Targeting IDH Mutations in AML: Wielding the Double-edged Sword of Differentiation

Author(s): Justin S. Becker, Amir T. Fathi*

Journal Name: Current Cancer Drug Targets

Volume 20 , Issue 7 , 2020

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer
Call for Editor


The genomic characterization of acute myeloid leukemia (AML) by DNA sequencing has illuminated subclasses of the disease, with distinct driver mutations, that might be responsive to targeted therapies. Approximately 15-23% of AML genomes harbor mutations in one of two isoforms of isocitrate dehydrogenase (IDH1 or IDH2). These enzymes are constitutive mediators of basic cellular metabolism, but their mutated forms in cancer synthesize an abnormal metabolite, 2- hydroxyglutarate, that in turn acts as a competitive inhibitor of multiple gene regulatory enzymes. As a result, leukemic IDH mutations cause changes in genome structure and gene activity, culminating in an arrest of normal myeloid differentiation. These discoveries have motivated the development of a new class of selective small molecules with the ability to inhibit the mutant IDH enzymes while sparing normal cellular metabolism. These agents have shown promising anti-leukemic activity in animal models and early clinical trials, and are now entering Phase 3 study. This review will focus on the growing preclinical and clinical data evaluating IDH inhibitors for the treatment of IDH-mutated AML. These data suggest that inducing cellular differentiation is central to the mechanism of clinical efficacy for IDH inhibitors, while also mediating toxicity for patients who experience IDH Differentiation Syndrome. Ongoing trials are studying the efficacy of IDH inhibitors in combination with other AML therapies, both to evaluate potential synergistic combinations as well as to identify the appropriate place for IDH inhibitors within existing standard-of-care regimens.

Keywords: AML, isocitrate dehydrogenase, IDH1, IDH2, ivosidenib, enasidenib, differentiation syndrome, epigenetics.

Döhner, H.; Weisdorf, D.J.; Bloomfield, C.D. Acute Myeloid Leukemia. N. Engl. J. Med., 2015, 373(12), 1136-1152.
[] [PMID: 26376137]
Metzeler, K.H.; Herold, T.; Rothenberg-Thurley, M.; Amler, S.; Sauerland, M.C.; Görlich, D.; Schneider, S.; Konstandin, N.P.; Dufour, A.; Bräundl, K.; Ksienzyk, B.; Zellmeier, E.; Hartmann, L.; Greif, P.A.; Fiegl, M.; Subklewe, M.; Bohlander, S.K.; Krug, U.; Faldum, A.; Berdel, W.E.; Wörmann, B.; Büchner, T.; Hiddemann, W.; Braess, J.; Spiekermann, K. AMLCG Study Group. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood, 2016, 128(5), 686-698.
[] [PMID: 27288520]
Flavahan, W.A.; Gaskell, E.; Bernstein, B.E. Epigenetic plasticity and the hallmarks of cancer. Science, 2017, 357(6348) eaal2380
[] [PMID: 28729483]
Wouters, B.J.; Delwel, R. Epigenetics and approaches to targeted epigenetic therapy in acute myeloid leukemia. Blood, 2016, 127(1), 42-52.
[] [PMID: 26660432]
Allis, C.D.; Jenuwein, T. The molecular hallmarks of epigenetic control. Nat. Rev. Genet., 2016, 17(8), 487-500.
[] [PMID: 27346641]
Jones, P.A. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet., 2012, 13(7), 484-492.
[] [PMID: 22641018]
Gardin, C.; Dombret, H. Hypomethylating agents as a therapy for AML. Curr. Hematol. Malig. Rep., 2017, 12(1), 1-10.
[] [PMID: 28286907]
Medeiros, B.C.; Satram-Hoang, S.; Hurst, D.; Hoang, K.Q.; Momin, F.; Reyes, C. Big data analysis of treatment patterns and outcomes among elderly acute myeloid leukemia patients in the United States. Ann. Hematol., 2015, 94(7), 1127-1138.
[] [PMID: 25791241]
Dombret, H.; Seymour, J.F.; Butrym, A.; Wierzbowska, A.; Selleslag, D.; Jang, J.H.; Kumar, R.; Cavenagh, J.; Schuh, A.C.; Candoni, A.; Récher, C.; Sandhu, I.; Bernal del Castillo, T.; Al-Ali, H.K.; Martinelli, G.; Falantes, J.; Noppeney, R.; Stone, R.M.; Minden, M.D.; McIntyre, H.; Songer, S.; Lucy, L.M.; Beach, C.L.; Döhner, H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood, 2015, 126(3), 291-299.
