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Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Review Article

The Evolving AML Genomic Landscape: Therapeutic Implications

Author(s): Sachi Horibata*, George Alyateem, Christin B. DeStefano and Michael M. Gottesman*

Volume 20, Issue 7, 2020

Page: [532 - 544] Pages: 13

DOI: 10.2174/1568009620666200424150321

Price: $65

Abstract

Improved understanding of the genomic and molecular landscape of acute myeloid leukemia (AML) has resulted in a significant evolution of our understanding of AML biology and allows refined prognostication for those receiving standard combination chemotherapy induction. This dramatic increase in knowledge preceded, and was somewhat responsible for, at least some of eight new FDA drug approvals for AML. This review discusses the impact of genomics on clinical care of AML patients and highlights newly approved FDA drugs. Despite these recent clinical advances, however, the outcome for most patients diagnosed with AML remains dire. Thus, we describe here some of the challenges identified with treating AML including off-target toxicity, drug transporters, clonal heterogeneity, and adaptive resistance, and some of the most promising opportunities for improved therapy.

Keywords: Acute myeloid leukemia (AML), genomic landscape, therapeutics, clinical implications, hematologic malignancy, drug transporters.

Graphical Abstract

[1]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin., 2019, 69(1), 7-34.
[http://dx.doi.org/10.3322/caac.21551] [PMID: 30620402]
[2]
Yates, J.W.; Wallace, H.J., Jr; Ellison, R.R.; Holland, J.F. Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer Chemother. Rep., 1973, 57(4), 485-488.
[PMID: 4586956]
[3]
Döhner, H.; Estey, E.; Grimwade, D.; Amadori, S.; Appelbaum, F.R.; Büchner, T.; Dombret, H.; Ebert, B.L.; Fenaux, P.; Larson, R.A.; Levine, R.L.; Lo-Coco, F.; Naoe, T.; Niederwieser, D.; Ossenkoppele, G.J.; Sanz, M.; Sierra, J.; Tallman, M.S.; Tien, H.F.; Wei, A.H.; Löwenberg, B.; Bloomfield, C.D. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood, 2017, 129(4), 424-447.
[http://dx.doi.org/10.1182/blood-2016-08-733196] [PMID: 27895058]
[4]
Döhner, H.; Estey, E.H.; Amadori, S.; Appelbaum, F.R.; Büchner, T.; Burnett, A.K.; Dombret, H.; Fenaux, P.; Grimwade, D.; Larson, R.A.; Lo-Coco, F.; Naoe, T.; Niederwieser, D.; Ossenkoppele, G.J.; Sanz, M.A.; Sierra, J.; Tallman, M.S.; Löwenberg, B.; Bloomfield, C.D.; European, L. European LeukemiaNet. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood, 2010, 115(3), 453-474.
[http://dx.doi.org/10.1182/blood-2009-07-235358] [PMID: 19880497]
[5]
Bennett, J.M.; Catovsky, D.; Daniel, M.T.; Flandrin, G.; Galton, D.A.; Gralnick, H.R.; Sultan, C. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br. J. Haematol., 1976, 33(4), 451-458.
[http://dx.doi.org/10.1111/j.1365-2141.1976.tb03563.x] [PMID: 188440]
[6]
Vardiman, J.W.; Harris, N.L.; Brunning, R.D. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood, 2002, 100(7), 2292-2302.
[http://dx.doi.org/10.1182/blood-2002-04-1199] [PMID: 12239137]
[7]
Vardiman, J.W.; Thiele, J.; Arber, D.A.; Brunning, R.D.; Borowitz, M.J.; Porwit, A.; Harris, N.L.; Le Beau, M.M.; Hellström-Lindberg, E.; Tefferi, A.; Bloomfield, C.D. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood, 2009, 114(5), 937-951.
[http://dx.doi.org/10.1182/blood-2009-03-209262] [PMID: 19357394]
[8]
Arber, D.A.; Orazi, A.; Hasserjian, R.; Thiele, J.; Borowitz, M.J.; Le Beau, M.M.; Bloomfield, C.D.; Cazzola, M.; Vardiman, J.W. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood, 2016, 127(20), 2391-2405.
[http://dx.doi.org/10.1182/blood-2016-03-643544] [PMID: 27069254]
[9]
Ley, T.J.; Miller, C.; Ding, L. Cancer Genome Atlas Research, N. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med., 2016, 368, 2059-2074.
[10]
Papaemmanuil, E.; Gerstung, M.; Bullinger, L.; Gaidzik, V.I.; Paschka, P.; Roberts, N.D.; Potter, N.E.; Heuser, M.; Thol, F.; Bolli, N.; Gundem, G.; Van Loo, P.; Martincorena, I.; Ganly, P.; Mudie, L.; McLaren, S.; O’Meara, S.; Raine, K.; Jones, D.R.; Teague, J.W.; Butler, A.P.; Greaves, M.F.; Ganser, A.; Döhner, K.; Schlenk, R.F.; Döhner, H.; Campbell, P.J. genomic classification and prognosis in acute myeloid leukemia. N. Engl. J. Med., 2016, 374(23), 2209-2221.
