FLT3 Inhibition in Acute Myeloid Leukaemia – Current Knowledge and Future Prospects

Author(s): Francesca L. Hogan, Victoria Williams, Steven Knapper*

Journal Name: Current Cancer Drug Targets

Volume 20 , Issue 7 , 2020


DOI : 10.2174/1570163817666200518075820

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

Graphical Abstract:


Abstract:

Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in 30% of acute myeloid leukaemia (AML) patients at diagnosis and confer an adverse clinical prognosis. Mutated FLT3 has emerged as a viable therapeutic target and a number of FLT3-directed tyrosine kinase inhibitors have progressed through clinical development over the last 10-15 years. The last two years have seen United States Food and Drug Administration (US FDA) approvals of the multi-kinase inhibitor midostaurin for newly-diagnosed FLT3-mutated patients, when used in combination with intensive chemotherapy, and of the more FLT3-selective agent gilteritinib, used as monotherapy, for patients with relapsed or treatment-refractory FLT3-mutated AML. The ‘second generation’ agents, quizartinib and crenolanib, are also at advanced stages of clinical development. Significant challenges remain in negotiating a variety of potential acquired drug resistance mechanisms and in optimizing sequencing of FLT3 inhibitory drugs with existing and novel treatment approaches in different clinical settings, including frontline therapy, relapsed/refractory disease, and maintenance treatment. In this review, the biology of FLT3, the clinical challenge posed by FLT3-mutated AML, the developmental history of the key FLT3-inhibitory compounds, mechanisms of disease resistance, and the future outlook for this group of agents, including current and planned clinical trials, is discussed.

Keywords: Acute myeloid leukaemia (AML), FLT3 inhibitor, midostaurin, quizartinib, gilteritinib main text, chemotherapy.