[] [PMID: 25987659]
Mardis, E.R.; Ding, L.; Dooling, D.J.; Larson, D.E.; McLellan, M.D.; Chen, K.; Koboldt, D.C.; Fulton, R.S.; Delehaunty, K.D.; McGrath, S.D.; Fulton, L.A.; Locke, D.P.; Magrini, V.J.; Abbott, R.M.; Vickery, T.L.; Reed, J.S.; Robinson, J.S.; Wylie, T.; Smith, S.M.; Carmichael, L.; Eldred, J.M.; Harris, C.C.; Walker, J.; Peck, J.B.; Du, F.; Dukes, A.F.; Sanderson, G.E.; Brummett, A.M.; Clark, E.; McMichael, J.F.; Meyer, R.J.; Schindler, J.K.; Pohl, C.S.; Wallis, J.W.; Shi, X.; Lin, L.; Schmidt, H.; Tang, Y.; Haipek, C.; Wiechert, M.E.; Ivy, J.V.; Kalicki, J.; Elliott, G.; Ries, R.E.; Payton, J.E.; Westervelt, P.; Tomasson, M.H.; Watson, M.A.; Baty, J.; Heath, S.; Shannon, W.D.; Nagarajan, R.; Link, D.C.; Walter, M.J.; Graubert, T.A.; DiPersio, J.F.; Wilson, R.K.; Ley, T.J. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med., 2009, 361(11), 1058-1066.
[] [PMID: 19657110]
Yan, H.; Parsons, D.W.; Jin, G.; McLendon, R.; Rasheed, B.A.; Yuan, W.; Kos, I.; Batinic-Haberle, I.; Jones, S.; Riggins, G.J.; Friedman, H.; Friedman, A.; Reardon, D.; Herndon, J.; Kinzler, K.W.; Velculescu, V.E.; Vogelstein, B.; Bigner, D.D. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med., 2009, 360(8), 765-773.
[] [PMID: 19228619]
Ward, P.S.; Patel, J.; Wise, D.R.; Abdel-Wahab, O.; Bennett, B.D.; Coller, H.A.; Cross, J.R.; Fantin, V.R.; Hedvat, C.V.; Perl, A.E.; Rabinowitz, J.D.; Carroll, M.; Su, S.M.; Sharp, K.A.; Levine, R.L.; Thompson, C.B. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell, 2010, 17(3), 225-234.
[] [PMID: 20171147]
Parker, S.J.; Metallo, C.M. Metabolic consequences of oncogenic IDH mutations. Pharmacol. Ther., 2015, 152, 54-62.
[] [PMID: 25956465]
Waitkus, M.S.; Diplas, B.H.; Yan, H. Isocitrate dehydrogenase mutations in gliomas. Neuro-oncol., 2016, 18(1), 16-26.
[] [PMID: 26188014]
DiNardo, C.D.; Stein, E.M.; de Botton, S.; Roboz, G.J.; Altman, J.K.; Mims, A.S.; Swords, R.; Collins, R.H.; Mannis, G.N.; Pollyea, D.A.; Donnellan, W.; Fathi, A.T.; Pigneux, A.; Erba, H.P.; Prince, G.T.; Stein, A.S.; Uy, G.L.; Foran, J.M.; Traer, E.; Stuart, R.K.; Arellano, M.L.; Slack, J.L.; Sekeres, M.A.; Willekens, C.; Choe, S.; Wang, H.; Zhang, V.; Yen, K.E.; Kapsalis, S.M.; Yang, H.; Dai, D.; Fan, B.; Goldwasser, M.; Liu, H.; Agresta, S.; Wu, B.; Attar, E.C.; Tallman, M.S.; Stone, R.M.; Kantarjian, H.M. durable remissions with ivosidenib in idh1-mutated relapsed or refractory AML. N. Engl. J. Med., 2018, 378(25), 2386-2398.
[] [PMID: 29860938]
Kosmider, O.; Gelsi-Boyer, V.; Slama, L.; Dreyfus, F.; Beyne-Rauzy, O.; Quesnel, B.; Hunault-Berger, M.; Slama, B.; Vey, N.; Lacombe, C.; Solary, E.; Birnbaum, D.; Bernard, O.A.; Fontenay, M. Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms. Leukemia, 2010, 24(5), 1094-1096.
[] [PMID: 20376084]
Thol, F.; Weissinger, E.M.; Krauter, J.; Wagner, K.; Damm, F.; Wichmann, M.; Göhring, G.; Schumann, C.; Bug, G.; Ottmann, O.; Hofmann, W.K.; Schlegelberger, B.; Ganser, A.; Heuser, M. IDH1 mutations in patients with myelodysplastic syndromes are associated with an unfavorable prognosis. Haematologica, 2010, 95(10), 1668-1674.
[] [PMID: 20494930]
Tefferi, A.; Lasho, T.L.; Abdel-Wahab, O.; Guglielmelli, P.; Patel, J.; Caramazza, D.; Pieri, L.; Finke, C.M.; Kilpivaara, O.; Wadleigh, M.; Mai, M.; McClure, R.F.; Gilliland, D.G.; Levine, R.L.; Pardanani, A.; Vannucchi, A.M. IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis. Leukemia, 2010, 24(7), 1302-1309.
[] [PMID: 20508616]
Soverini, S.; Score, J.; Iacobucci, I.; Poerio, A.; Lonetti, A.; Gnani, A.; Colarossi, S.; Ferrari, A.; Castagnetti, F.; Rosti, G.; Cervantes, F.; Hochhaus, A.; Delledonne, M.; Ferrarini, A.; Sazzini, M.; Luiselli, D.; Baccarani, M.; Cross, N.C.; Martinelli, G. IDH2 somatic mutations in chronic myeloid leukemia patients in blast crisis. Leukemia, 2011, 25(1), 178-181.