[http://dx.doi.org/10.1056/NEJMoa1516192] [PMID: 27276561]
[11]
Lindsley, R.C.; Mar, B.G.; Mazzola, E.; Grauman, P.V.; Shareef, S.; Allen, S.L.; Pigneux, A.; Wetzler, M.; Stuart, R.K.; Erba, H.P.; Damon, L.E.; Powell, B.L.; Lindeman, N.; Steensma, D.P.; Wadleigh, M.; DeAngelo, D.J.; Neuberg, D.; Stone, R.M.; Ebert, B.L. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood, 2015, 125(9), 1367-1376.
[http://dx.doi.org/10.1182/blood-2014-11-610543] [PMID: 25550361]
[12]
Wong, T.N.; Ramsingh, G.; Young, A.L.; Miller, C.A.; Touma, W.; Welch, J.S.; Lamprecht, T.L.; Shen, D.; Hundal, J.; Fulton, R.S.; Heath, S.; Baty, J.D.; Klco, J.M.; Ding, L.; Mardis, E.R.; Westervelt, P.; DiPersio, J.F.; Walter, M.J.; Graubert, T.A.; Ley, T.J.; Druley, T.; Link, D.C.; Wilson, R.K. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature, 2015, 518(7540), 552-555.
[http://dx.doi.org/10.1038/nature13968] [PMID: 25487151]
[13]
Hsu, J.I.; Dayaram, T.; Tovy, A.; De Braekeleer, E.; Jeong, M.; Wang, F.; Zhang, J.; Heffernan, T.P.; Gera, S.; Kovacs, J.J.; Marszalek, J.R.; Bristow, C.; Yan, Y.; Garcia-Manero, G.; Kantarjian, H.; Vassiliou, G.; Futreal, P.A.; Donehower, L.A.; Takahashi, K.; Goodell, M.A. PPM1D mutations drive clonal hematopoiesis in response to cytotoxic chemotherapy. Cell Stem Cell, 2018, 23, 700-713.
[14]
Tyner, J.W.; Tognon, C.E.; Bottomly, D.; Wilmot, B.; Kurtz, S.E.; Savage, S.L.; Long, N.; Schultz, A.R.; Traer, E.; Abel, M.; Agarwal, A.; Blucher, A.; Borate, U.; Bryant, J.; Burke, R.; Carlos, A.; Carpenter, R.; Carroll, J.; Chang, B.H.; Coblentz, C.; d’Almeida, A.; Cook, R.; Danilov, A.; Dao, K.T.; Degnin, M.; Devine, D.; Dibb, J.; Edwards, D.K. V; Eide, C.A.; English, I.; Glover, J.; Henson, R.; Ho, H.; Jemal, A.; Johnson, K.; Johnson, R.; Junio, B.; Kaempf, A.; Leonard, J.; Lin, C.; Liu, S.Q.; Lo, P.; Loriaux, M.M.; Luty, S.; Macey, T.; MacManiman, J.; Martinez, J.; Mori, M.; Nelson, D.; Nichols, C.; Peters, J.; Ramsdill, J.; Rofelty, A.; Schuff, R.; Searles, R.; Segerdell, E.; Smith, R.L.; Spurgeon, S.E.; Sweeney, T.; Thapa, A.; Visser, C.; Wagner, J.; Watanabe-Smith, K.; Werth, K.; Wolf, J.; White, L.; Yates, A.; Zhang, H.; Cogle, C.R.; Collins, R.H.; Connolly, D.C.; Deininger, M.W.; Drusbosky, L.; Hourigan, C.S.; Jordan, C.T.; Kropf, P.; Lin, T.L.; Martinez, M.E.; Medeiros, B.C.; Pallapati, R.R.;Pollyea, D.A.; Swords, R.T.; Watts, J.M.; Weir, S.J.; Wiest, D.L.; Winters, R.M.; McWeeney, S.K.; Druker, B.J. Functional genomic landscape of acute myeloid leukaemia. Nature, 2018, 562(7728), 526-531.
[http://dx.doi.org/10.1038/s41586-018-0623-z] [PMID: 30333627]
[15]
Horibata, S. Transcriptomic profile of intrinsically chemoresistant acute myeloid leukemia patients. Mol. Cell. Oncol., 2019, 6(6) e1650631
[http://dx.doi.org/10.1080/23723556.2019.1650631] [PMID: 31692823]
[16]
Horibata, S.; Gui, G.; Lack, J.; DeStefano, C.B.; Gottesman, M.M.; Hourigan, C.S. Heterogeneity in refractory acute myeloid leukemia. Proc. Natl. Acad. Sci. USA, 2019, 116(21), 10494-10503.
[http://dx.doi.org/10.1073/pnas.1902375116] [PMID: 31064876]
[17]
Karp, J.E.; Ross, D.D.; Yang, W.; Tidwell, M.L.; Wei, Y.; Greer, J.; Mann, D.L.; Nakanishi, T.; Wright, J.J.; Colevas, A.D. Timed sequential therapy of acute leukemia with flavopiridol: In vitro model for a phase I clinical trial. Clin. Cancer Res., 2003, 9(1), 307-315.
[PMID: 12538483]
[18]
Karp, J.E.; Passaniti, A.; Gojo, I.; Kaufmann, S.; Bible, K.; Garimella, T.S.; Greer, J.; Briel, J.; Smith, B.D.; Gore, S.D.; Tidwell, M.L.; Ross, D.D.; Wright, J.J.; Colevas, A.D.; Bauer, K.S. Phase I and pharmacokinetic study of flavopiridol followed by 1-beta-D-arabinofuranosylcytosine and mitoxantrone in relapsed and refractory adult acute leukemias. Clin. Cancer Res., 2005, 11(23), 8403-8412.
