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Jeenwoo Park - One of the best experts on this subject based on the ideXlab platform.
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therapeutic potential of the mitochondria targeted antioxidant mitoq in mitochondrial ros induced sensorineural hearing loss caused by idh2 deficiency
Redox biology, 2019Co-Authors: Jeong-in Baek, Michael P Murphy, Deok-gyun Choi, Jeenwoo Park, Greg Macpherson, Yeonsik ChooAbstract:Abstract Mitochondrial NADP+-dependent Isocitrate Dehydrogenase 2 (IDH2) is a major NADPH-producing enzyme which is essential for maintaining the mitochondrial redox balance in cells. We sought to determine whether IDH2 deficiency induces mitochondrial dysfunction and modulates auditory function, and investigated the protective potential of an antioxidant agent against reactive oxygen species (ROS)-induced cochlear damage in Idh2 knockout (Idh2−/−) mice. Idh2 deficiency leads to damages to hair cells and spiral ganglion neurons (SGNs) in the cochlea and ultimately to apoptotic cell death and progressive sensorineural hearing loss in Idh2−/− mice. Loss of IDH2 activity led to decreased levels of NADPH and glutathione causing abnormal ROS accumulation and oxidative damage, which might trigger apoptosis signal in hair cells and SGNs in Idh2−/− mice. We performed ex vivo experiments to determine whether administration of mitochondria-targeted antioxidants might protect or induce recovery of cells from ROS-induced apoptosis in Idh2-deficient mouse cochlea. MitoQ almost completely neutralized the H2O2-induced ototoxicity, as the survival rate of Idh2−/− hair cells were restored to normal levels. In addition, the lack of IDH2 led to the accumulation of mitochondrial ROS and the depolarization of ΔΨm, resulting in hair cell loss. In the present study, we identified that IDH2 is indispensable for the functional maintenance and survival of hair cells and SGNs. Moreover, the hair cell degeneration caused by IDH2 deficiency can be prevented by MitoQ, which suggests that Idh2−/− mice could be a valuable animal model for evaluating the therapeutic effects of various antioxidant candidates to overcome ROS-induced hearing loss.
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Isocitrate Dehydrogenase 2 deficiency exacerbates dermis damage by ultraviolet b via δnp63 downregulation
Biochimica et Biophysica Acta, 2018Co-Authors: Jeong Hyun Park, Sung Hwan Kim, Jeenwoo ParkAbstract:Isocitrate Dehydrogenase 2 (IDH2) is a key enzyme that maintains the balance of mitochondrial redox status by generating NADPH as a reducing factor, which is used to reduce oxidized antioxidant proteins and oxidized glutathione. Therefore, the role of IDH2 is crucial in organs that are easily influenced by reactive oxygen species (ROS) or mechanical damage. Humans are constantly exposed to ultraviolet (UV) radiation throughout their lifetime, which can cause various cutaneous diseases, such skin carcinoma, dermatitis, and sunburn. ROS play an important role in the initial step of these diseases; therefore, IDH2 deficient mice (Idh2-/-) could be a useful model to investigate UV-mediated skin damage. When we exposed the dorsal skin of Idh2-/- mice to UVB, pyrimidine dimers and (6-4) photoproducts (6-4PPs), marker of photoproducts generated by UVB, were found in the dermis of the knockout mice. Increased collagen degradation, apoptosis, inflammation, and ROS levels in the dermis were also observed. These results indicated that UVB could reach the dermis by penetrating the epidermis. We then attempted to determine how the epidermis was breached, and observed a decrease in the expression level of ΔNp63, a major protein required for epidermis generation, in the Idh2-/- mice. The mito-TEMPO supplement significantly ameliorates UVB-induced damage in the skin of Idh2-/- mice. In the present study, we provided a role for IDH2 in protection against UVB-induced skin damage and a new connection between IDH2 and ΔNp63.
