently detected mutations in these patients.The binding of FLT3L to FLT3 activates the phosphatidylinositol 3-kinase(PI3K)and RAS pathways,producing increased cell proliferation and the inhibition of apoptosis.Two types of FLT3 mutations exist:FLT3-ITD and FLT3-TKD(point mutations in D835 and I836 or deletion of codon I836).A class of drugs,tyrosine-kinase inhibitors(TKI),targeting mutated FLT3,is already available with 1st and 2nd generation molecules,but only midostaurin and gilteritinib are currently approved.However,the emergence of resistance or the selection of clones not responding to FLT3 inhibitors has become an important clinical dilemma,as the duration of clinical responses is generally limited to a few months.This review analyzes the insights into mechanisms of resistance to TKI and poses a particular view on the clinical relevance of this phenomenon.Has resistance been overlooked?Indeed,FLT3 inhibitors have significantly contributed to reducing the negative impact of FLT3 mutations on the prognosis of AML patients who are no longer considered at high risk by the European LeukemiaNet(ELN)2022.Finally,several ongoing efforts to overcome resistance to FLT3-inhibitors will be presented:new generation FLT3 inhibitors in monotherapy or combined with standard chemotherapy,hypomethylating drugs,or IDH1/2 inhibitors,Bcl2 inhibitors;novel anti-human FLT3 monoclonal antibodies(e.g.,FLT3/CD3 bispecific antibodies);FLT3-CAR T-cells;CDK4/6 kinase inhibitor(e.g.,palbociclib).展开更多
文摘目的挖掘和评价国内3种急性髓系白血病靶向治疗药物上市后不良反应信号。方法利用OpenVigil数据平台,从美国FDA不良事件报告系统分别获取维奈克拉、吉瑞替尼、艾伏尼布上市后药物不良反应(adverse drug reaction,ADR)报告。采用比例报告比法和报告比值比法检测维奈克拉、吉瑞替尼、艾伏尼布ADR信号,并分别按照发生频次和信号强度进行排序。结果共收集以维奈克拉首要怀疑药物的ADR报告14193份,ADR信号219个;吉瑞替尼ADR报告1885份,ADR信号125个;艾伏尼布ADR报告699份,ADR信号41个。从ADR报告的基本情况来看,3种药物的患者人群均为男性比例高于女性,患者的年龄分布均集中在60~74岁。维奈克拉、吉瑞替尼、艾伏尼布发生频次最高ADR分别为“死亡”“血小板计数减少”“疲乏”;信号强度最高ADR分别为“FLT3基因突变”“原始粒细胞计数增加”“分化综合征”。3种药物发生频次前20的ADR信号共累及系统器官10个,包括各类检查、血液及淋巴系统疾病、感染及侵染类疾病等。维奈克拉与吉瑞替尼发生频次前20的ADR占比最高的系统器官为“血液及淋巴系统疾病”,艾伏尼布发生频次前20的ADR占比最高的系统器官为“各类检查”。结论建议临床应对维奈克拉致心房颤动,吉瑞替尼致脓毒症等ADR给予关注。
文摘Modern therapy of acute myeloid leukemia(AML)began in 1973 with the first report of the successful combination of daunorubicin and cytarabine,which led to complete remission in approximately 45%of patients.Accurate AML diagnosis was dependent on morphology,aided initially only by cytochemistry.Unlike acute lymphoblastic leukemia(ALL),immunophenotyping offered little in the diagnosis of AML,at least during the 1970s and 1980s.The advent of reliable cytogenetics changed the entire prognostic outlook of AML.With karyotypic analysis,different groups of AML could be classified and stratified for various therapies.Unique mutational profiling was a major advance in further categorizing AML patients,aided by the immunophenotypic identification of antigenic markers on the cells.All these advances were occurring as the understanding of the importance of the tumor burden—known as minimal residual disease(MRD)—became crucial for the management of AML patients.The efficacy of MRD has rapidly progressed in the past decade,from a specificity of 103 with immunophenotyping to 104 with polymerase chain reaction(PCR),which is only appropriate for some patients with AML,and finally to 105 or even 106 cells with the extraordinary sensitivity of next-generation sequencing(NGS).All of these advances have promoted the concept of personalized medicine,which has led to the advent of targeted agents that can accurately be used for specific diagnostic subtypes.Responses can be predicted and measured accurately.Such targeted agents have now become a cornerstone in the management of AML,increasing effi-cacy and dramatically reducing toxicity.The focus of this review is on one of the most well-studied targeted agents in AML:the FMS-like tyrosine kinase 3(FLT3)inhibitors,which have impacted the prognostication and therapeutics of AML.This review selectively discusses the FLT3 inhibitors in detail,as a model for the other burgeoning targeted agents that have already been approved,as well as those that are currently in development.
文摘FMS-related tyrosine kinase 3(FLT3)mutations,present in about 25%-30%of acute myeloid leukemia(AML)patients,constitute one of the most frequently detected mutations in these patients.The binding of FLT3L to FLT3 activates the phosphatidylinositol 3-kinase(PI3K)and RAS pathways,producing increased cell proliferation and the inhibition of apoptosis.Two types of FLT3 mutations exist:FLT3-ITD and FLT3-TKD(point mutations in D835 and I836 or deletion of codon I836).A class of drugs,tyrosine-kinase inhibitors(TKI),targeting mutated FLT3,is already available with 1st and 2nd generation molecules,but only midostaurin and gilteritinib are currently approved.However,the emergence of resistance or the selection of clones not responding to FLT3 inhibitors has become an important clinical dilemma,as the duration of clinical responses is generally limited to a few months.This review analyzes the insights into mechanisms of resistance to TKI and poses a particular view on the clinical relevance of this phenomenon.Has resistance been overlooked?Indeed,FLT3 inhibitors have significantly contributed to reducing the negative impact of FLT3 mutations on the prognosis of AML patients who are no longer considered at high risk by the European LeukemiaNet(ELN)2022.Finally,several ongoing efforts to overcome resistance to FLT3-inhibitors will be presented:new generation FLT3 inhibitors in monotherapy or combined with standard chemotherapy,hypomethylating drugs,or IDH1/2 inhibitors,Bcl2 inhibitors;novel anti-human FLT3 monoclonal antibodies(e.g.,FLT3/CD3 bispecific antibodies);FLT3-CAR T-cells;CDK4/6 kinase inhibitor(e.g.,palbociclib).