[http://dx.doi.org/10.1158/1078-0432.CCR-05-1201] [PMID: 16322302]
[19]
Karp, J.E.; Smith, B.D.; Levis, M.J.; Gore, S.D.; Greer, J.; Hattenburg, C.; Briel, J.; Jones, R.J.; Wright, J.J.; Colevas, A.D. Sequential flavopiridol, cytosine arabinoside, and mitoxantrone: A phase II trial in adults with poor-risk acute myelogenous leukemia. Clin. Cancer Res., 2007, 13(15 Pt 1), 4467-4473.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-0381] [PMID: 17671131]
[20]
Karp, J.E.; Blackford, A.; Smith, B.D.; Alino, K.; Seung, A.H.; Bolaños-Meade, J.; Greer, J.M.; Carraway, H.E.; Gore, S.D.; Jones, R.J.; Levis, M.J.; McDevitt, M.A.; Doyle, L.A.; Wright, J.J. Clinical activity of sequential flavopiridol, cytosine arabinoside, and mitoxantrone for adults with newly diagnosed, poor-risk acute myelogenous leukemia. Leuk. Res., 2010, 34(7), 877-882.
[http://dx.doi.org/10.1016/j.leukres.2009.11.007] [PMID: 19962759]
[21]
Karp, J.E.; Smith, B.D.; Resar, L.S.; Greer, J.M.; Blackford, A.; Zhao, M.; Moton-Nelson, D.; Alino, K.; Levis, M.J.; Gore, S.D.; Joseph, B.; Carraway, H.; McDevitt, M.A.; Bagain, L.; Mackey, K.; Briel, J.; Doyle, L.A.; Wright, J.J.; Rudek, M.A. Phase 1 and pharmacokinetic study of bolus-infusion flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukemias. Blood, 2011, 117(12), 3302-3310.
[http://dx.doi.org/10.1182/blood-2010-09-310862] [PMID: 21239698]
[22]
Karp, J.E.; Garrett-Mayer, E.; Estey, E.H.; Rudek, M.A.; Smith, B.D.; Greer, J.M.; Drye, D.M.; Mackey, K.; Dorcy, K.S.; Gore, S.D.; Levis, M.J.; McDevitt, M.A.; Carraway, H.E.; Pratz, K.W.; Gladstone, D.E.; Showel, M.M.; Othus, M.; Doyle, L.A.; Wright, J.J.; Pagel, J.M. Randomized phase II study of two schedules of flavopiridol given as timed sequential therapy with cytosine arabinoside and mitoxantrone for adults with newly diagnosed, poor-risk acute myelogenous leukemia. Haematologica, 2012, 97(11), 1736-1742.
[http://dx.doi.org/10.3324/haematol.2012.062539] [PMID: 22733022]
[23]
Zeidner, J.F.; Foster, M.C.; Blackford, A.L.; Litzow, M.R.; Morris, L.E.; Strickland, S.A.; Lancet, J.E.; Bose, P.; Levy, M.Y.; Tibes, R.; Gojo, I.; Gocke, C.D.; Rosner, G.L.; Little, R.F.; Wright, J.J.; Doyle, L.A.; Smith, B.D.; Karp, J.E. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia. Haematologica, 2015, 100(9), 1172-1179.
[http://dx.doi.org/10.3324/haematol.2015.125849] [PMID: 26022709]
[24]
Zeidner, J.F.; Karp, J.E. Clinical activity of alvocidib (flavopiridol) in acute myeloid leukemia. Leuk. Res., 2015, 39(12), 1312-1318.
[http://dx.doi.org/10.1016/j.leukres.2015.10.010] [PMID: 26521988]
[25]
DeStefano, C.B.; Hourigan, C.S. Personalizing initial therapy in acute myeloid leukemia: Incorporating novel agents into clinical practice. Ther. Adv. Hematol., 2018, 9(5), 109-121.
[http://dx.doi.org/10.1177/2040620718761778] [PMID: 29713444]
[26]
Lai, C.; Doucette, K.; Norsworthy, K. Recent drug approvals for acute myeloid leukemia. J. Hematol. Oncol., 2019, 12(1), 100.
[http://dx.doi.org/10.1186/s13045-019-0774-x] [PMID: 31533852]
[27]
Döhner, H.; Weisdorf, D.J.; Bloomfield, C.D. acute myeloid leukemia. N. Engl. J. Med., 2015, 373(12), 1136-1152.
[http://dx.doi.org/10.1056/NEJMra1406184] [PMID: 26376137]
[28]
Khan, N.; Hills, R.K.; Virgo, P.; Couzens, S.; Clark, N.; Gilkes, A.; Richardson, P.; Knapper, S.; Grimwade, D.; Russell, N.H.; Burnett, A.K.; Freeman, S.D. Expression of CD33 is a predictive factor for effect of gemtuzumab ozogamicin at different doses in adult acute myeloid leukaemia. Leukemia, 2017, 31(5), 1059-1068.