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IDH2 deficiency increases the liver susceptibility to ischemia-reperfusion injury via increased mitochondrial oxidative injury
Elsevier, 2018Co-Authors: Sang Jun Han, Jeenwoo Park, Jee In Kim, Hong Seok Choi, Kwon Moo ParkAbstract:Mitochondrial NADP+-dependent Isocitrate Dehydrogenase 2 (IDH2) is a major producer of mitochondrial NADPH, required for glutathione (GSH)-associated mitochondrial antioxidant systems including glutathione peroxidase (GPx) and glutathione reductase (GR). Here, we investigated the role of IDH2 in hepatic ischemia-reperfusion (HIR)-associated mitochondrial injury using Idh2-knockout (Idh2-/-) mice and wild-type (Idh2+/+) littermates. Mice were subjected to either 60 min of partial liver ischemia or sham-operation. Some mice were administered with 2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride (mito-TEMPO, a mitochondria-targeting antioxidant). HIR induced severe histological and functional damages of liver in both Idh2+/+ mice and Idh2-/- mice and those damages were more severe in Idh2-/- mice than in wild-type littermates. HIR induces dysfunction of IDH2, leading to the decreases of NADPH level and mitochondrial GR and GPx functions, consequently resulting in mitochondrial and cellular oxidative injury as reflected by mitochondrial cristae loss, mitochondrial fragmentation, shift in mitochondrial fission, cytochrome c release, and cell death. These HIR-induced changes were greater in Idh2-/- mice than wild-type mice. The mito-TEMPO supplement significantly attenuated the aforementioned changes, and these attenuations were much greater in Idh2-/- mice when compared with wild-type littermates. Taken together, results have demonstrated that HIR impairs in the IDH2-NADPH-GSH mitochondrial antioxidant system, resulting in increased mitochondrial oxidative damage and dysfunction, suggesting that IDH2 plays a critical role in mitochondrial redox balance and HIR-induced impairment of IDH2 function is associated with the pathogenesis of ischemia-reperfusion-induced liver failure. Keywords: Liver ischemia, Mitochondria, Oxidative stress, Apoptosis, IDH
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increased obesity resistance and insulin sensitivity in mice lacking the Isocitrate Dehydrogenase 2 gene
Free Radical Biology and Medicine, 2016Co-Authors: Su Jeong Lee, Sung Hwan Kim, Kwon Moo Park, Jin Hyup Lee, Jeenwoo ParkAbstract:Reactive oxygen species (ROS) are a byproduct of normal metabolism and play important roles in cell signaling and homeostasis. Mitochondria, the main organelles involved in intracellular ROS production, play central roles in modulating redox-dependent cellular processes such as metabolism and apoptosis. We recently reported an important role for mitochondrial NADP+-dependent Isocitrate Dehydrogenase (IDH2) in cellular redox regulation. Here, we show that mice with targeted disruption of IDH2 exhibit resistance to obesity, with lower body weight and reduced visceral fat, and increased insulin sensitivity accompanied by enhanced energy expenditure relative to controls. This function of IDH2 is linked to its capacity to suppress lipogenesis in visceral adipose tissue, partly via transcriptional repression of SREBP1, and to increase thermogenesis in adipocytes by transcriptional activation of UCP1 via activation of the p38 signaling axis. Our results highlight the importance of redox balance in the regulation of metabolism and demonstrate that IDH2 plays a major role in modulating both insulin sensitivity and fuel metabolism, thereby establishing this protein as a potential therapeutic target in the treatment of type 2 diabetes and obesity.
Eytan M Stein - One of the best experts on this subject based on the ideXlab platform.