[] [PMID: 20962862]
Dang, L.; White, D.W.; Gross, S.; Bennett, B.D.; Bittinger, M.A.; Driggers, E.M.; Fantin, V.R.; Jang, H.G.; Jin, S.; Keenan, M.C.; Marks, K.M.; Prins, R.M.; Ward, P.S.; Yen, K.E.; Liau, L.M.; Rabinowitz, J.D.; Cantley, L.C.; Thompson, C.B.; Vander Heiden, M.G.; Su, S.M. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature, 2009, 462(7274), 739-744.
[] [PMID: 19935646]
Fathi, A.T.; Sadrzadeh, H.; Borger, D.R.; Ballen, K.K.; Amrein, P.C.; Attar, E.C.; Foster, J.; Burke, M.; Lopez, H.U.; Matulis, C.R.; Edmonds, K.M.; Iafrate, A.J.; Straley, K.S.; Yen, K.E.; Agresta, S.; Schenkein, D.P.; Hill, C.; Emadi, A.; Neuberg, D.S.; Stone, R.M.; Chen, Y.B. Prospective serial evaluation of 2-hydroxyglutarate, during treatment of newly diagnosed acute myeloid leukemia, to assess disease activity and therapeutic response. Blood, 2012, 120(23), 4649-4652.
[] [PMID: 23074281]
Xu, W.; Yang, H.; Liu, Y.; Yang, Y.; Wang, P.; Kim, S-H.; Ito, S.; Yang, C.; Wang, P.; Xiao, M-T.; Liu, L.X.; Jiang, W.Q.; Liu, J.; Zhang, J.Y.; Wang, B.; Frye, S.; Zhang, Y.; Xu, Y.H.; Lei, Q.Y.; Guan, K.L.; Zhao, S.M.; Xiong, Y. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell, 2011, 19(1), 17-30.
[] [PMID: 21251613]
Tahiliani, M.; Koh, K.P.; Shen, Y.; Pastor, W.A.; Bandukwala, H.; Brudno, Y.; Agarwal, S.; Iyer, L.M.; Liu, D.R.; Aravind, L.; Rao, A. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science, 2009, 324(5929), 930-935.
[] [PMID: 19372391]
Guo, J.U.; Su, Y.; Zhong, C.; Ming, G.L.; Song, H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell, 2011, 145(3), 423-434.
[] [PMID: 21496894]
He, Y-F.; Li, B-Z.; Li, Z.; Liu, P.; Wang, Y.; Tang, Q.; Ding, J.; Jia, Y.; Chen, Z.; Li, L.; Sun, Y.; Li, X.; Dai, Q.; Song, C.X.; Zhang, K.; He, C.; Xu, G.L. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science, 2011, 333(6047), 1303-1307.
[] [PMID: 21817016]
Ito, S.; Shen, L.; Dai, Q.; Wu, S.C.; Collins, L.B.; Swenberg, J.A.; He, C.; Zhang, Y. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science, 2011, 333(6047), 1300-1303.
[] [PMID: 21778364]
Figueroa, M.E.; Abdel-Wahab, O.; Lu, C.; Ward, P.S.; Patel, J.; Shih, A.; Li, Y.; Bhagwat, N.; Vasanthakumar, A.; Fernandez, H.F.; Tallman, M.S.; Sun, Z.; Wolniak, K.; Peeters, J.K.; Liu, W.; Choe, S.E.; Fantin, V.R.; Paietta, E.; Löwenberg, B.; Licht, J.D.; Godley, L.A.; Delwel, R.; Valk, P.J.; Thompson, C.B.; Levine, R.L.; Melnick, A. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell, 2010, 18(6), 553-567.
[] [PMID: 21130701]
Losman, J-A.; Looper, R.E.; Koivunen, P.; Lee, S.; Schneider, R.K.; McMahon, C.; Cowley, G.S.; Root, D.E.; Ebert, B.L.; Kaelin, W.G., Jr (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science, 2013, 339(6127), 1621-1625.
[] [PMID: 23393090]
Lu, C.; Ward, P.S.; Kapoor, G.S.; Rohle, D.; Turcan, S.; Abdel-Wahab, O.; Edwards, C.R.; Khanin, R.; Figueroa, M.E.; Melnick, A.; Wellen, K.E.; O’Rourke, D.M.; Berger, S.L.; Chan, T.A.; Levine, R.L.; Mellinghoff, I.K.; Thompson, C.B. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature, 2012, 483(7390), 474-478.
[] [PMID: 22343901]
Abbas, S.; Lugthart, S.; Kavelaars, F.G.; Schelen, A.; Koenders, J.E.; Zeilemaker, A.; van Putten, W.J.L.; Rijneveld, A.W.; Löwenberg, B.; Valk, P.J.M. Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: Prevalence and prognostic value. Blood, 2010, 116(12), 2122-2126.
[] [PMID: 20538800]
Paschka, P.; Schlenk, R.F.; Gaidzik, V.I.; Habdank, M.; Krönke, J.; Bullinger, L.; Späth, D.; Kayser, S.; Zucknick, M.; Götze, K.; Horst, H.A.; Germing, U.; Döhner, H.; Döhner, K. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J. Clin. Oncol., 2010, 28(22), 3636-3643.