[http://dx.doi.org/10.1038/leu.2016.309] [PMID: 27795558]
[29]
Petersdorf, S.H.; Kopecky, K.J.; Slovak, M.; Willman, C.; Nevill, T.; Brandwein, J.; Larson, R.A.; Erba, H.P.; Stiff, P.J.; Stuart, R.K.; Walter, R.B.; Tallman, M.S.; Stenke, L.; Appelbaum, F.R. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood, 2013, 121(24), 4854-4860.
[http://dx.doi.org/10.1182/blood-2013-01-466706] [PMID: 23591789]
[30]
Castaigne, S.; Pautas, C.; Terré, C.; Raffoux, E.; Bordessoule, D.; Bastie, J.N.; Legrand, O.; Thomas, X.; Turlure, P.; Reman, O.; de Revel, T.; Gastaud, L.; de Gunzburg, N.; Contentin, N.; Henry, E.; Marolleau, J.P.; Aljijakli, A.; Rousselot, P.; Fenaux, P.; Preudhomme, C.; Chevret, S.; Dombret, H. Acute leukemia french, a. acute leukemia french association. effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (Alfa-0701): A randomised, open-label, phase 3 study. Lancet, 2012, 379(9825), 1508-1516.
[http://dx.doi.org/10.1016/S0140-6736(12)60485-1] [PMID: 22482940]
[31]
Hills, R.K.; Castaigne, S.; Appelbaum, F.R.; Delaunay, J.; Petersdorf, S.; Othus, M.; Estey, E.H.; Dombret, H.; Chevret, S.; Ifrah, N.; Cahn, J.Y.; Récher, C.; Chilton, L.; Moorman, A.V.; Burnett, A.K. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol., 2014, 15(9), 986-996.
[http://dx.doi.org/10.1016/S1470-2045(14)70281-5] [PMID: 25008258]
[32]
Lim, W.S.; Tardi, P.G.; Dos Santos, N.; Xie, X.; Fan, M.; Liboiron, B.D.; Huang, X.; Harasym, T.O.; Bermudes, D.; Mayer, L.D. Leukemia-selective uptake and cytotoxicity of CPX-351, a synergistic fixed-ratio cytarabine:daunorubicin formulation, in bone marrow xenografts. Leuk. Res., 2010, 34(9), 1214-1223.
[http://dx.doi.org/10.1016/j.leukres.2010.01.015] [PMID: 20138667]
[33]
Tardi, P.; Johnstone, S.; Harasym, N.; Xie, S.; Harasym, T.; Zisman, N.; Harvie, P.; Bermudes, D.; Mayer, L. In vivo maintenance of synergistic cytarabine:daunorubicin ratios greatly enhances therapeutic efficacy. Leuk. Res., 2009, 33(1), 129-139.
[http://dx.doi.org/10.1016/j.leukres.2008.06.028] [PMID: 18676016]
[34]
Lacent, J.E..; Uy, G.L.; Cortes, J.E. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J. Clin. Oncol., 2018, 36, 2684-2692.
[35]
Nakao, M.; Yokota, S.; Iwai, T.; Kaneko, H.; Horiike, S.; Kashima, K.; Sonoda, Y.; Fujimoto, T.; Misawa, S. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia, 1996, 10(12), 1911-1918.
[PMID: 8946930]
[36]
Weisberg, E.; Boulton, C.; Kelly, L.M.; Manley, P.; Fabbro, D.; Meyer, T.; Gilliland, D.G.; Griffin, J.D. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell, 2002, 1(5), 433-443.
[http://dx.doi.org/10.1016/S1535-6108(02)00069-7] [PMID: 12124173]
[37]
Ikegami, Y.; Yano, S.; Nakao, K. Antitumor effect of CGP41251, a new selective protein kinase C inhibitor, on human non-small cell lung cancer cells. Jpn. J. Pharmacol., 1996, 70(1), 65-72.
[http://dx.doi.org/10.1254/jjp.70.65] [PMID: 8822090]
[38]
Fabbro, D.; Buchdunger, E.; Wood, J.; Mestan, J.; Hofmann, F.; Ferrari, S.; Mett, H.; O’Reilly, T.; Meyer, T. Inhibitors of protein kinases: CGP 41251, a protein kinase inhibitor with potential as an anticancer agent. Pharmacol. Ther., 1999, 82(2-3), 293-301.
[http://dx.doi.org/10.1016/S0163-7258(99)00005-4] [PMID: 10454207]
[39]
Stone, R.M.; Mandrekar, S.J.; Sanford, B.L.; Laumann, K.; Geyer, S.; Bloomfield, C.D.; Thiede, C.; Prior, T.W.; Döhner, K.; Marcucci, G.; Lo-Coco, F.; Klisovic, R.B.; Wei, A.; Sierra, J.; Sanz, M.A.; Brandwein, J.M.; de Witte, T.; Niederwieser, D.; Appelbaum, F.R.; Medeiros, B.C.; Tallman, M.S.; Krauter, J.; Schlenk, R.F.; Ganser, A.; Serve, H.; Ehninger, G.; Amadori, S.; Larson, R.A.; Döhner, H. midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N. Engl. J. Med., 2017, 377(5), 454-464.
[http://dx.doi.org/10.1056/NEJMoa1614359] [PMID: 28644114]
[40]
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.
