BACKGROUND Therapy-related acute promyelocytic leukemia(t-APL)is a rare complication observed in solitary bone plasmacytoma(SBP),and SBP after radiotherapy evolving to APL harboring the FMS-like tyrosine kinase 3-inte...BACKGROUND Therapy-related acute promyelocytic leukemia(t-APL)is a rare complication observed in solitary bone plasmacytoma(SBP),and SBP after radiotherapy evolving to APL harboring the FMS-like tyrosine kinase 3-internal tandem duplication(FLT3-ITD)mutation has never been reported.Here,we present the first case reported until now.CASE SUMMARY We describe a 64-year-old woman who presented with lumbar pain and was initially diagnosed with SBP.However,after one year of radiotherapy treatment,this patient experienced a long-standing bone-marrow-suppressive period and finally developed APL harboring the FLT3-ITD mutation,as confirmed by analyses of clinical features,bone marrow morphology,flow cytometry,cytogenetic examination,and molecular biology.On admission,the patient had disseminated intravascular coagulation and intracranial hemorrhage,and the peripheral blood and bone marrow smear displayed abundant abnormal promyelocytes.Unfortunately,she died when the definite diagnosis was made.CONCLUSION The patient with t-APL harboring FLT3-ITD mutation evolving from SBP after radiotherapy had not been reported and had poor clinical outcomes.FLT3-ITD mutation in t-APL may be a potential pathogenesis of leukemogenesis.We should consider the potential risk of secondary neoplasms in SBP patients after radiotherapy.展开更多
All-trans retinoic acid(ATRA)and pre-upfront arsenic trioxide(ATO)have revolutionized the therapy of acute promyelocytic leukemia(APL).However,internal tandem duplication of FMS-like tyrosine kinase 3(FLT3-ITD)mutatio...All-trans retinoic acid(ATRA)and pre-upfront arsenic trioxide(ATO)have revolutionized the therapy of acute promyelocytic leukemia(APL).However,internal tandem duplication of FMS-like tyrosine kinase 3(FLT3-ITD)mutations is associated with increased risk of relapse.The aim of this study was to analyze the prognostic impact of FLT3-ITD on APL patients who received remission induction with ATRA,idarubicin(IDA)and/or ATO,followed by ATRA plus ATO along with anthracycline,as consolidation therapy.A total of 72 patients newly diagnosed with APL were included in this study.83.3%of the patients achieved complete remission(CR)after induction therapy.FLT3-ITD mutations were detected in 16(22.2%)patients and closely related to bcr-3 PML-RARa transcript(P<0.001).The 5-year overall survival(OS)rate was 100%in both FLT3-ITDposltlve and FLT3-ITD^(negatlve)groups,and there was no significant difference in 5-year event-free survival(EFS)between the two groups(78.3%vs.83.3%,P=0.85).ATRA plus ATO and anthracycline-based chemotherapy achieved great outcome in newly diagnosed APL regardless of the FLT3-ITD mutation status.展开更多
FMS-like tyrosine kinase 3(FLT3) is classified as a type Ⅲ receptor tyrosine kinase, which exerts a key role in regulation of normal hematopoiesis. FLT3 mutation is the most common genetic mutation in acute myeloid l...FMS-like tyrosine kinase 3(FLT3) is classified as a type Ⅲ receptor tyrosine kinase, which exerts a key role in regulation of normal hematopoiesis. FLT3 mutation is the most common genetic mutation in acute myeloid leukemia(AML) and represents an attractive therapeutic target. Targeted therapy with FLT3 inhibitors in AML shows modest promising results in current ongoing clinical trials suggesting the complexity of FLT3 targeting in therapeutics. Importantly, resistance to FLT3 inhibitors may explain the lack of overwhelming response and could obstruct the successful treatment for AML. Here, we summarize the molecular mechanisms of primary resistance and acquired resistance to FLT3 inhibitors and discuss the strategies to circumvent the emergency of drug resistance and to develop novel treatment intervention.展开更多
