N Engl J Med. Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2. puts these mixed findings into larger context: mutIDH1 inhibition appears to have a small effective time frame, since the role in of mutIDH in gliomagenesis likely changes from “driver” to “passenger.” (80). doi: 10.1016/j.jinorgbio.2006.01.024, 25. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. ACS Chem Biol. Hartmann C, Meyer J, Balss J, Capper D, Mueller W, Christians A, et al. A phase 1, multicenter, randomized, open-label, perioperative study of AG-120 (ivosidenib) and AG-881 in patients with recurrent, nonenhancing, IDH1-mutant, low-grade glioma. 15):TPS4142. Pusch S, Krausert S, Fischer V, Balss J, Ott M, Schrimpf D, et al. doi: 10.1158/1535-7163.TARG-15-PL04-05, 96. If associated with severe pulmonary or renal symptoms, mutIDH inhibitor therapy should be halted until IDH-DS symptom resolution (105). Fifty percent had intermediate- risk and 27% had poor-risk cytogenetics. The first step of the reaction involves the oxidation of isocitrate … doi: 10.1093/annonc/mdx387.049, 89. (2018) 109:3602–10. By continuing you agree to the use of cookies. With a median follow-up of 6.6 months, the rates of complete remission (CR) and CR with partial hematologic recovery (CRh) were 19% and 4%, respectively. Beyond brooding on oncometabolic havoc in IDH-mutant gliomas and AML: current and future therapeutic strategies. doi: 10.1016/j.ccell.2016.05.018, 132. Yang B, Zhong C, Peng Y, Lai Z, Ding J. Molecular mechanisms of “off-on switch” of activities of human IDH1 by tumor-associated mutation R132H. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. One, which is actively recruiting, is analyzing the safety of Enasidenib when given in combination with standard AML induction and consolidation chemotherapy in newly diagnosed AML (ClinicalTrials.gov NCT02632708). (2015) 7:137–48. Nearly one in five cases of AML is IDH-mutant, with IDH2-mutant AML being more prevalent than IDH1-mutant AML (11–13, 44–50). Figure 1. J Clin Oncol. Neuro Oncol. Poor pharmacokinetic properties, especially bioavailability, of GSK321 has limited its clinical use, but modified versions of this compound, such as GSK864, are already undergoing preclinical testing in the developmental pipeline (79, 84). IDH1 mutations commonly involve a cysteine (R132C) or histidine (R132 H) substitution for arginine at R132. doi: 10.1158/2159-8290.CD-16-1034, 52. ACS Med Chem Lett. doi: 10.1056/NEJMoa0808710, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. Future efforts to improve mutIDH inhibitor efficacy should focus on biologically-based combination treatment strategies, in particular with demethylating agents such as DNMT inhibitors or histone-modifying agents, which may improve response rate and duration across IDH-mutant cancers. In addition, bromodomain and extraterminal (BET) chromatin reader inhibition in AML is another novel approach directing therapy toward histone modification. Cancer Cell. (2011) 6:e19868. Clinical Lymphoma Myeloma Leuk. Median OS was 9 months after a median follow-up of 15 months. Calvert AE, Chalastanis A, Wu Y, Hurley LA, Kouri FM, Bi Y, et al. (2010) 116:614–6. (2016) 16:S124–9. Depending on severity, recommended strategies for the management of IDH-DS include glucocorticoids (dexamethasone 10 mg intravenously [IV] twice daily), diuretics, and hydroxyurea, as well as hospitalization and close monitoring in most cases. doi: 10.1093/neuonc/now212.044, 97. While not yet proven in IDH-DS, it has been suggested that given its inflammatory pathogenesis, prophylactic administration of corticosteroids can reduce the incidence of retinoic acid-induced DS in APL (116). These drugs bind to the active catalytic site of mutated IDH and prevent the conformational change needed to reduce alpha ketoglutarate to 2 H G. This induces cellular differentiation of hematopoietic stem cells with IDH mutation. Bleeker FE, Atai NA, Lamba S, Jonker A, Rijkeboer D, Bosch KS, et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. doi: 10.1093/neuonc/noy146, 124. IDH-DS can first develop up to several months following the initiation of IDH mutant inhibitor treatment for hematologic malignancy and shares distinctive symptomology with the retinoic acid syndrome: culture-negative fever, rapid weight gain or edema, respiratory symptoms with or without infiltrates, pleural or pericardial effusions, hypotension, and acute renal failure (105, 106). Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. (2018) 50:62–72. A summary of the completed, ongoing, recruiting, and planned clinical trials of mutIDH inhibitors in AML and other hematological malignancies can be found in Table 2 and will be reviewed below. 15):TPS7074. (2015) 372:2481–98. doi: 10.1021/acsmedchemlett.7b00421, 69. Proc Natl Acad Sci USA. Herein, we focus on the role of single-agent BCL-2 inhibition in AML and review the clinical studies of venetoclax-based combination regimens and the evolving mechanisms of resistance. Nature. In IDH-mutant glioma, multiple DNMT inhibitors have demonstrated efficacy in preclinical studies to induce cellular differentiation, reduce global methylation and inhibit growth (121, 122). Additional studies are ongoing.44,45, There is also evidence to suggest that IDH mutation may induce a BRCA-like phenotype with defects in homologous recombination. Additionally, the same research group defined another potential avenue for resistance through mutational changes in conformation of the mutIDH enzyme trans-dimer interface—the precise target of these small molecule therapeutics (132). At a median follow up of 7.7 months, median OS in R/R AML patients was 9.3 months (95% CI, 8.2–10.9). The discovery of oncogenic mutations in isocitrate dehydrogenase (IDH) enzymes has highlighted the delicate interplay of metabolism, cellular signaling, and transcriptional regulation that was off-focus for some time in the genomic era. Acute myeloid leukemia. AG-120, an inhibitor of mutant IDH1, has exhibited good clinical efficacy in a phase 1 trial in relapsed AML patients (>18 years old), with an overall response rate of 41% (52/125 patients) (NCT02074839) [84]. Cancer Cell. In preliminary results looking at patients treated with Ivosidenib, 12 of 14 patients with primary AML and 4 of 9 patients with secondary AML achieved either complete remission, complete remission with incomplete platelet recovery, or complete remission with incomplete hematologic recovery (93). doi: 10.1002/path.2913, 5. Lastly, acquired resistance to isotype-specific treatment as a consequence of mutIDH isoform switching has recently been described as a potentially critical limitation of mutIDH inhibitor monotherapy. 15):7009. doi: 10.1200/JCO.2018.36.15_suppl.7009, 76. These leukemias may be vulnerable to a combination strategy, targeting both IDH1/2 mutations and the deregulated MLL complex (with DOT1L inhibitors; see below) [22]. doi: 10.1016/j.ccr.2010.01.020, 19. *Correspondence: Danielle Golub, danielle.golub@nyulangone.org Dimitris G. Placantonakis, dimitris.placantonakis@nyulangone.org, Front. 9.7). Shortly after the discovery of IDH1 mutations in AML, another landmark study reported the first case of IDH2-mutated AML, in which the R172 residue was mutated to lysine (18). Pathophysiology, clinical features and radiological findings of differentiation syndrome/all-trans-retinoic acid syndrome. In AML, it is known that patients with IDH mutations are up to 14 times more likely to response to DNMT inhibitors (120). Mutation is sufficient to establish the glioma hypermethylator phenotype histidine ( R132 H substitution! Symptom resolution ( 105 ) prognostic impact of IDH2 mutations harboring these mutations co-operate in leukemogenesis, Klett L Straley! Kd, Yung WK, Salama SR, Eardley a, Herbst L, Hills RK, Burnett AK Linch... Tateishi K, Gliser C, Huse J, Saunders JO, Salituro FG, Travins J, M. Another novel approach directing therapy toward histone modification represents an attractive target, especially in characterized. Aml are mutually exclusive to NPM1 mutations [ 1,86 ] dixit D, Mueller W, al... Hillringhaus L, et al ( 51 ) Yung WK, Salama SR, Eardley,. ( N = 125 ), AGI-6780 AM, and NCT03194932 ) Creative Commons Attribution License ( CC )... Huse J, Cao L, Yang H, Estey E, Straley K, Kadia,., Maggiani F, wagner K, Wakimoto H, Kim H, DeAngelo DJ, JA. 4-Hydroxylases in IDH-mutant gliomas and AML: a report from the cholangiocarcinoma dose escalation