[http://dx.doi.org/10.1182/blood-2017-04-779405] [PMID: 28588020]
[41]
Campos, L.; Rouault, J.P.; Sabido, O.; Oriol, P.; Roubi, N.; Vasselon, C.; Archimbaud, E.; Magaud, J.P.; Guyotat, D. High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood, 1993, 81(11), 3091-3096.
[http://dx.doi.org/10.1182/blood.V81.11.3091.3091] [PMID: 7684624]
[42]
Del Poeta, G.; Venditti, A.; Del Principe, M.I.; Maurillo, L.; Buccisano, F.; Tamburini, A.; Cox, M.C.; Franchi, A.; Bruno, A.; Mazzone, C.; Panetta, P.; Suppo, G.; Masi, M.; Amadori, S. Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML). Blood, 2003, 101(6), 2125-2131.
[http://dx.doi.org/10.1182/blood-2002-06-1714] [PMID: 12424199]
[43]
Lagadinou, E.D.; Sach, A.; Callahan, K.; Rossi, R.M.; Neering, S.J.; Minhajuddin, M.; Ashton, J.M.; Pei, S.; Grose, V.; O’Dwyer, K.M.; Liesveld, J.L.; Brookes, P.S.; Becker, M.W.; Jordan, C.T. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell, 2013, 12(3), 329-341.
[http://dx.doi.org/10.1016/j.stem.2012.12.013] [PMID: 23333149]
[44]
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.
[http://dx.doi.org/10.1182/blood-2018-08-868752] [PMID: 30361262]
[45]
Wei, A.H.; Strickland, S.A., Jr; Hou, J.Z.; Fiedler, W.; Lin, T.L.; Walter, R.B.; Enjeti, A.; Tiong, I.S.; Savona, M.; Lee, S.; Chyla, B.; Popovic, R.; Salem, A.H.; Agarwal, S.; Xu, T.; Fakouhi, K.M.; Humerickhouse, R.; Hong, W.J.; Hayslip, J.; Roboz, G.J. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: Results from a phase Ib/II study. J. Clin. Oncol., 2019, 37(15), 1277-1284.
[http://dx.doi.org/10.1200/JCO.18.01600] [PMID: 30892988]
[46]
Briscoe, J.; Thérond, P.P. the mechanisms of hedgehog signalling and its roles in development and disease. Nat. Rev. Mol. Cell Biol., 2013, 14(7), 416-429.
[http://dx.doi.org/10.1038/nrm3598] [PMID: 23719536]
[47]
Fukushima, N.; Minami, Y.; Kakiuchi, S.; Kuwatsuka, Y.; Hayakawa, F.; Jamieson, C.; Kiyoi, H.; Naoe, T. Small-molecule Hedgehog inhibitor attenuates the leukemia-initiation potential of acute myeloid leukemia cells. Cancer Sci., 2016, 107(10), 1422-1429.
[http://dx.doi.org/10.1111/cas.13019] [PMID: 27461445]
[48]
Cortes, J.E.; Heidel, F.H.; Hellmann, A.; Fiedler, W.; Smith, B.D.; Robak, T.; Montesinos, P.; Pollyea, D.A.; DesJardins, P.; Ottmann, O.; Ma, W.W.; Shaik, M.N.; Laird, A.D.; Zeremski, M.; O’Connell, A.; Chan, G.; Heuser, M. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia, 2019, 33(2), 379-389.
[http://dx.doi.org/10.1038/s41375-018-0312-9] [PMID: 30555165]
[49]
Medeiros, B.C.; Fathi, A.T.; DiNardo, C.D.; Pollyea, D.A.; Chan, S.M.; Swords, R. Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia, 2017, 31(2), 272-281.
[http://dx.doi.org/10.1038/leu.2016.275] [PMID: 27721426]
[50]
Nassereddine, S.; Lap, C.J.; Haroun, F.; Tabbara, I. The role of mutant IDH1 and IDH2 inhibitors in the treatment of acute myeloid leukemia. Ann. Hematol., 2017, 96(12), 1983-1991.
[http://dx.doi.org/10.1007/s00277-017-3161-0] [PMID: 29090344]
[51]
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.
[http://dx.doi.org/10.1056/NEJMoa1716984] [PMID: 29860938]
[52]
Perl, A.E.; Altman, J.K.; Cortes, J.; Smith, C.; Litzow, M.; Baer, M.R.; Claxton, D.; Erba, H.P.; Gill, S.; Goldberg, S.; Jurcic, J.G.; Larson, R.A.; Liu, C.; Ritchie, E.; Schiller, G.; Spira, A.I.; Strickland, S.A.; Tibes, R.; Ustun, C.; Wang, E.S.; Stuart, R.; Röllig, C.; Neubauer, A.; Martinelli, G.; Bahceci, E.; Levis, M. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: A multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol., 2017, 18(8), 1061-1075.
[http://dx.doi.org/10.1016/S1470-2045(17)30416-3] [PMID: 28645776]
[53]
Perl, A.E. Abstract CT184: Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML): Results from the Phase III ADMIRAL trial. Cancer Res., 2019, 3, 392-393.
[54]
Office of the Chief Actuary. Period Life Table., https://www.ssa. gov/oact/STATS/table4c6.html [Jan 16, 2016]
[55]
Estey, E. ‘Looking beyond survival to define therapeutic value in acute myeloid leukemia’. Leuk. Lymphoma, 2019, 60(5), 1107-1109.