Mutations of fins-like tyrosine kinase 3 （FLT3） and nucleophosmin （NPM1） exon 12 genes are the most common abnormalities in adult acute myeloid leukemia （AML） with normal cytogenetics. To assess the prognostic i...Mutations of fins-like tyrosine kinase 3 （FLT3） and nucleophosmin （NPM1） exon 12 genes are the most common abnormalities in adult acute myeloid leukemia （AML） with normal cytogenetics. To assess the prognostic impact of the two gene mutations in Chinese AML patients, we used multiplex polymerase chain reaction （PCR） and capillary electrophoresis to screen 76 AML patients with normal cytogenetics for mutations in FLT3 internal tandem duplication （FLT3/ITD） and exon 12 of the NPM1 gene. FLT3/ITD mutation was detected in 15 （19.7%） of 76 subjects, and NPM1 mutation in 20 （26.3%） subjects. Seven （9.2%） cases were positive for both FLT3/ITD and NPM1 mutations Significantly more FLT3/ITD aberration was detected in subjects with French-American-British （FAB） M1 （42.8%）. NPM1 mutation was frequently detected in subjects with M5 （47.1%） and infrequently in subjects with M2 （11.1%）. FLT3 and NPM1 mutations were significantly associated with a higher white blood cell count in peripheral blood and a lower CD34 antigen expression, but not age, sex, or platelet count. Statistical analysis revealed that the FLT3/ITD- positive group had a lower complete remission （CR） rate （53.3% vs. 83.6%）. Survival analysis showed that the FLT3/ITD-positive/NPM1 mutation-negative group had worse overall survival （OS） and relapse-free survival （RFS）. The FLT3/ITD-positive/NPM1 mutation-positive group showed a trend towards favorable survival compared with the FLT3/ITD-positive/NPM1 mutation-negative group （P=0.069）. Our results indicate that the FLT3/ITD mutation might be a prognostic factor for an unfavorable outcome in Chinese AML subjects with normal cytogenetics, while NPM1 mutation may be a favorable prognostic factor for OS and RFS in the presence of FLT3/ITD.展开更多
基金Natural Science Foundation of Zhejiang Province,No.LY19H290003Zhejiang Provincial Medical and Health Science and Technology Project,No.2020KY196and Foundation of Zhejiang Province Chinese Medicine Science and Technology Planes,No.2017ZB030.
文摘BACKGROUND Therapy-related acute promyelocytic leukemia(t-APL)is a rare complication observed in solitary bone plasmacytoma(SBP),and SBP after radiotherapy evolving to APL harboring the FMS-like tyrosine kinase 3-internal tandem duplication(FLT3-ITD)mutation has never been reported.Here,we present the first case reported until now.CASE SUMMARY We describe a 64-year-old woman who presented with lumbar pain and was initially diagnosed with SBP.However,after one year of radiotherapy treatment,this patient experienced a long-standing bone-marrow-suppressive period and finally developed APL harboring the FLT3-ITD mutation,as confirmed by analyses of clinical features,bone marrow morphology,flow cytometry,cytogenetic examination,and molecular biology.On admission,the patient had disseminated intravascular coagulation and intracranial hemorrhage,and the peripheral blood and bone marrow smear displayed abundant abnormal promyelocytes.Unfortunately,she died when the definite diagnosis was made.CONCLUSION The patient with t-APL harboring FLT3-ITD mutation evolving from SBP after radiotherapy had not been reported and had poor clinical outcomes.FLT3-ITD mutation in t-APL may be a potential pathogenesis of leukemogenesis.We should consider the potential risk of secondary neoplasms in SBP patients after radiotherapy.