[] [PMID: 20567020]
Marcucci, G.; Maharry, K.; Wu, Y-Z.; Radmacher, M.D.; Mrózek, K.; Margeson, D.; Holland, K.B.; Whitman, S.P.; Becker, H.; Schwind, S.; Metzeler, K.H.; Powell, B.L.; Carter, T.H.; Kolitz, J.E.; Wetzler, M.; Carroll, A.J.; Baer, M.R.; Caligiuri, M.A.; Larson, R.A.; Bloomfield, C.D. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J. Clin. Oncol., 2010, 28(14), 2348-2355.
[] [PMID: 20368543]
Boissel, N.; Nibourel, O.; Renneville, A.; Gardin, C.; Reman, O.; Contentin, N.; Bordessoule, D.; Pautas, C.; de Revel, T.; Quesnel, B.; Huchette, P.; Philippe, N.; Geffroy, S.; Terre, C.; Thomas, X.; Castaigne, S.; Dombret, H.; Preudhomme, C. Prognostic impact of isocitrate dehydrogenase enzyme isoforms 1 and 2 mutations in acute myeloid leukemia: A study by the Acute Leukemia French Association group. J. Clin. Oncol., 2010, 28(23), 3717-3723.
[] [PMID: 20625116]
Upadhyay, V.A.; Brunner, A.M.; Fathi, A.T. Isocitrate dehydrogenase (IDH) inhibition as treatment of myeloid malignancies: Progress and future directions. Pharmacol. Ther., 2017, 177, 123-128.
[] [PMID: 28315358]
Weissmann, S.; Alpermann, T.; Grossmann, V.; Kowarsch, A.; Nadarajah, N.; Eder, C.; Dicker, F.; Fasan, A.; Haferlach, C.; Haferlach, T.; Kern, W.; Schnittger, S.; Kohlmann, A. Landscape of TET2 mutations in acute myeloid leukemia. Leukemia, 2012, 26(5), 934-942.
[] [PMID: 22116554]
Liu, W-J.; Tan, X-H.; Luo, X-P.; Guo, B-P.; Wei, Z-J.; Ke, Q.; He, S.; Cen, H. Prognostic significance of Tet methylcytosine dioxygenase 2 (TET2) gene mutations in adult patients with acute myeloid leukemia: a meta-analysis. Leuk. Lymphoma, 2014, 55(12), 2691-2698.
[] [PMID: 24524305]
Brunner, A.M.; Neuberg, D.S.; Wander, S.A.; Sadrzadeh, H.; Ballen, K.K.; Amrein, P.C.; Attar, E.; Hobbs, G.S.; Chen, Y-B.; Perry, A.; Connolly, C.; Joseph, C.; Burke, M.; Ramos, A.; Galinsky, I.; Yen, K.; Yang, H.; Straley, K.; Agresta, S.; Adamia, S.; Borger, D.R.; Iafrate, A.; Graubert, T.A.; Stone, R.M.; Fathi, A.T. Isocitrate dehydrogenase 1 and 2 mutations, 2-hydroxyglutarate levels, and response to standard chemotherapy for patients with newly diagnosed acute myeloid leukemia. Cancer, 2019, 125(4), 541-549.
[] [PMID: 30422308]
Green, C.L.; Evans, C.M.; Hills, R.K.; Burnett, A.K.; Linch, D.C.; Gale, R.E. The prognostic significance of IDH1 mutations in younger adult patients with acute myeloid leukemia is dependent on FLT3/ITD status. Blood, 2010, 116(15), 2779-2782.
[] [PMID: 20651067]
Green, C.L.; Evans, C.M.; Zhao, L.; Hills, R.K.; Burnett, A.K.; Linch, D.C.; Gale, R.E. The prognostic significance of IDH2 mutations in AML depends on the location of the mutation. Blood, 2011, 118(2), 409-412.
[] [PMID: 21596855]
Fathi, A.T.; Wander, S.A.; Faramand, R.; Emadi, A. Biochemical, epigenetic, and metabolic approaches to target IDH mutations in acute myeloid leukemia. Semin. Hematol., 2015, 52(3), 165-171.
[] [PMID: 26111463]
Golub, D.; Iyengar, N.; Dogra, S.; Wong, T.; Bready, D.; Tang, K.; Modrek, A.S.; Placantonakis, D.G. mutant isocitrate dehydrogenase inhibitors as targeted cancer therapeutics. Front. Oncol., 2019, 9, 417.
[] [PMID: 31165048]
Urban, D.J.; Martinez, N.J.; Davis, M.I.; Brimacombe, K.R.; Cheff, D.M.; Lee, T.D.; Henderson, M.J.; Titus, S.A.; Pragani, R.; Rohde, J.M.; Liu, L.; Fang, Y.; Karavadhi, S.; Shah, P.; Lee, O.W.; Wang, A.; McIver, A.; Zheng, H.; Wang, X.; Xu, X.; Jadhav, A.; Simeonov, A.; Shen, M.; Boxer, M.B.; Hall, M.D. Assessing inhibitors of mutant isocitrate dehydrogenase using a suite of pre-clinical discovery assays. Sci. Rep., 2017, 7(1), 12758.