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molecular remission and response patterns in patients with mutant idh2 acute myeloid leukemia treated with enasidenib
Blood, 2019Co-Authors: Eytan M Stein, Amir T Fathi, Courtney D Dinardo, Daniel A Pollyea, Gail J Roboz, Jessica K Altman, Richard Stone, Manish R PatelAbstract:Approximately 8% to 19% of patients with acute myeloid leukemia (AML) have Isocitrate Dehydrogenase-2 (IDH2) mutations, which occur at active site arginine residues R140 and R172. IDH2 mutations produce an oncometabolite, 2-hydroxyglutarate (2-HG), which leads to DNA and histone hypermethylation and impaired hematopoietic differentiation. Enasidenib is an oral inhibitor of mutant-IDH2 proteins. This first-in-human phase 1/2 study evaluated enasidenib doses of 50 to 650 mg/d, administered in continuous 28-day cycles, in patients with mutant-IDH2 hematologic malignancies. Overall, 214 of 345 patients (62%) with relapsed or refractory (R/R) AML received enasidenib, 100 mg/d. Median age was 68 years. Forty-two patients (19.6%) attained complete remission (CR), 19 patients (10.3%) proceeded to an allogeneic bone marrow transplant, and the overall response rate was 38.8% (95% confidence interval [CI], 32.2-45.7). Median overall survival was 8.8 months (95% CI, 7.7-9.6). Response and survival were comparable among patients with IDH2-R140 or IDH2-R172 mutations. Response rates were similar among patients who, at study entry, were in relapse (37.7%) or were refractory to intensive (37.5%) or nonintensive (43.2%) therapies. Sixty-six (43.1%) red blood cell transfusion-dependent and 53 (40.2%) platelet transfusion-dependent patients achieved transfusion independence. The magnitude of 2-HG reduction on study was associated with CR in IDH2-R172 patients. Clearance of mutant-IDH2 clones was also associated with achievement of CR. Among all 345 patients, the most common grade 3 or 4 treatment-related adverse events were hyperbilirubinemia (10%), thrombocytopenia (7%), and IDH differentiation syndrome (6%). Enasidenib was well tolerated and induced molecular remissions and hematologic responses in patients with AML for whom prior treatments had failed. The study is registered at www.clinicaltrials.gov as #NCT01915498.
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differentiation syndrome associated with enasidenib a selective inhibitor of mutant Isocitrate Dehydrogenase 2 analysis of a phase 1 2 study
JAMA Oncology, 2018Co-Authors: Amir T Fathi, Eytan M Stein, Stephane De Botton, Courtney D Dinardo, Irina Kline, Laurie Kenvin, Ira Gupta, Eyal C Attar, Ag Study C InvestigatorsAbstract:Importance Enasidenib mesylate, a mutant Isocitrate Dehydrogenase 2 (IDH2) protein inhibitor that promotes differentiation of leukemic myeloblasts, was recently approved by the US Food and Drug Administration for use in relapsed/refractory (R/R) mutantIDH2acute myeloid leukemia (AML). During the first study of enasidenib in humans, a minority of patients with advanced myeloid neoplasms experienced unexpected signs/symptoms of a differentiation syndrome (DS), a potentially lethal entity. Objective To characterize IDH-inhibitor–associated DS (IDH-DS) and its effective management. Design, Setting, and Participants Using data obtained from a multicenter, open-label, pivotal phase 1/2 study of enasidenib, a differentiation syndrome review committee retrospectively evaluated potential cases of IDH-DS in enasidenib-treated patients with R/R AML. Data were collected between August 27, 2013, and October 14, 2016. The committee identified and agreed on signs and symptoms characteristic of IDH-DS and developed an algorithm for identification and treatment. Among 281 patients with R/R AML enrolled in the trial, the committee identified 72 patients for review based on investigator-reported cases of DS (n = 33) or reported adverse events or signs and symptoms characteristic of IDH-DS. Interventions Treatment with enasidenib at a dosage of 50 to 650 mg/d was evaluated during the dose-escalation phase, and a dosage of 100 mg/d was used in the phase 1 expansion and phase 2, all in continual 28-day cycles. Main Outcomes and Measures Unexpected adverse events of IDH-DS during the phase 1/2 study. Results Thirty-three of the 281 patients (11.7%) were identified as having possible or probable IDH-DS. Median age of those 33 patients was 70 years (range, 38-80 years); 20 (60.6%) were male. The most frequent manifestations were dyspnea, fever, pulmonary infiltrates, and hypoxia. Median time to onset was 30 days (range, 7-129 days). Patients who experienced IDH-DS were less likely to have less than 20% bone