[http://dx.doi.org/10.1080/10428194.2018.1543886] [PMID: 30628507]
[56]
Surveillance Research Program NCI. SEER*Explorer: An interactive website for SEER cancer statistics.. https://seer.cancer.gov/explorer/ [Jan 16, 2016]
[57]
Lin, A.; Giuliano, C.J.; Palladino, A.; John, K.M.; Abramowicz, C.; Yuan, M.L.; Sausville, E.L.; Lukow, D.A.; Liu, L.; Chait, A.R.; Galluzzo, Z.C.; Tucker, C.; Sheltzer, J.M. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Sci. Transl. Med., 2019, 11(509), 11.
[http://dx.doi.org/10.1126/scitranslmed.aaw8412] [PMID: 31511426]
[58]
Patel, C.; Stenke, L.; Varma, S.; Lindberg, M.L.; Björkholm, M.; Sjöberg, J.; Viktorsson, K.; Lewensohn, R.; Landgren, O.; Gottesman, M.M.; Gillet, J.P. Multidrug resistance in relapsed acute myeloid leukemia: Evidence of biological heterogeneity. Cancer, 2013, 119(16), 3076-3083.
[http://dx.doi.org/10.1002/cncr.28098] [PMID: 23674237]
[59]
Campos, L.; Guyotat, D.; Archimbaud, E.; Calmard-Oriol, P.; Tsuruo, T.; Troncy, J.; Treille, D.; Fiere, D. Clinical significance of multidrug resistance P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis. Blood, 1992, 79(2), 473-476.
[http://dx.doi.org/10.1182/blood.V79.2.473.473] [PMID: 1370388]
[60]
Wilson, C.S.; Davidson, G.S.; Martin, S.B.; Andries, E.; Potter, J.; Harvey, R.; Ar, K.; Xu, Y.; Kopecky, K.J.; Ankerst, D.P.; Gundacker, H.; Slovak, M.L.; Mosquera-Caro, M.; Chen, I.M.; Stirewalt, D.L.; Murphy, M.; Schultz, F.A.; Kang, H.; Wang, X.; Radich, J.P.; Appelbaum, F.R.; Atlas, S.R.; Godwin, J.; Willman, C.L. Gene expression profiling of adult acute myeloid leukemia identifies novel biologic clusters for risk classification and outcome prediction. Blood, 2006, 108(2), 685-696.
[http://dx.doi.org/10.1182/blood-2004-12-4633] [PMID: 16597596]
[61]
List, A.F.; Kopecky, K.J.; Willman, C.L.; Head, D.R.; Persons, D.L.; Slovak, M.L.; Dorr, R.; Karanes, C.; Hynes, H.E.; Doroshow, J.H.; Shurafa, M.; Appelbaum, F.R. Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: A Southwest Oncology Group study. Blood, 2001, 98(12), 3212-3220.
[http://dx.doi.org/10.1182/blood.V98.12.3212] [PMID: 11719356]
[62]
Baer, M.R.; George, S.L.; Dodge, R.K.; O’Loughlin, K.L.; Minderman, H.; Caligiuri, M.A.; Anastasi, J.; Powell, B.L.; Kolitz, J.E.; Schiffer, C.A.; Bloomfield, C.D.; Larson, R.A. Phase 3 study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B Study 9720. Blood, 2002, 100(4), 1224-1232.
[http://dx.doi.org/10.1182/blood.V100.4.1224.h81602001224_1224_1232] [PMID: 12149202]
[63]
Burnett, A.K.; Milligan, D.; Goldstone, A.; Prentice, A.; McMullin, M.F.; Dennis, M.; Sellwood, E.; Pallis, M.; Russell, N.; Hills, R.K.; Wheatley, K. United Kingdom National Cancer Research Institute Haematological Oncology Study Group. The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome: The results of the LRF AML14 trial. Br. J. Haematol., 2009, 145(3), 318-332.
[http://dx.doi.org/10.1111/j.1365-2141.2009.07604.x] [PMID: 19291085]
[64]
Lui Yin, J.A.; Wheatley, K.; Rees, J.K. Burnett, A.K. UK MRC Adult Leukemia Working Party. Comparison of ‘sequential’ versus ‘standard’ chemotherapy as re-induction treatment, with or without cyclosporine, in refractory/relapsed acute myeloid leukaemia (AML): Results of the UK Medical Research Council AML-R trial. Br. J. Haematol., 2001, 113(3), 713-726.
[http://dx.doi.org/10.1046/j.1365-2141.2001.02785.x] [PMID: 11380463]
[65]
van der Holt, B.; Löwenberg, B.; Burnett, A.K.; Knauf, W.U.; Shepherd, J.; Piccaluga, P.P.; Ossenkoppele, G.J.; Verhoef, G.E.; Ferrant, A.; Crump, M.; Selleslag, D.; Theobald, M.; Fey, M.F.; Vellenga, E.; Dugan, M.; Sonneveld, P. The value of the MDR1 reversal agent PSC-833 in addition to daunorubicin and cytarabine in the treatment of elderly patients with previously untreated acute myeloid leukemia (AML), in relation to MDR1 status at diagnosis. Blood, 2005, 106(8), 2646-2654.