[] [PMID: 28986582]
Jones, S.; Ahmet, J.; Ayton, K.; Ball, M.; Cockerill, M.; Fairweather, E.; Hamilton, N.; Harper, P.; Hitchin, J.; Jordan, A.; Levy, C.; Lopez, R.; McKenzie, E.; Packer, M.; Plant, D.; Simpson, I.; Simpson, P.; Sinclair, I.; Somervaille, T.C.; Small, H.; Spencer, G.J.; Thomson, G.; Tonge, M.; Waddell, I.; Walsh, J.; Waszkowycz, B.; Wigglesworth, M.; Wiseman, D.H.; Ogilvie, D. Discovery and optimization of allosteric inhibitors of mutant isocitrate dehydrogenase 1 (R132H IDH1) displaying activity in human acute myeloid leukemia cells. J. Med. Chem., 2016, 59(24), 11120-11137.
[] [PMID: 28002956]
Levell, J.R.; Caferro, T.; Chenail, G.; Dix, I.; Dooley, J.; Firestone, B.; Fortin, P.D.; Giraldes, J.; Gould, T.; Growney, J.D.; Jones, M.D.; Kulathila, R.; Lin, F.; Liu, G.; Mueller, A.; van der Plas, S.; Slocum, K.; Smith, T.; Terranova, R.; Touré, B.B.; Tyagi, V.; Wagner, T.; Xie, X.; Xu, M.; Yang, F.S.; Zhou, L.X.; Pagliarini, R.; Cho, Y.S. Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as allosteric and mutant specific inhibitors of IDH1. ACS Med. Chem. Lett., 2016, 8(2), 151-156.
[] [PMID: 28197303]
Wang, F.; Travins, J.; DeLaBarre, B.; Penard-Lacronique, V.; Schalm, S.; Hansen, E.; Straley, K.; Kernytsky, A.; Liu, W.; Gliser, C.; Yang, H.; Gross, S.; Artin, E.; Saada, V.; Mylonas, E.; Quivoron, C.; Popovici-Muller, J.; Saunders, J.O.; Salituro, F.G.; Yan, S.; Murray, S.; Wei, W.; Gao, Y.; Dang, L.; Dorsch, M.; Agresta, S.; Schenkein, D.P.; Biller, S.A.; Su, S.M.; de Botton, S.; Yen, K.E. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science, 2013, 340(6132), 622-626.
[] [PMID: 23558173]
Kernytsky, A.; Wang, F.; Hansen, E.; Schalm, S.; Straley, K.; Gliser, C.; Yang, H.; Travins, J.; Murray, S.; Dorsch, M.; Agresta, S.; Schenkein, D.P.; Biller, S.A.; Su, S.M.; Liu, W.; Yen, K.E. IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition. Blood, 2015, 125(2), 296-303.
[] [PMID: 25398940]
Wang, F.; Travins, J.; Chen, Y.; Yang, H.; Straley, K.; Choe, S.; Dorsch, M.; Schenkein, D.P.; Agresta, S.; Biller, S. AG-221 offers a survival advantage in a primary human IDH2 Mutant AML xenograft model. Blood, 2013, 122(21), 240.
Yen, K.; Travins, J.; Wang, F.; David, M.D.; Artin, E.; Straley, K.; Padyana, A.; Gross, S.; DeLaBarre, B.; Tobin, E.; Chen, Y.; Nagaraja, R.; Choe, S.; Jin, L.; Konteatis, Z.; Cianchetta, G.; Saunders, J.O.; Salituro, F.G.; Quivoron, C.; Opolon, P.; Bawa, O.; Saada, V.; Paci, A.; Broutin, S.; Bernard, O.A.; de Botton, S.; Marteyn, B.S.; Pilichowska, M.; Xu, Y.; Fang, C.; Jiang, F.; Wei, W.; Jin, S.; Silverman, L.; Liu, W.; Yang, H.; Dang, L.; Dorsch, M.; Penard-Lacronique, V.; Biller, S.A.; Su, S.M. AG-221, a first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discov., 2017, 7(5), 478-493.
[] [PMID: 28193778]
Lemieux, R.; Popovici-Muller, J.; Chen, Y.; Yang, H.; Straley, K.; Choe, S.; Dorsch, M.; Agresta, S.; Schenkein, D.P.; Biller, S. IDH1 mutant inhibitor induces cellular differentiation and offers a combination benefit with Ara-C in a primary human Idh1 mutant AML xenograft model. Blood, 2013, 122(21), 3946.
Hansen, E.; Quivoron, C.; Straley, K.; Lemieux, R.M.; Popovici-Muller, J.; Sadrzadeh, H.; Fathi, A.T.; Gliser, C.; David, M.; Saada, V. AG-120, an oral, selective, first-in-class, potent inhibitor of mutant IDH1, reduces intracellular 2hg and induces cellular differentiation in TF-1 R132H cells and primary human IDH1 mutant AML patient samples treated ex vivo. Blood, 2014, 124(21), 3734.
Popovici-Muller, J.; Lemieux, R.M.; Artin, E.; Saunders, J.O.; Salituro, F.G.; Travins, J.; Cianchetta, G.; Cai, Z.; Zhou, D.; Cui, D.; Chen, P.; Straley, K.; Tobin, E.; Wang, F.; David, M.D.; Penard-Lacronique, V.; Quivoron, C.; Saada, V.; de Botton, S.; Gross, S.; Dang, L.; Yang, H.; Utley, L.; Chen, Y.; Kim, H.; Jin, S.; Gu, Z.; Yao, G.; Luo, Z.; Lv, X.; Fang, C.; Yan, L.; Olaharski, A.; Silverman, L.; Biller, S.; Su, S.M.; Yen, K. Discovery of AG-120 (Ivosidenib): A First-in-class mutant IDH1 inhibitor for the treatment of IDH1 mutant cancers. ACS Med. Chem. Lett., 2018, 9(4), 300-305.