marrow blasts (6% vs 22%,P = .04) and more likely to have undergone fewer previous anticancer regimens (median, 1.0 [range, 1-4] vs 2.0 [range, 1-14],P = .05) at study entry than those who did not. Thirteen patients (39.4%) had concomitant leukocytosis. Isocitrate Dehydrogenase differentiation syndrome was effectively managed with systemic corticosteroids. The enasidenib regimen was interrupted for 15 patients (45.5%), but permanent discontinuation of treatment was not required. Conclusions and Relevance Isocitrate Dehydrogenase differentiation syndrome is a recognizable and potentially lethal clinical entity, occurring in approximately 12% of enasidenib-treated patients with mutant-IDH2R/R AML. It requires prompt recognition and management. As use of mutant IDH inhibitors increases, these findings and recommendations are increasingly germane to care of patients with mutant-IDHneoplasms. Trial Registration clinicaltrials.gov Identifier:NCT01915498
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enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response
Blood, 2017Co-Authors: Michael Amatangelo, Lynn Quek, Alan Shih, Eytan M Stein, Mikhail Roshal, Muriel D David, Benoit S Marteyn, Noushin Farnoud, Stephane De Botton, Olivier A BernardAbstract:Recurrent mutations at R140 and R172 in Isocitrate Dehydrogenase 2 (IDH2) occur in many cancers, including ∼12% of acute myeloid leukemia (AML). In preclinical models these mutations cause accumulation of the oncogenic metabolite R-2-hydroxyglutarate (2-HG) and induce hematopoietic differentiation block. Single-agent enasidenib (AG-221/CC-90007), a selective mutant IDH2 (mIDH2) inhibitor, produced an overall response rate of 40.3% in relapsed/refractory AML (rrAML) patients with mIDH2 in a phase 1 trial. However, its mechanism of action and biomarkers associated with response remain unclear. Here, we measured 2-HG, mIDH2 allele burden, and co-occurring somatic mutations in sequential patient samples from the clinical trial and correlated these with clinical response. Furthermore, we used flow cytometry to assess inhibition of mIDH2 on hematopoietic differentiation. We observed potent 2-HG suppression in both R140 and R172 mIDH2 AML subtypes, with different kinetics, which preceded clinical response. Suppression of 2-HG alone did not predict response, because most nonresponding patients also exhibited 2-HG suppression. Complete remission (CR) with persistence of mIDH2 and normalization of hematopoietic stem and progenitor compartments with emergence of functional mIDH2 neutrophils were observed. In a subset of CR patients, mIDH2 allele burden was reduced and remained undetectable with response. Co-occurring mutations in NRAS and other MAPK pathway effectors were enriched in nonresponding patients, consistent with RAS signaling contributing to primary therapeutic resistance. Together, these data support differentiation as the main mechanism of enasidenib efficacy in relapsed/refractory AML patients and provide insight into resistance mechanisms to inform future mechanism-based combination treatment studies.
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enasidenib in mutant idh2 relapsed or refractory acute myeloid leukemia
Blood, 2017Co-Authors: Eytan M Stein, Amir T Fathi, Courtney D Dinardo, Daniel A Pollyea, Gail J Roboz, Jessica K Altman, Richard Stone, Daniel J DeangeloAbstract:Recurrent mutations in Isocitrate Dehydrogenase 2 (IDH2) occur in ∼12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML, from the phase 1 dose-escalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50 to 650 mg per day. Enasidenib 100 mg once daily was selected for the expansion phase on the basis of pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3 to 4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with a median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission, overall survival was 19.7 months. Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib. This trial was registered at www.clinicaltrials.gov as #NCT01915498.
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enasidenib in mutant idh2 relapsed or refractory acute myeloid leukemia r r aml results of a phase i dose escalation and expansion study
Journal of Clinical Oncology, 2017Co-Authors: Eytan M Stein, Amir T Fathi, Courtney D Dinardo, Daniel A Pollyea, Gail J Roboz, Jessica K Altman, Richard Stone, Ian W Flinn, Hagop M Kantarjian, Robert H CollinsAbstract:7004Background: Recurrent mutations in Isocitrate Dehydrogenase 2 (mIDH2) occur in 8-15% of AML pts. mIDH2 proteins synthesize an oncometabolite, 2-hydroxyglutarate (2HG), causing DNA and histone h...
