Isocitrate dehydrogenase(IDH)mutations frequently occur in lower-grade gliomas and secondary glioblastomas.Mutant IDHs exhibit a gain-of-function activity,leading to the production of D-2-hydroxyglutarate(D-2HG)by red...Isocitrate dehydrogenase(IDH)mutations frequently occur in lower-grade gliomas and secondary glioblastomas.Mutant IDHs exhibit a gain-of-function activity,leading to the production of D-2-hydroxyglutarate(D-2HG)by reducing α-ketoglutarate(α-KG),a central player in metabolism and epigenetic modifications.However,the role ofα-KG homeostasis in IDH-mutated gliomagenesis remains elusive.In this study,we found that low expression of oxoglutarate dehydrogenase(OGDH)was a common feature in IDH-mutated gliomas,as well as inastrocytes.This low expression of OGDH resultedin the accumulation of α-KG and promoted astrocyte maturation.However,IDH1 mutation significantly reducedα-KG levels and increased glutaminolysis and DNA/histone methylation in astrocytes.These metabolic and epigenetic alterations inhibited astrocyte maturation and led to cortical dysplasia in mice.Moreover,our results also indicated that reduced OGDH expression can promote the differentiation of glioma cells,while IDH1 mutations impeded the differentiation of glioma cells with low OGDH by reducing the accumulation ofα-KG and increasing glutaminolysis.Finally,we found that l-glutamine increasedα-KG levels and augmented the differentiation-promoting effects of AGI5198,an IDH1-mutant inhibitor,in IDH1-mutant glioma cells.Collectively,this study reveals that low OGDH expression is a crucial metabolic characteristic of IDH-mutant gliomas,providing a potential strategy for the treatment of IDH-mutant gliomas by targetingα-KG homeostasis.展开更多
Acute myeloid leukemia(AML)is characterized by the accumulation of cytogenetic and molecular abnormalities.Isocitrate dehydrogenase 1 and 2(IDH1/2)mutations occur in 11%to 20%of adults with AML.The outcome of IDH1/2-m...Acute myeloid leukemia(AML)is characterized by the accumulation of cytogenetic and molecular abnormalities.Isocitrate dehydrogenase 1 and 2(IDH1/2)mutations occur in 11%to 20%of adults with AML.The outcome of IDH1/2-mutated AML is heterogeneous and affected by co-mutational patterns.We retrospectively analyzed 118 patients with IDH1/2-mutated AML who were retrieved from 1597 patients newly diagnosed with AML and treated with intensive chemotherapy.Univariate analysis revealed the NPM1 mutation was a favorable factor(p=0.019)for overall survival(OS),whereas the DNMT3A mutation was consistently associated with a poor outcome(3-year OS,52.0%;3-year relapse-free survival[RFS],44.8%;and 3-year cumulative incidence of relapse[CIR],42.6%).Interestingly,the DNMT3A mutation still identified patients with a poorer prognosis,even when measurable residual disease(MRD)was negative after 2 courses of chemotherapy.In a multivariate regression model,age,DNMT3A mutation and MRD positivity were retained as independent adverse markers for OS,RFS,and CIR.In the absence of the DNMT3A or FLT3-ITD mutations,the NPM1 mutation identified patients with a very favorable OS(3-year OS,96.3%and 86.3%,respectively).Finally,hematopoietic stem cell transplantation in first complete remission significantly improved RFS(p=0.015)and there was a trend toward improvement in OS(p=0.282)for patients with the DNMT3A mutation but it did not benefit 2 subgroups with the IDH1/2+/NPM1+/DNMT3A−and IDH1/2+/NPM1+/FLT3-ITD−genotypes.In summary,this study provides a reference for risk stratification and treatment implications for patients with IDH1/2-mutated AML as well as for comparison with results of IDH inhibitor-or venetoclax-based combination therapy.展开更多
Ivosidenib,an isocitrate dehydrogenase 1(IDH1)inhibitor,has demonstrated clinical benefits in a pivotal study(AG120-C-001)in patients with IDH1-mutated(mIDH1)acute myeloid leukemia(AML).A registry study(CS3010-101:NCT...Ivosidenib,an isocitrate dehydrogenase 1(IDH1)inhibitor,has demonstrated clinical benefits in a pivotal study(AG120-C-001)in patients with IDH1-mutated(mIDH1)acute myeloid leukemia(AML).A registry study(CS3010-101:NCT04176393)was conducted to assess the pharmacokinetic(PK)characteristics,safety,and efficacy of ivosidenib in Chinese patients with relapsed or refractory(R/R)mIDH1 AML.Patients received ivosidenib 500 mg once daily for 28-day cycles until disease progression.Ten subjects underwent intensive PK/progressive disease(PD)assessments.All subjects had the clinical response assessed at screening,every 28 days through month 12,and then every 56 days.Between November 12,2019,and April 2,2021,30 patients were enrolled;26(86.7%)had de novo AML and 18(60.0%)were transfusion-dependent at baseline.Following single and repeated doses of ivosidenib,median time to maximum plasma concentration(T_(max))was 4.0 and 2.0 hours,respectively.The inter-individual variability of pharmacokinetic exposure was moderate to high(coefficient of variation[CV],25%–53%).No obvious accumulation was observed after repeated doses at cycle 2 day 1.Regarding the clinical response,the CR+CRh rate was 36.7%(95%confidence interval[CI]:19.9%–56.1%),the median duration of CR+CRh was 19.7 months(95%CI:2.9 months–not reached[NR]),and median duration of response(DoR)was 14.3 months(95%CI:6.4 months–NR).Consistent clinical benefits and safety of ivosidenib were consistently observed at the final data cutoff with median follow-up time 26.0 months,as compared with primary data cutoff,and the data from Chinese R/R mIDH1 AML patients were also consistent with results from pivotal study.展开更多
基金supported by funds from the National Key Research and Development Program of China(2022YFA0806501)the National Natural Science Foundation of China(81972342 to J.Y.,82173120 to Y.G.,and 82070298 to L.Z.)the Natural Science Basic Research Plan in ShaanxiProvince(2020JZ-29 to J.Y.).