文摘All-trans retinoic acid(ATRA)and pre-upfront arsenic trioxide(ATO)have revolutionized the therapy of acute promyelocytic leukemia(APL).However,internal tandem duplication of FMS-like tyrosine kinase 3(FLT3-ITD)mutations is associated with increased risk of relapse.The aim of this study was to analyze the prognostic impact of FLT3-ITD on APL patients who received remission induction with ATRA,idarubicin(IDA)and/or ATO,followed by ATRA plus ATO along with anthracycline,as consolidation therapy.A total of 72 patients newly diagnosed with APL were included in this study.83.3%of the patients achieved complete remission(CR)after induction therapy.FLT3-ITD mutations were detected in 16(22.2%)patients and closely related to bcr-3 PML-RARa transcript(P<0.001).The 5-year overall survival(OS)rate was 100%in both FLT3-ITDposltlve and FLT3-ITD^(negatlve)groups,and there was no significant difference in 5-year event-free survival(EFS)between the two groups(78.3%vs.83.3%,P=0.85).ATRA plus ATO and anthracycline-based chemotherapy achieved great outcome in newly diagnosed APL regardless of the FLT3-ITD mutation status.
基金Supported by the Singapore National Research Foundation and the Ministry of Education under the Research Center of Excellence Program(to Chng WJ)NMRC Clinician-Scientist IRG Grant,No.CNIG11nov38(to Zhou J)+1 种基金supported by NMRC Clinician Scientist Investigator awardsupported by the RNA Biology Center at CSI Singapore,NUS,from funding by the Singapore Ministry of Education’s Tier 3 grants,No.MOE2014-T3-1-006
文摘FMS-like tyrosine kinase 3(FLT3) is classified as a type Ⅲ receptor tyrosine kinase, which exerts a key role in regulation of normal hematopoiesis. FLT3 mutation is the most common genetic mutation in acute myeloid leukemia(AML) and represents an attractive therapeutic target. Targeted therapy with FLT3 inhibitors in AML shows modest promising results in current ongoing clinical trials suggesting the complexity of FLT3 targeting in therapeutics. Importantly, resistance to FLT3 inhibitors may explain the lack of overwhelming response and could obstruct the successful treatment for AML. Here, we summarize the molecular mechanisms of primary resistance and acquired resistance to FLT3 inhibitors and discuss the strategies to circumvent the emergency of drug resistance and to develop novel treatment intervention.
文摘Mutations of fins-like tyrosine kinase 3 （FLT3） and nucleophosmin （NPM1） exon 12 genes are the most common abnormalities in adult acute myeloid leukemia （AML） with normal cytogenetics. To assess the prognostic impact of the two gene mutations in Chinese AML patients, we used multiplex polymerase chain reaction （PCR） and capillary electrophoresis to screen 76 AML patients with normal cytogenetics for mutations in FLT3 internal tandem duplication （FLT3/ITD） and exon 12 of the NPM1 gene. FLT3/ITD mutation was detected in 15 （19.7%） of 76 subjects, and NPM1 mutation in 20 （26.3%） subjects. Seven （9.2%） cases were positive for both FLT3/ITD and NPM1 mutations Significantly more FLT3/ITD aberration was detected in subjects with French-American-British （FAB） M1 （42.8%）. NPM1 mutation was frequently detected in subjects with M5 （47.1%） and infrequently in subjects with M2 （11.1%）. FLT3 and NPM1 mutations were significantly associated with a higher white blood cell count in peripheral blood and a lower CD34 antigen expression, but not age, sex, or platelet count. Statistical analysis revealed that the FLT3/ITD- positive group had a lower complete remission （CR） rate （53.3% vs. 83.6%）. Survival analysis showed that the FLT3/ITD-positive/NPM1 mutation-negative group had worse overall survival （OS） and relapse-free survival （RFS）. The FLT3/ITD-positive/NPM1 mutation-positive group showed a trend towards favorable survival compared with the FLT3/ITD-positive/NPM1 mutation-negative group （P=0.069）. Our results indicate that the FLT3/ITD mutation might be a prognostic factor for an unfavorable outcome in Chinese AML subjects with normal cytogenetics, while NPM1 mutation may be a favorable prognostic factor for OS and RFS in the presence of FLT3/ITD.