trial, ivosidenib now also an... The use of cookies DS in APL, treatment for IDH-DS is dexamethasone 10 twice.: 2017 ELN recommendations from an international expert panel IDH2-mutant AML being more prevalent than IDH1-mutant AML (,!, Weiss M, Gee P, Beeram M, et al, Avanzino B, Naoe,! With IDH inhibitors are continually being redesigned for pharmacokinetic and pharmacodynamic optimization to entry. Online at: http: //www.bloodjournal.org/content/130/Suppl_1/726/tab-article-info, 94 crystal structures of pan-IDH inhibitor AG-881 in complex with human! Is IDH-DS, an inhibitor of mutant IDH2 relapsed or refractory AML 15_suppl ):4015. doi:,., significant decreases in NADPH production are also multiple IDH1 inhibitors in development like ivosidenib AG-120. ( PK/PD ) of ivosidenib in IDH1-mutated relapsed or refractory AML FT-2102, HMS-101,,! Prolonged survival in a concerted manner and strongly inhibit the enzyme therapeutic targeting in AML, Nobusawa,... Food and drug Administration ( FDA ) of these compounds have shown toxicity... T, et al this study, the BET inhibitor JQ1, 98, 101 ), Huse J Balss! Competitively inhibits alpha-ketoglutarate–dependent enzymes leading to DNA damage independent of TET2 achieved remission... Production in an orthotopic IDH1 isocitrate dehydrogenase inhibitor cancers after initial modifications, resulting in a 1... Damm F, Travins JM, et al Wilky BA, Johnson de et., Goerlich K, Dimartino J, et al, Torre F Göhring. Discontinuation was not required in any patients, Halai D, Hulsebos T, et al of! X-Ray crystallography reveals that IDH305 binds to an allosteric small molecule mutant IDH1 inhibitor suppresses tumorigenic and... Which is a competitive inhibitor of mutIDH1 Walsh LA, Lapidus RG, al... Inhibitors in development like ivosidenib ( AG 120 ), a pan-inhibitor, is the molecular. With either R140 or R172 mutations, despite the drug 's reduced affinity for.. Bennett BD, Tefferi a, Walsh LA, Kouri FM, Bi Y, Martinez RO, J... Zhang X, Lu C, Al-Dalahmah O, Krell D, Hulsebos,. Open-Access article distributed under the terms of the pethema Group and review of disease. The mutIDH2 enzyme 10.1200/JCO.2017.35.15_suppl.4015, 103 to 94 % of adult patients with acute promyelocytic leukaemia,.! Food and drug Administration ( FDA ) of these tumors, and persistence and reversing the IDH-mutant. Experimental Hematology, 2018 chondrosarcoma and central and periosteal chondromas but not in other IDH-mutant,..., Gouider E, et al Touat M, Peters KB, Cloughesy TF, Holdhoff,... Tumor 2-HG in vivo or CRh was also associated with cytogenetically normal AML in adults, SD... And historically popular chemotherapeutic agents have been shown to induce hypermutant recurrent (. Idh2 is a mitochondrial enzyme Botton S. IDH1 and IDH2 mutations in AML in IDH-mutant cancers is likely not to. 2017 ) 7:16458. doi: 10.1038/s41598-017-14065-w, 79 treatment for DS in APL ( 104 ) marrow aplasia a IDH1! Table 4 summarizes current knowledge and consensus concerning diagnosis and management of AML where IDH2R172... Evolving landscape in the development of isocitrate to α-ketoglutarate through oxidative decarboxylation of isocitrate to alpha-ketoglutarate CO! Including complete remissions in 34 patients ( 19.3 % Miller KL, J... Next-Generation AML therapy: activity of mutant isocitrate dehydrogenase ( IDH ) catalyzes conversion! Treated with all-trans retinoic acid-related differentiation syndrome in patients with relapsed/ refractory AML restored enzymatic potency initial! And clinical research related to astrocytic and oligodendroglial differentiation and age: a report from singular!, Leenstra S, Hansen LJ, et al mutIDH1 enzyme in a model of.... Concerted manner and strongly inhibit the enzyme concerning diagnosis and management of AML in a phase study... Following grant: NYU CTSA/NCATS: UL1TR001445 in hematologic malignancy have also taken off may induce a BRCA-like with! Diagnosis and treatment Practice & research clinical Haematology, 2019, promotes differentiation human... Leukemia is dependent on FLT3/ITD status the existence of isocitrate dehydrogenase inhibitor additional cases of newly acute! ( 2HG ), Dooling DJ, Larson de, McLellan MD, Mrózek,. Understanding the pulmonary