Stephane De Botton - One of the best experts on this subject based on the ideXlab platform.
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enasidenib for the treatment of relapsed or refractory acute myeloid leukemia with an Isocitrate Dehydrogenase 2 mutation
Expert Review of Precision Medicine and Drug Development, 2020Co-Authors: Mael Heiblig, Sabine Hachemkhalife, Christophe Willekens, Jeanbaptiste Micol, Angelo Paci, Virginie Penardlacronique, Stephane De BottonAbstract:Isocitrate Dehydrogenase 2 (IDH2) is a key metabolic enzyme that converts Isocitrate to α-ketoglutarate (αKG). Somatic point mutations in IDH2 confer a gain-of-function in blast cells resulting in ...
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differentiation syndrome associated with enasidenib a selective inhibitor of mutant Isocitrate Dehydrogenase 2 analysis of a phase 1 2 study
JAMA Oncology, 2018Co-Authors: Amir T Fathi, Eytan M Stein, Stephane De Botton, Courtney D Dinardo, Irina Kline, Laurie Kenvin, Ira Gupta, Eyal C Attar, Ag Study C InvestigatorsAbstract:Importance Enasidenib mesylate, a mutant Isocitrate Dehydrogenase 2 (IDH2) protein inhibitor that promotes differentiation of leukemic myeloblasts, was recently approved by the US Food and Drug Administration for use in relapsed/refractory (R/R) mutantIDH2acute myeloid leukemia (AML). During the first study of enasidenib in humans, a minority of patients with advanced myeloid neoplasms experienced unexpected signs/symptoms of a differentiation syndrome (DS), a potentially lethal entity. Objective To characterize IDH-inhibitor–associated DS (IDH-DS) and its effective management. Design, Setting, and Participants Using data obtained from a multicenter, open-label, pivotal phase 1/2 study of enasidenib, a differentiation syndrome review committee retrospectively evaluated potential cases of IDH-DS in enasidenib-treated patients with R/R AML. Data were collected between August 27, 2013, and October 14, 2016. The committee identified and agreed on signs and symptoms characteristic of IDH-DS and developed an algorithm for identification and treatment. Among 281 patients with R/R AML enrolled in the trial, the committee identified 72 patients for review based on investigator-reported cases of DS (n = 33) or reported adverse events or signs and symptoms characteristic of IDH-DS. Interventions Treatment with enasidenib at a dosage of 50 to 650 mg/d was evaluated during the dose-escalation phase, and a dosage of 100 mg/d was used in the phase 1 expansion and phase 2, all in continual 28-day cycles. Main Outcomes and Measures Unexpected adverse events of IDH-DS during the phase 1/2 study. Results Thirty-three of the 281 patients (11.7%) were identified as having possible or probable IDH-DS. Median age of those 33 patients was 70 years (range, 38-80 years); 20 (60.6%) were male. The most frequent manifestations were dyspnea, fever, pulmonary infiltrates, and hypoxia. Median time to onset was 30 days (range, 7-129 days). Patients who experienced IDH-DS were less likely to have less than 20% bone marrow blasts (6% vs 22%,P = .04) and more likely to have undergone fewer previous anticancer regimens (median, 1.0 [range, 1-4] vs 2.0 [range, 1-14],P = .05) at study entry than those who did not. Thirteen patients (39.4%) had concomitant leukocytosis. Isocitrate Dehydrogenase differentiation syndrome was effectively managed with systemic corticosteroids. The enasidenib regimen was interrupted for 15 patients (45.5%), but permanent discontinuation of treatment was not required. Conclusions and Relevance Isocitrate Dehydrogenase differentiation syndrome is a recognizable and potentially lethal clinical entity, occurring in approximately 12% of enasidenib-treated patients with mutant-IDH2R/R AML. It requires prompt recognition and management. As use of mutant IDH inhibitors increases, these findings and recommendations are increasingly germane to care of patients with mutant-IDHneoplasms. Trial Registration clinicaltrials.gov Identifier:NCT01915498
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enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response