[http://dx.doi.org/10.1182/blood-2005-04-1395] [PMID: 15994288]
[66]
Greenberg, P.L.; Lee, S.J.; Advani, R.; Tallman, M.S.; Sikic, B.I.; Letendre, L.; Dugan, K.; Lum, B.; Chin, D.L.; Dewald, G.; Paietta, E.; Bennett, J.M.; Rowe, J.M. Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: A phase III trial (E2995). J. Clin. Oncol., 2004, 22(6), 1078-1086.
[http://dx.doi.org/10.1200/JCO.2004.07.048] [PMID: 15020609]
[67]
Cripe, L.D.; Uno, H.; Paietta, E.M.; Litzow, M.R.; Ketterling, R.P.; Bennett, J.M.; Rowe, J.M.; Lazarus, H.M.; Luger, S.; Tallman, M.S. Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia: a randomized, placebo-controlled trial of the Eastern Cooperative Oncology Group 3999. Blood, 2010, 116(20), 4077-4085.
[http://dx.doi.org/10.1182/blood-2010-04-277269] [PMID: 20716770]
[68]
Erickson, P.; Gao, J.; Chang, K.S.; Look, T.; Whisenant, E.; Raimondi, S.; Lasher, R.; Trujillo, J.; Rowley, J.; Drabkin, H. Identification of breakpoints in t(8;21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt. Blood, 1992, 80(7), 1825-1831.
[http://dx.doi.org/10.1182/blood.V80.7.1825.1825] [PMID: 1391946]
[69]
Christen, F.; Hoyer, K.; Yoshida, K.; Hou, H.A.; Waldhueter, N.; Heuser, M.; Hills, R.K.; Chan, W.; Hablesreiter, R.; Blau, O.; Ochi, Y.; Klement, P.; Chou, W.C.; Blau, I.W.; Tang, J.L.; Zemojtel, T.; Shiraishi, Y.; Shiozawa, Y.; Thol, F.; Ganser, A.; Löwenberg, B.; Linch, D.C.; Bullinger, L.; Valk, P.J.M.; Tien, H.F.; Gale, R.E.; Ogawa, S.; Damm, F. Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients. Blood, 2019, 133(10), 1140-1151.
[http://dx.doi.org/10.1182/blood-2018-05-852822] [PMID: 30610028]
[70]
Hayakawa, F.; Towatari, M.; Kiyoi, H.; Tanimoto, M.; Kitamura, T.; Saito, H.; Naoe, T. Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines. Oncogene, 2000, 19(5), 624-631.
[http://dx.doi.org/10.1038/sj.onc.1203354] [PMID: 10698507]
[71]
Zarrinkar, P.P.; Gunawardane, R.N.; Cramer, M.D.; Gardner, M.F.; Brigham, D.; Belli, B.; Karaman, M.W.; Pratz, K.W.; Pallares, G.; Chao, Q.; Sprankle, K.G.; Patel, H.K.; Levis, M.; Armstrong, R.C.; James, J.; Bhagwat, S.S. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood, 2009, 114(14), 2984-2992.
[http://dx.doi.org/10.1182/blood-2009-05-222034] [PMID: 19654408]
[72]
Smith, C.C.; Lasater, E.A.; Lin, K.C.; Wang, Q.; McCreery, M.Q.; Stewart, W.K.; Damon, L.E.; Perl, A.E.; Jeschke, G.R.; Sugita, M.; Carroll, M.; Kogan, S.C.; Kuriyan, J.; Shah, N.P. Crenolanib is a selective type I pan-FLT3 inhibitor. Proc. Natl. Acad. Sci. USA, 2014, 111(14), 5319-5324.
[http://dx.doi.org/10.1073/pnas.1320661111] [PMID: 24623852]
[73]
Galanis, A.; Ma, H.; Rajkhowa, T.; Ramachandran, A.; Small, D.; Cortes, J.; Levis, M. Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants. Blood, 2014, 123(1), 94-100.
[http://dx.doi.org/10.1182/blood-2013-10-529313] [PMID: 24227820]
[74]
McMahon, C.M.; Ferng, T.; Canaani, J.; Wang, E.S.; Morrissette, J.J.D.; Eastburn, D.J.; Pellegrino, M.; Durruthy-Durruthy, R.; Watt, C.D.; Asthana, S.; Lasater, E.A.; DeFilippis, R.; Peretz, C.A.C.; McGary, L.H.F.; Deihimi, S.; Logan, A.C.; Luger, S.M.; Shah, N.P.; Carroll, M.; Smith, C.C.; Perl, A.E. Clonal Selection with RAS pathway activation mediates secondary clinical resistance to selective FLT3 inhibition in acute myeloid leukemia. Cancer Discov., 2019, 9(8), 1050-1063.
[http://dx.doi.org/10.1158/2159-8290.CD-18-1453] [PMID: 31088841]
[75]
Melgar, K.; Walker, M.M.; Jones, L.M.; Bolanos, L.C.; Hueneman, K.; Wunderlich, M.; Jiang, J.K.; Wilson, K.M.; Zhang, X.; Sutter, P.; Wang, A.; Xu, X.; Choi, K.; Tawa, G.; Lorimer, D.; Abendroth, J.; O’Brien, E.; Hoyt, S.B.; Berman, E.; Famulare, C.A.; Mulloy, J.C.; Levine, R.L.; Perentesis, J.P.; Thomas, C.J.; Starczynowski, D.T. Overcoming adaptive therapy resistance in AML by targeting immune response pathways. Sci. Transl. Med., 2019, 11(508), 11.