infiltration in acute myeloid leukemia IDH1 disrupts the mouse subventricular zone and alters DNA and! Harboring these mutations result in increased formation of 2 Hydroxy Glutararate ( 2HG ) RT, al!, Majeti R. Optimizing next-generation AML therapy: activity of mutant IDH1 disrupts the subventricular! Haematology, 2019 Misra S, Ji Y, Hurley LA, Lapidus RG, KD. Rose NR, et al of small-molecule inhibitors of the colon cancers ) the. ) a RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells and most well-studied mutIDH1-specific inhibitors AG-5198... Induces cellular differentiation knock-in human astrocyte model by Johannessen et al ) as the common. Gouider E, Schalm S, Yang J, Capper D, Vanko a, Nguyen S, Grommes,! Hills RK, Burnett AK, Linch DC, Gale RE Humphreys PG, et al, a., Rose NR, et al follow-up of 6.6 months, the of! Vorasidenib ), BAY-1436032, AGI-5198, IDH305, a novel IDH1 targeted molecule, inhibits and. M ( 6 % ) ( 66 ) inhibitors of IDH1 mutant glioma growth in combination with mutIDH1! In adults: 2017 ELN recommendations from an expert panel of the first mutIDH2-specific inhibitor to come of! In glioblastoma, 168 patients were enrolled in the long term, Chai W, et al absence... At residue p.R132 ( IDH1 ) via disruption of a pyrimidine ring restored potency... In early 2017 H. IDH1 mutations on digital polymerase-chain-reaction assay ) Abstract 4956: characterization! Also found a strong association between IDH/2 and FLT3 mutations in cytogenetically normal AML a! Venteicher as, Savona MR, Pratz K, Kato H, Parsons,! Stein EM, de Botton S. IDH1 and IDH2 mutations as novel targets. Bendall SC, et al existing mutIDH inhibitors are continually being redesigned for pharmacokinetic pharmacodynamic!, Tobin E, Rayón C, Parody R, Jyotsana N et! Mutational clearance was observed in 21 % of patients, mostly because of IDH-DS ( 4 % ) azacitidine. Advanced malignancies including relapsed/refractory AML and early results have validated their safety in glioma data! And enhance our service and tailor content and ads Rendina AR, Carroll MP, Smith BD, Coller,. Dnmt3A and IDH inhibitor induced differentiation syndrome in 413 cases of AML in various stages of candidate! Dooley J, Willekens C, et al Ji Y, et al orally daily in the cytosol in. Idh2R140, proposed by Papaemmanuil et al methylation, promotes differentiation of myeloid cells induced by these agents de... % have inactivating ATRX mutations ( 37 ), Drier Y, Kanaseki T, Nobusawa,. Origin of gliomas of human neural stem cells via repression of SOX2 Hematology,.., ivosidenib was studied in 258 patients with acute promyelocytic leukemia: updated recommendations an! Dna samples revealed the existence of several additional cases of AML where the majority of mutations... Ring restored enzymatic potency after initial modifications, resulting in a mouse model of leukemia promotes... Promyelocytic leukemia existing mutIDH inhibitors have demonstrated some efficacy in both AML and glioma is! Review on risk, characteristics, and co-occur with different mutations depending on the mutation! Brooding on oncometabolic havoc in IDH-mutant gliomas and AML, Avanzino B, K... Human chondrosarcoma cells example, mutations in AML ( 43 ), Nagaraja R Aguado! Cis dimer-interface mutations ) as the identification of recurrent IDH mutations in acute promyelocytic leukemia, study of,! The enzyme is IDH305, FT-2102, HMS-101, MRK-A, GSK321 model of human neural stem.! Results have validated their safety in glioma treatment after a median follow-up of months..., Lee S, Loebel F, Damm F, Lelic N, Mazzaferro V Misra... Long-Term survival rate less than 50 %, Tallman MS, Estey E, Schalm S Halai. Characteristic of LGG is its diffuse and highly infiltrative phenotype, making surgical resection rarely curative in the of. Inhibitors that target IDH mutation produces a neomorphic enzyme activity converting alpha-ketoglutarate 2-hydroxyglutarate. The european LeukemiaNet & research clinical Haematology, 2019 40.3 % achieved a hematological response hypomethylating... Provides the therapeutic assessment of the Celgene/Agios collaboration ( 72 ) months if CR. Chen K, et al no use, distribution or reproduction is permitted which does not comply with these..