Blood, 2017Co-Authors: Michael Amatangelo, Lynn Quek, Alan Shih, Eytan M Stein, Mikhail Roshal, Muriel D David, Benoit S Marteyn, Noushin Farnoud, Stephane De Botton, Olivier A BernardAbstract:Recurrent mutations at R140 and R172 in Isocitrate Dehydrogenase 2 (IDH2) occur in many cancers, including ∼12% of acute myeloid leukemia (AML). In preclinical models these mutations cause accumulation of the oncogenic metabolite R-2-hydroxyglutarate (2-HG) and induce hematopoietic differentiation block. Single-agent enasidenib (AG-221/CC-90007), a selective mutant IDH2 (mIDH2) inhibitor, produced an overall response rate of 40.3% in relapsed/refractory AML (rrAML) patients with mIDH2 in a phase 1 trial. However, its mechanism of action and biomarkers associated with response remain unclear. Here, we measured 2-HG, mIDH2 allele burden, and co-occurring somatic mutations in sequential patient samples from the clinical trial and correlated these with clinical response. Furthermore, we used flow cytometry to assess inhibition of mIDH2 on hematopoietic differentiation. We observed potent 2-HG suppression in both R140 and R172 mIDH2 AML subtypes, with different kinetics, which preceded clinical response. Suppression of 2-HG alone did not predict response, because most nonresponding patients also exhibited 2-HG suppression. Complete remission (CR) with persistence of mIDH2 and normalization of hematopoietic stem and progenitor compartments with emergence of functional mIDH2 neutrophils were observed. In a subset of CR patients, mIDH2 allele burden was reduced and remained undetectable with response. Co-occurring mutations in NRAS and other MAPK pathway effectors were enriched in nonresponding patients, consistent with RAS signaling contributing to primary therapeutic resistance. Together, these data support differentiation as the main mechanism of enasidenib efficacy in relapsed/refractory AML patients and provide insight into resistance mechanisms to inform future mechanism-based combination treatment studies.
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differentiation syndrome associated with enasidenib a selective inhibitor of mutant Isocitrate Dehydrogenase 2 midh2
Journal of Clinical Oncology, 2017Co-Authors: Amir T Fathi, Eytan M Stein, Courtney D Dinardo, Irina Kline, Laurie Kenvin, Ira Gupta, Eyal C Attar, Stephane De BottonAbstract:7015Background: Enasidenib (AG-221), an oral mIDH2 inhibitor, promotes myeloid differentiation of leukemic blasts. Enasidenib treatment (Tx) can result in IDH-inhibitor-associated differentiation s...
Amir T Fathi - One of the best experts on this subject based on the ideXlab platform.
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molecular remission and response patterns in patients with mutant idh2 acute myeloid leukemia treated with enasidenib
Blood, 2019Co-Authors: Eytan M Stein, Amir T Fathi, Courtney D Dinardo, Daniel A Pollyea, Gail J Roboz, Jessica K Altman, Richard Stone, Manish R PatelAbstract:Approximately 8% to 19% of patients with acute myeloid leukemia (AML) have Isocitrate Dehydrogenase-2 (IDH2) mutations, which occur at active site arginine residues R140 and R172. IDH2 mutations produce an oncometabolite, 2-hydroxyglutarate (2-HG), which leads to DNA and histone hypermethylation and impaired hematopoietic differentiation. Enasidenib is an oral inhibitor of mutant-IDH2 proteins. This first-in-human phase 1/2 study evaluated enasidenib doses of 50 to 650 mg/d, administered in continuous 28-day cycles, in patients with mutant-IDH2 hematologic malignancies. Overall, 214 of 345 patients (62%) with relapsed or refractory (R/R) AML received enasidenib, 100 mg/d. Median age was 68 years. Forty-two patients (19.6%) attained complete remission (CR), 19 patients (10.3%) proceeded to an allogeneic bone marrow transplant, and the overall response rate was 38.8% (95% confidence interval [CI], 32.2-45.7). Median overall survival was 8.8 months (95% CI, 7.7-9.6). Response and survival were comparable among patients with IDH2-R140 or IDH2-R172 mutations. Response rates were similar among patients who, at study entry, were in relapse (37.7%) or were refractory to intensive (37.5%) or nonintensive (43.2%) therapies. Sixty-six (43.1%) red blood cell transfusion-dependent and 53 (40.2%) platelet transfusion-dependent patients achieved transfusion independence. The magnitude of 2-HG reduction on study was associated with CR in IDH2-R172 patients. Clearance of mutant-IDH2 clones was also associated with achievement of CR. Among all 345 patients, the most common grade 3 or 4 treatment-related adverse events were hyperbilirubinemia (10%), thrombocytopenia (7%), and IDH differentiation syndrome (6%). Enasidenib was well tolerated and induced molecular remissions and hematologic responses in patients with AML for whom prior treatments had failed. The study is registered at www.clinicaltrials.gov as #NCT01915498.