[] [PMID: 29670690]
Stein, E.M.; DiNardo, C.D.; Pollyea, D.A.; Fathi, A.T.; Roboz, G.J.; Altman, J.K.; Stone, R.M.; DeAngelo, D.J.; Levine, R.L.; Flinn, I.W.; Kantarjian, H.M.; Collins, R.; Patel, M.R.; Frankel, A.E.; Stein, A.; Sekeres, M.A.; Swords, R.T.; Medeiros, B.C.; Willekens, C.; Vyas, P.; Tosolini, A.; Xu, Q.; Knight, R.D.; Yen, K.E.; Agresta, S.; de Botton, S.; Tallman, M.S. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood, 2017, 130(6), 722-731.
[] [PMID: 28588020]
Stein, E.M.; DiNardo, C.D.; Fathi, A.T.; Pollyea, D.A.; Stone, R.M.; Altman, J.K.; Roboz, G.J.; Patel, M.R.; Collins, R.; Flinn, I.W.; Sekeres, M.A.; Stein, A.S.; Kantarjian, H.M.; Levine, R.L.; Vyas, P.; MacBeth, K.J.; Tosolini, A.; VanOostendorp, J.; Xu, Q.; Gupta, I.; Lila, T.; Risueno, A.; Yen, K.E.; Wu, B.; Attar, E.C.; Tallman, M.S.; de Botton, S. Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib. Blood, 2019, 133(7), 676-687.
[] [PMID: 30510081]
Fathi, A.T.; DiNardo, C.D.; Kline, I.; Kenvin, L.; Gupta, I.; Attar, E.C.; Stein, E.M.; de Botton, S. AG221-C-001 study investigators. differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2: analysis of a phase 1/2 study. JAMA Oncol., 2018, 4(8), 1106-1110.
[] [PMID: 29346478]
Roboz, G.J.; Rosenblat, T.; Arellano, M.; Gobbi, M.; Altman, J.K.; Montesinos, P.; O’Connell, C.; Solomon, S.R.; Pigneux, A.; Vey, N.; Hills, R.; Jacobsen, T.F.; Gianella-Borradori, A.; Foss, Ø.; Vetrhusand, S.; Giles, F.J. International randomized phase III study of elacytarabine versus investigator choice in patients with relapsed/refractory acute myeloid leukemia. J. Clin. Oncol., 2014, 32(18), 1919-1926.
[] [PMID: 24841975]
Tallman, M.S.; Andersen, J.W.; Schiffer, C.A.; Appelbaum, F.R.; Feusner, J.H.; Ogden, A.; Shepherd, L.; Rowe, J.M.; François, C.; Larson, R.S.; Wiernik, P.H. Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome. Blood, 2000, 95(1), 90-95.
[PMID: 10607690]
Tallman, M.S.; Knight, R.D.; Glasmacher, A.G.; Dohner, H. IDHENTIFY Study Investigators Group. Phase III randomized, open-label study comparing the efficacy and safety of AG-221 vs conventional care regimens (CCR) in older patients with advanced acute myeloid leukemia (AML) with isocitrate dehydrogenase (IDH)-2 mutations in relapse or refractory to multiple prior treatments: The IDH ENTIFY trial. J. Clin. Oncol., 2016, 34(15suppl), TPS7074-TPS7074.
Pollyea, D.A.; Tallman, M.S.; de Botton, S.; Kantarjian, H.M.; Collins, R.; Stein, A.S.; Frattini, M.G.; Xu, Q.; Tosolini, A.; See, W.L.; MacBeth, K.J. Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia. Leukemia, 2019, 33(11), 2575-2584.
Birendra, K.C.; DiNardo, C.D. Evidence for clinical differentiation and differentiation syndrome in patients with acute myeloid leukemia and IDH1 mutations treated with the targeted mutant IDH1 Inhibitor, AG-120. Clin. Lymphoma Myeloma Leuk., 2016, 16(8), 460-465.
[] [PMID: 27245312]
Watts, J.; Baer, M.R.; Yang, J.; Dinner, S.; Lee, S.; Seiter, K.; Prebet, T.; Schiller, G.J.; Ferrell, P.B.; Dao, K-H. Phase 1 study of the IDH1m inhibitor FT-2102 as a single agent in patients with IDH1 Acute Myeloid Leukemia (AML) or myelodysplastic syndrome (MDS). Blood, 2018, 132(Suppl. 1), 1453.
Watts, J.M.; Baer, M.R.; Lee, S.; Yang, J.; Dinner, S.N.; Prebet, T.; Schiller, G.J.; Seiter, K.; Ferrell, P.B.; Kelly, P.F. A Phase 1 dose escalation study of the IDH1 M inhibitor, FT-2102, in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). J. Clin. Oncol., 2018, 36(15Suppl), 7009-7009.