文摘Isocitrate dehydrogenase(IDH)mutations frequently occur in lower-grade gliomas and secondary glioblastomas.Mutant IDHs exhibit a gain-of-function activity,leading to the production of D-2-hydroxyglutarate(D-2HG)by reducing α-ketoglutarate(α-KG),a central player in metabolism and epigenetic modifications.However,the role ofα-KG homeostasis in IDH-mutated gliomagenesis remains elusive.In this study,we found that low expression of oxoglutarate dehydrogenase(OGDH)was a common feature in IDH-mutated gliomas,as well as inastrocytes.This low expression of OGDH resultedin the accumulation of α-KG and promoted astrocyte maturation.However,IDH1 mutation significantly reducedα-KG levels and increased glutaminolysis and DNA/histone methylation in astrocytes.These metabolic and epigenetic alterations inhibited astrocyte maturation and led to cortical dysplasia in mice.Moreover,our results also indicated that reduced OGDH expression can promote the differentiation of glioma cells,while IDH1 mutations impeded the differentiation of glioma cells with low OGDH by reducing the accumulation ofα-KG and increasing glutaminolysis.Finally,we found that l-glutamine increasedα-KG levels and augmented the differentiation-promoting effects of AGI5198,an IDH1-mutant inhibitor,in IDH1-mutant glioma cells.Collectively,this study reveals that low OGDH expression is a crucial metabolic characteristic of IDH-mutant gliomas,providing a potential strategy for the treatment of IDH-mutant gliomas by targetingα-KG homeostasis.
基金supported by the National Key Research and Development Program of China(2021YFC2500300)the National Natural Science Foundation of China(82341213,82000131)CAMS Innovation Fund for Medical Sciences(2021-I2M-1-041).
文摘Acute myeloid leukemia(AML)is characterized by the accumulation of cytogenetic and molecular abnormalities.Isocitrate dehydrogenase 1 and 2(IDH1/2)mutations occur in 11%to 20%of adults with AML.The outcome of IDH1/2-mutated AML is heterogeneous and affected by co-mutational patterns.We retrospectively analyzed 118 patients with IDH1/2-mutated AML who were retrieved from 1597 patients newly diagnosed with AML and treated with intensive chemotherapy.Univariate analysis revealed the NPM1 mutation was a favorable factor(p=0.019)for overall survival(OS),whereas the DNMT3A mutation was consistently associated with a poor outcome(3-year OS,52.0%;3-year relapse-free survival[RFS],44.8%;and 3-year cumulative incidence of relapse[CIR],42.6%).Interestingly,the DNMT3A mutation still identified patients with a poorer prognosis,even when measurable residual disease(MRD)was negative after 2 courses of chemotherapy.In a multivariate regression model,age,DNMT3A mutation and MRD positivity were retained as independent adverse markers for OS,RFS,and CIR.In the absence of the DNMT3A or FLT3-ITD mutations,the NPM1 mutation identified patients with a very favorable OS(3-year OS,96.3%and 86.3%,respectively).Finally,hematopoietic stem cell transplantation in first complete remission significantly improved RFS(p=0.015)and there was a trend toward improvement in OS(p=0.282)for patients with the DNMT3A mutation but it did not benefit 2 subgroups with the IDH1/2+/NPM1+/DNMT3A−and IDH1/2+/NPM1+/FLT3-ITD−genotypes.In summary,this study provides a reference for risk stratification and treatment implications for patients with IDH1/2-mutated AML as well as for comparison with results of IDH inhibitor-or venetoclax-based combination therapy.
文摘Ivosidenib,an isocitrate dehydrogenase 1(IDH1)inhibitor,has demonstrated clinical benefits in a pivotal study(AG120-C-001)in patients with IDH1-mutated(mIDH1)acute myeloid leukemia(AML).A registry study(CS3010-101:NCT04176393)was conducted to assess the pharmacokinetic(PK)characteristics,safety,and efficacy of ivosidenib in Chinese patients with relapsed or refractory(R/R)mIDH1 AML.Patients received ivosidenib 500 mg once daily for 28-day cycles until disease progression.Ten subjects underwent intensive PK/progressive disease(PD)assessments.All subjects had the clinical response assessed at screening,every 28 days through month 12,and then every 56 days.Between November 12,2019,and April 2,2021,30 patients were enrolled;26(86.7%)had de novo AML and 18(60.0%)were transfusion-dependent at baseline.Following single and repeated doses of ivosidenib,median time to maximum plasma concentration(T_(max))was 4.0 and 2.0 hours,respectively.The inter-individual variability of pharmacokinetic exposure was moderate to high(coefficient of variation[CV],25%–53%).No obvious accumulation was observed after repeated doses at cycle 2 day 1.Regarding the clinical response,the CR+CRh rate was 36.7%(95%confidence interval[CI]:19.9%–56.1%),the median duration of CR+CRh was 19.7 months(95%CI:2.9 months–not reached[NR]),and median duration of response(DoR)was 14.3 months(95%CI:6.4 months–NR).Consistent clinical benefits and safety of ivosidenib were consistently observed at the final data cutoff with median follow-up time 26.0 months,as compared with primary data cutoff,and the data from Chinese R/R mIDH1 AML patients were also consistent with results from pivotal study.