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differentiation syndrome associated with enasidenib a selective inhibitor of mutant Isocitrate Dehydrogenase 2 analysis of a phase 1 2 study
JAMA Oncology, 2018Co-Authors: Amir T Fathi, Eytan M Stein, Stephane De Botton, Courtney D Dinardo, Irina Kline, Laurie Kenvin, Ira Gupta, Eyal C Attar, Ag Study C InvestigatorsAbstract:Importance Enasidenib mesylate, a mutant Isocitrate Dehydrogenase 2 (IDH2) protein inhibitor that promotes differentiation of leukemic myeloblasts, was recently approved by the US Food and Drug Administration for use in relapsed/refractory (R/R) mutantIDH2acute myeloid leukemia (AML). During the first study of enasidenib in humans, a minority of patients with advanced myeloid neoplasms experienced unexpected signs/symptoms of a differentiation syndrome (DS), a potentially lethal entity. Objective To characterize IDH-inhibitor–associated DS (IDH-DS) and its effective management. Design, Setting, and Participants Using data obtained from a multicenter, open-label, pivotal phase 1/2 study of enasidenib, a differentiation syndrome review committee retrospectively evaluated potential cases of IDH-DS in enasidenib-treated patients with R/R AML. Data were collected between August 27, 2013, and October 14, 2016. The committee identified and agreed on signs and symptoms characteristic of IDH-DS and developed an algorithm for identification and treatment. Among 281 patients with R/R AML enrolled in the trial, the committee identified 72 patients for review based on investigator-reported cases of DS (n = 33) or reported adverse events or signs and symptoms characteristic of IDH-DS. Interventions Treatment with enasidenib at a dosage of 50 to 650 mg/d was evaluated during the dose-escalation phase, and a dosage of 100 mg/d was used in the phase 1 expansion and phase 2, all in continual 28-day cycles. Main Outcomes and Measures Unexpected adverse events of IDH-DS during the phase 1/2 study. Results Thirty-three of the 281 patients (11.7%) were identified as having possible or probable IDH-DS. Median age of those 33 patients was 70 years (range, 38-80 years); 20 (60.6%) were male. The most frequent manifestations were dyspnea, fever, pulmonary infiltrates, and hypoxia. Median time to onset was 30 days (range, 7-129 days). Patients who experienced IDH-DS were less likely to have less than 20% bone marrow blasts (6% vs 22%,P = .04) and more likely to have undergone fewer previous anticancer regimens (median, 1.0 [range, 1-4] vs 2.0 [range, 1-14],P = .05) at study entry than those who did not. Thirteen patients (39.4%) had concomitant leukocytosis. Isocitrate Dehydrogenase differentiation syndrome was effectively managed with systemic corticosteroids. The enasidenib regimen was interrupted for 15 patients (45.5%), but permanent discontinuation of treatment was not required. Conclusions and Relevance Isocitrate Dehydrogenase differentiation syndrome is a recognizable and potentially lethal clinical entity, occurring in approximately 12% of enasidenib-treated patients with mutant-IDH2R/R AML. It requires prompt recognition and management. As use of mutant IDH inhibitors increases, these findings and recommendations are increasingly germane to care of patients with mutant-IDHneoplasms. Trial Registration clinicaltrials.gov Identifier:NCT01915498
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enasidenib in mutant idh2 relapsed or refractory acute myeloid leukemia
Blood, 2017Co-Authors: Eytan M Stein, Amir T Fathi, Courtney D Dinardo, Daniel A Pollyea, Gail J Roboz, Jessica K Altman, Richard Stone, Daniel J DeangeloAbstract:Recurrent mutations in Isocitrate Dehydrogenase 2 (IDH2) occur in ∼12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML, from the phase 1 dose-escalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50 to 650 mg per day. Enasidenib 100 mg once daily was selected for the expansion phase on the basis of pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3 to 4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with a median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission, overall survival was 19.7 months. Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib. This trial was registered at www.clinicaltrials.gov as #NCT01915498.