Cortes, J.E.; Watts, J.; Prebet, T.; Schiller, G.J.; Lee, S.; Yang, J.; Wang, E.S.; Dinner, S.; Ferrell, P.B.; Donnellan, W. FT-2102, an IDH1m inhibitor, in combination with azacitidine in patients with acute myeloid leukemia (AML) or myelodysplastic ayndrome (MDS): Results from a phase 1 study. Blood, 2018, 132(Suppl. 1), 1452-1452.
Cho, Y.S.; Levell, J.R.; Liu, G.; Caferro, T.; Sutton, J.; Shafer, C.M.; Costales, A.; Manning, J.R.; Zhao, Q.; Sendzik, M.; Shultz, M.; Chenail, G.; Dooley, J.; Villalba, B.; Farsidjani, A.; Chen, J.; Kulathila, R.; Xie, X.; Dodd, S.; Gould, T.; Liang, G.; Heimbach, T.; Slocum, K.; Firestone, B.; Pu, M.; Pagliarini, R.; Growney, J.D. discovery and evaluation of clinical candidate idh305, a brain penetrant mutant IDH1 Inhibitor. ACS Med. Chem. Lett., 2017, 8(10), 1116-1121.
[] [PMID: 29057061]
DiNardo, C.D.; Schimmer, A.D.; Yee, K.W.L.; Hochhaus, A.; Kraemer, A.; Carvajal, R.D.; Janku, F.; Bedard, P.; Carpio, C.; Wick, A. A Phase I study of IDH305 in patients with advanced malignancies including relapsed/refractory AML and MDS that harbor IDH1 R132 Mutations. Blood, 2016, 128(22), 1073.
Chaturvedi, A.; Herbst, L.; Pusch, S.; Klett, L.; Goparaju, R.; Stichel, D.; Kaulfuss, S.; Panknin, O.; Zimmermann, K.; Toschi, L.; Neuhaus, R.; Haegebarth, A.; Rehwinkel, H.; Hess-Stumpp, H.; Bauser, M.; Bochtler, T.; Struys, E.A.; Sharma, A.; Bakkali, A.; Geffers, R.; Araujo-Cruz, M.M.; Thol, F.; Gabdoulline, R.; Ganser, A.; Ho, A.D.; von Deimling, A.; Rippe, K.; Heuser, M.; Krämer, A. Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo. Leukemia, 2017, 31(10), 2020-2028.
[] [PMID: 28232670]
Galkin, M.; Jonas, B.A. Enasidenib in the treatment of relapsed/refractory acute myeloid leukemia: an evidence-based review of its place in therapy. Core Evid., 2019, 14, 3-17.
[] [PMID: 31118877]
Stein, E.M.; DiNardo, C.D.; Fathi, A.T.; Mims, A.S.; Pratz, K.W.; Savona, M.R.; Stein, A.S.; Stone, R.M.; Winer, E.S.; Seet, C.S. Ivosidenib or enasidenib combined with induction and consolidation chemotherapy in patients with newly diagnosed AML with an IDH1 or IDH2 mutation is safe, effective, and leads to MRD-negative complete remissions. Blood, 2018, 132(Suppl. 1), 560.
Emadi, A.; Faramand, R.; Carter-Cooper, B.; Tolu, S.; Ford, L.A.; Lapidus, R.G.; Wetzler, M.; Wang, E.S.; Etemadi, A.; Griffiths, E.A. Presence of isocitrate dehydrogenase mutations may predict clinical response to hypomethylating agents in patients with acute myeloid leukemia. Am. J. Hematol., 2015, 90(5), E77-E79.
[] [PMID: 25651001]
Yen, K.; Chopra, V.S.; Tobin, E.; Avanzino, B.; Mavrommatis, K.; DiMartino, J.; MacBeth, K.J. Abstract 4956: Functional characterization of the ivosidenib (AG-120) and azacitidine combination in a mutant IDH1 AML cell model. Exper. Mol. Ther., 2018, 4956-4956.
Chaturvedi, A.; Gupta, C.; Goparaju, R.; Gabdoulline, R.; Kaulfuss, S.; Görlich, K.; Schottmann, R.; Panknin, O.; Wagner, M.; Geffers, R. Synergistic activity of IDH1 Inhibitor bay-1436032 with azacitidine in IDH1 mutant acute myeloid leukemia. Blood, 2017, 130(Suppl. 1), 1352.
DiNardo, C.D.; Stein, A.S.; Fathi, A.T.; Montesinos, P.; Odenike, O.; Kantarjian, H.M.; Stone, R.M.; Koralek, D.O.; Van Oostendorp, J.; Gong, J. Mutant Isocitrate dehydrogenase (mIDH) Inhibitors, enasidenib or ivosidenib, in combination with azacitidine (AZA): Preliminary results of a phase 1b/2 study in patients with newly diagnosed acute myeloid leukemia (AML). Blood, 2017, 130(Suppl. 1), 639.
DiNardo, C.D.; Stein, A.S.; Stein, E.M.; Fathi, A.T.; Schuh, A.C.; Montesinos Fernández, P.; Odenike, O.; Kantarjian, H.M.; Stone, R.M.; Collins, R. Mutant IDH (mIDH) inhibitors, ivosidenib or enasidenib, with azacitidine (AZA) in patients with acute myeloid leukemia (AML). J. Clin. Oncol., 2018, 36(15)(Suppl.), 7042-7042.