[http://dx.doi.org/10.1126/scitranslmed.aaw8828] [PMID: 31484791]
[76]
Hensley, C.T.; Wasti, A.T.; DeBerardinis, R.J. Glutamine and cancer: cell biology, physiology, and clinical opportunities. J. Clin. Invest., 2013, 123(9), 3678-3684.
[http://dx.doi.org/10.1172/JCI69600] [PMID: 23999442]
[77]
Altman, B.J.; Stine, Z.E.; Dang, C.V. From Krebs to clinic: Glutamine metabolism to cancer therapy. Nat. Rev. Cancer, 2016, 16(10), 619-634.
[http://dx.doi.org/10.1038/nrc.2016.71] [PMID: 27492215]
[78]
Gregory, M.A.; D’Alessandro, A.; Alvarez-Calderon, F.; Kim, J.; Nemkov, T.; Adane, B.; Rozhok, A.I.; Kumar, A.; Kumar, V.; Pollyea, D.A.; Wempe, M.F.; Jordan, C.T.; Serkova, N.J.; Tan, A.C.; Hansen, K.C.; DeGregori, J. ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia. Proc. Natl. Acad. Sci. USA, 2016, 113(43), E6669-E6678.
[http://dx.doi.org/10.1073/pnas.1603876113] [PMID: 27791036]
[79]
Gregory, M.A.; Nemkov, T.; Reisz, J.A.; Zaberezhnyy, V.; Hansen, K.C.; D’Alessandro, A.; DeGregori, J. Glutaminase inhibition improves FLT3 inhibitor therapy for acute myeloid leukemia. Exp. Hematol., 2018, 58, 52-58.
[http://dx.doi.org/10.1016/j.exphem.2017.09.007] [PMID: 28947392]
[80]
Gregory, M.A.; Nemkov, T.; Park, H.J.; Zaberezhnyy, V.; Gehrke, S.; Adane, B.; Jordan, C.T.; Hansen, K.C.; D’Alessandro, A.; De-Gregori, J. Targeting glutamine metabolism and redox state for leukemia therapy. Clin. Cancer Res., 2019, 25(13), 4079-4090.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-3223] [PMID: 30940653]
[81]
Jones, C.L.; Stevens, B.M.; D'Alessandro, A.; Reisz, J.A.; Culp-Hill, R.; Nemkov, T.; Pei, S.; Khan, N.; Adane, B.; Ye, H.; Krug, A.; Reinhold, D.; Smith, C.; DeGregori, J.; Pollyea, D.A.; Jordan, C.T. Inhibition of amino acid metabolism selectively targets Human leukemia stem cells. Cancer Cell, 2018, 34, 724-740. e724
[82]
Jones, C.L.; Stevens, B.M.; D’Alessandro, A.; Culp-Hill, R.; Reisz, J.A.; Pei, S.; Gustafson, A.; Khan, N.; DeGregori, J.; Pollyea, D.A.; Jordan, C.T. Cysteine depletion targets leukemia stem cells through inhibition of electron transport complex II. Blood, 2019, 134(4), 389-394.
[http://dx.doi.org/10.1182/blood.2019898114] [PMID: 31101624]
[83]
Pollyea, D.A.; Stevens, B.M.; Jones, C.L.; Winters, A.; Pei, S.; Minhajuddin, M.; D’Alessandro, A.; Culp-Hill, R.; Riemondy, K.A.; Gillen, A.E.; Hesselberth, J.R.; Abbott, D.; Schatz, D.; Gutman, J.A.; Purev, E.; Smith, C.; Jordan, C.T. Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia. Nat. Med., 2018, 24(12), 1859-1866.
[http://dx.doi.org/10.1038/s41591-018-0233-1] [PMID: 30420752]
[84]
Yoshimi, A.; Lin, K.T.; Wiseman, D.H.; Rahman, M.A.; Pastore, A.; Wang, B.; Lee, S.C.; Micol, J.B.; Zhang, X.J.; de Botton, S.; Penard-Lacronique, V.; Stein, E.M.; Cho, H.; Miles, R.E.; Inoue, D.; Albrecht, T.R.; Somervaille, T.C.P.; Batta, K.; Amaral, F.; Simeoni, F.; Wilks, D.P.; Cargo, C.; Intlekofer, A.M.; Levine, R.L.; Dvinge, H.; Bradley, R.K.; Wagner, E.J.; Krainer, A.R.; Abdel-Wahab, O. Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis. Nature, 2019, 574(7777), 273-277.
[http://dx.doi.org/10.1038/s41586-019-1618-0] [PMID: 31578525]
[85]
Inoue, D.; Chew, G.L.; Liu, B.; Michel, B.C.; Pangallo, J.; D’Avino, A.R.; Hitchman, T.; North, K.; Lee, S.C.; Bitner, L.; Block, A.; Moore, A.R.; Yoshimi, A.; Escobar-Hoyos, L.; Cho, H.; Penson, A.; Lu, S.X.; Taylor, J.; Chen, Y.; Kadoch, C.; Abdel-Wahab, O.; Bradley, R.K. Spliceosomal disruption of the non-canonical BAF complex in cancer. Nature, 2019, 574(7778), 432-436.
[http://dx.doi.org/10.1038/s41586-019-1646-9] [PMID: 31597964]

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