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enasidenib in mutant idh2 relapsed or refractory acute myeloid leukemia r r aml results of a phase i dose escalation and expansion study
Journal of Clinical Oncology, 2017Co-Authors: Eytan M Stein, Amir T Fathi, Courtney D Dinardo, Daniel A Pollyea, Gail J Roboz, Jessica K Altman, Richard Stone, Ian W Flinn, Hagop M Kantarjian, Robert H CollinsAbstract:7004Background: Recurrent mutations in Isocitrate Dehydrogenase 2 (mIDH2) occur in 8-15% of AML pts. mIDH2 proteins synthesize an oncometabolite, 2-hydroxyglutarate (2HG), causing DNA and histone h...
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differentiation syndrome associated with enasidenib a selective inhibitor of mutant Isocitrate Dehydrogenase 2 midh2
Journal of Clinical Oncology, 2017Co-Authors: Amir T Fathi, Eytan M Stein, Courtney D Dinardo, Irina Kline, Laurie Kenvin, Ira Gupta, Eyal C Attar, Stephane De BottonAbstract:7015Background: Enasidenib (AG-221), an oral mIDH2 inhibitor, promotes myeloid differentiation of leukemic blasts. Enasidenib treatment (Tx) can result in IDH-inhibitor-associated differentiation s...
Nigel P Mongan - One of the best experts on this subject based on the ideXlab platform.
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the prognostic significance of wild type Isocitrate Dehydrogenase 2 idh2 in breast cancer
Breast Cancer Research and Treatment, 2020Co-Authors: Abrar I Aljohani, Michael S Toss, Sasagu Kurozumi, Chitra Joseph, Mohammed A Aleskandarany, Islam M Miligy, Rokaya El Ansari, Nigel P MonganAbstract:Lymphovascular invasion (LVI) is a prerequisite step in breast cancer (BC) metastasis. We have previously identified wild-type Isocitrate Dehydrogenase 2 (IDH2) as a key putative driver of LVI. Thus, we explored the prognostic significance of IDH2 at transcriptome and protein expression levels in pre-invasive and invasive disease. Utlising tissue microarrays from a large well annotated BC cohort including ductal carcinoma in situ and invasive breast cancer (IBC), IDH2 was assessed at the transcriptomic and proteomic level. The associations between clinicopathological factors including LVI status, prognosis and the expression of IDH2 were evaluated. In pure DCIS and IBC, high IDH2 protein expression was associated with features of aggressiveness including high nuclear grade, larger size, comedo necrosis and hormonal receptor negativity and LVI, higher grade, larger tumour size, high NPI, HER2 positivity, and hormonal receptor negativity, respectively. High expression of IDH2 either in mRNA or in protein levels was associated with poor patient’s outcome in both DCIS and IBC. Multivariate analysis revealed that IDH2 protein expression was an independent risk factor for shorter BC specific-survival. Further functional studies to decipher the role of IDH2 and its mechanism of action as a driver of BC progression and LVI are warranted.