DiNardo, C.D.; Stein, A.S.; Stein, E.M.; Fathi, A.T.; Frankfurt, O.; Schuh, A.C.; Martinelli, G.; Patel, P.A.; Raffoux, E.; Tan, P. Mutant IDH1 inhibitor ivosidenib (IVO; AG-120) in combination with azacitidine (AZA) for newly diagnosed acute myeloid leukemia (ND AML). J. Clin. Oncol., 2019, 37(15)(Suppl.), 7011-7011.
Stein, E.; Dinardo, C.D.; Jang, J.H.; Miyazaki, Y.; Ovilla Martinez, R.; Auer, J.; Zhang, V.; Koralek, D.O.; Wu, B. AGILE: A phase 3, multicenter, randomized, placebo-controlled study of ivosidenib in combination with azacitidine in adult patients with previously untreated acute myeloid leukemia with an IDH1 mutation. J. Clin. Oncol., 2018, 36(15)(Suppl.), TPS7074-TPS7074.
Chan, S.M.; Thomas, D.; Corces-Zimmerman, M.R.; Xavy, S.; Rastogi, S.; Hong, W-J.; Zhao, F.; Medeiros, B.C.; Tyvoll, D.A.; Majeti, R. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat. Med., 2015, 21(2), 178-184.
[] [PMID: 25599133]
Konopleva, M.; Pollyea, D.A.; Potluri, J.; Chyla, B.; Hogdal, L.; Busman, T.; McKeegan, E.; Salem, A.H.; Zhu, M.; Ricker, J.L.; Blum, W.; DiNardo, C.D.; Kadia, T.; Dunbar, M.; Kirby, R.; Falotico, N.; Leverson, J.; Humerickhouse, R.; Mabry, M.; Stone, R.; Kantarjian, H.; Letai, A. Efficacy and biological correlates of response in a phase ii study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov., 2016, 6(10), 1106-1117.
[] [PMID: 27520294]
Aldoss, I.; Yang, D.; Aribi, A.; Ali, H.; Sandhu, K.; Al Malki, M.M.; Mei, M.; Salhotra, A.; Khaled, S.; Nakamura, R.; Snyder, D.; O’Donnell, M.; Stein, A.S.; Forman, S.J.; Marcucci, G.; Pullarkat, V. Efficacy of the combination of venetoclax and hypomethylating agents in relapsed/refractory acute myeloid leukemia. Haematologica, 2018, 103(9), e404-e407.
[] [PMID: 29545346]
DiNardo, C.D.; Pratz, K.; Pullarkat, V.; Jonas, B.A.; Arellano, M.; Becker, P.S.; Frankfurt, O.; Konopleva, M.; Wei, A.H.; Kantarjian, H.M.; Xu, T.; Hong, W.J.; Chyla, B.; Potluri, J.; Pollyea, D.A.; Letai, A. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood, 2019, 133(1), 7-17.
[] [PMID: 30361262]
Cathelin, S.; Sharon, D.; Subedi, A.; Cojocari, D.; Phillips, D.C.; Leverson, J.D.; MacBeth, K.; Nicolay, B.; Narayanaswamy, R.; Ronseaux, S. Combination of enasidenib and venetoclax shows superior anti-leukemic activity against idh2 mutated aml in patient-derived xenograft models. Blood, 2018, 132(Suppl. 1), 562.
Intlekofer, A.M.; Shih, A.H.; Wang, B.; Nazir, A.; Rustenburg, A.S.; Albanese, S.K.; Patel, M.; Famulare, C.; Correa, F.M.; Takemoto, N.; Durani, V.; Liu, H.; Taylor, J.; Farnoud, N.; Papaemmanuil, E.; Cross, J.R.; Tallman, M.S.; Arcila, M.E.; Roshal, M.; Petsko, G.A.; Wu, B.; Choe, S.; Konteatis, Z.D.; Biller, S.A.; Chodera, J.D.; Thompson, C.B.; Levine, R.L.; Stein, E.M. Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations. Nature, 2018, 559(7712), 125-129.
[] [PMID: 29950729]
DiNardo, C.D.; de Botton, S.; Stein, E.M.; Roboz, G.J.; Swords, R.T.; Pollyea, D.A.; Fathi, A.T.; Collins, R.; Altman, J.K.; Flinn, I.W. Determination of IDH1 mutational burden and clearance via next-generation sequencing in patients with IDH1 mutation-positive hematologic malignancies receiving AG-120, a first-in-class inhibitor of mutant IDH1. Blood, 2016, 128(22), 1070.
Stein, E.M.; DiNardo, C.D.; Mims, A.S.; Savona, M.R.; Pratz, K.; Stein, A.S.; Fathi, A.T.; Stone, R.M.; Pollyea, D.A.; Odenike, O. Ivosidenib or enasidenib combined with standard induction chemotherapy is well tolerated and active in patients with newly diagnosed AML with an IDH1 or IDH2 mutation: Initial results from a phase 1 trial. Blood, 2017, 130(Suppl. 1), 726.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 24 April, 2020
Page: [490 - 500]
Pages: 11
DOI: 10.2174/1568009620666200424145622
Price: $65

Article Metrics

PDF: 51
PRC: 1