[1]
Grafone, T.; Palmisano, M.; Nicci, C.; Storti, S. An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: biology and treatment. Oncol. Rev., 2012, 6(1) e8
[http://dx.doi.org/10.4081/oncol.2012.e8] [PMID: 25992210]
[2]
Gilliland, D.G.; Griffin, J.D. The roles of FLT3 in hematopoiesis and leukemia. Blood, 2002, 100(5), 1532-1542.
[http://dx.doi.org/10.1182/blood-2002-02-0492] [PMID: 12176867]
[3]
Kottaridis, P.D.; Gale, R.E.; Linch, D.C. Flt3 mutations and leukaemia. Br. J. Haematol., 2003, 122(4), 523-538.
[http://dx.doi.org/10.1046/j.1365-2141.2003.04500.x] [PMID: 12899708]
[4]
Drexler, H.G. Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells. Leukemia, 1996, 10(4), 588-599.
[PMID: 8618433]
[5]
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]
[6]
Yamamoto, Y.; Kiyoi, H.; Nakano, Y.; Suzuki, R.; Kodera, Y.; Miyawaki, S.; Asou, N.; Kuriyama, K.; Yagasaki, F.; Shimazaki, C.; Akiyama, H.; Saito, K.; Nishimura, M.; Motoji, T.; Shinagawa, K.; Takeshita, A.; Saito, H.; Ueda, R.; Ohno, R.; Naoe, T. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood, 2001, 97(8), 2434-2439.
[http://dx.doi.org/10.1182/blood.V97.8.2434] [PMID: 11290608]
[7]
Levis, M.; Small, D. FLT3: ITDoes matter in leukemia. Leukemia, 2003, 17(9), 1738-1752.
[http://dx.doi.org/10.1038/sj.leu.2403099] [PMID: 12970773]
[8]
Kottaridis, P.D.; Gale, R.E.; Frew, M.E.; Harrison, G.; Langabeer, S.E.; Belton, A.A.; Walker, H.; Wheatley, K.; Bowen, D.T.; Burnett, A.K.; Goldstone, A.H.; Linch, D.C. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood, 2001, 98(6), 1752-1759.
[http://dx.doi.org/10.1182/blood.V98.6.1752] [PMID: 11535508]
[9]
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]
[10]
Schlenk, R.F.; Kayser, S.; Bullinger, L.; Kobbe, G.; Casper, J.; Ringhoffer, M.; Held, G.; Brossart, P.; Lübbert, M.; Salih, H.R.; Kindler, T.; Horst, H.A.; Wulf, G.; Nachbaur, D.; Götze, K.; Lamparter, A.; Paschka, P.; Gaidzik, V.I.; Teleanu, V.; Späth, D.; Benner, A.; Krauter, J.; Ganser, A.; Döhner, H.; Döhner, K. German-Austrian AML Study Group. Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood, 2014, 124(23), 3441-3449.
[http://dx.doi.org/10.1182/blood-2014-05-578070] [PMID: 25270908]
[11]
How, J.; Sykes, J.; Gupta, V.; Yee, K.W.; Schimmer, A.D.; Schuh, A.C.; Minden, M.D.; Kamel-Reid, S.; Brandwein, J.M. Influence of FLT3-internal tandem duplication allele burden and white blood cell count on the outcome in patients with intermediate-risk karyotype acute myeloid leukemia. Cancer, 2012, 118(24), 6110-6117.
[http://dx.doi.org/10.1002/cncr.27683] [PMID: 22736495]
[12]
Thiede, C.; Steudel, C.; Mohr, B.; Schaich, M.; Schäkel, U.; Platzbecker, U.; Wermke, M.; Bornhäuser, M.; Ritter, M.; Neubauer, A.; Ehninger, G.; Illmer, T. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: Association with FAB subtypes and identification of subgroups with poor prognosis. Blood, 2002, 99(12), 4326-4335.
[http://dx.doi.org/10.1182/blood.V99.12.4326] [PMID: 12036858]
[13]
Patel, J.P.; Gönen, M.; Figueroa, M.E.; Fernandez, H.; Sun, Z.; Racevskis, J.; Van Vlierberghe, P.; Dolgalev, I.; Thomas, S.; Aminova, O.; Huberman, K.; Cheng, J.; Viale, A.; Socci, N.D.; Heguy, A.; Cherry, A.; Vance, G.; Higgins, R.R.; Ketterling, R.P.; Gallagher, R.E.; Litzow, M.; van den Brink, M.R.; Lazarus, H.M.; Rowe, J.M.; Luger, S.; Ferrando, A.; Paietta, E.; Tallman, M.S.; Melnick, A.; Abdel-Wahab, O.; Levine, R.L. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N. Engl. J. Med., 2012, 366(12), 1079-1089.
[http://dx.doi.org/10.1056/NEJMoa1112304] [PMID: 22417203]
[14]
Whitman, S.P.; Archer, K.J.; Feng, L.; Baldus, C.; Becknell, B.; Carlson, B.D.; Carroll, A.J.; Mrózek, K.; Vardiman, J.W.; George, S.L.; Kolitz, J.E.; Larson, R.A.; Bloomfield, C.D.; Caligiuri, M.A. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: A cancer and leukemia group B study. Cancer Res., 2001, 61(19), 7233-7239.
[PMID: 11585760]
[15]
Fröhling, S.; Schlenk, R.F.; Breitruck, J.; Benner, A.; Kreitmeier, S.; Tobis, K.; Döhner, H.; Döhner, K. AML Study Group Ulm. Acute myeloid leukemia. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood, 2002, 100(13), 4372-4380.
[http://dx.doi.org/10.1182/blood-2002-05-1440] [PMID: 12393388]
[16]
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]
[17]
Schnittger, S.; Schoch, C.; Dugas, M.; Kern, W.; Staib, P.; Wuchter, C.; Löffler, H.; Sauerland, C.M.; Serve, H.; Büchner, T.; Haferlach, T.; Hiddemann, W. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood, 2002, 100(1), 59-66.
[http://dx.doi.org/10.1182/blood.V100.1.59] [PMID: 12070009]
[18]
Stirewalt, D.L.; Kopecky, K.J.; Meshinchi, S.; Engel, J.H.; Pogosova-Agadjanyan, E.L.; Linsley, J.; Slovak, M.L.; Willman, C.L.; Radich, J.P. Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia. Blood, 2006, 107(9), 3724-3726.
[http://dx.doi.org/10.1182/blood-2005-08-3453] [PMID: 16368883]
[19]
Liu, S.B.; Dong, H.J.; Bao, X.B.; Qiu, Q.C.; Li, H.Z.; Shen, H.J.; Ding, Z.X.; Wang, C.; Chu, X.L.; Yu, J.Q.; Tao, T.; Li, Z.; Tang, X.W.; Chen, S.N.; Wu, D.P.; Li, L.; Xue, S.L. Impact of FLT3-ITD length on prognosis of acute myeloid leukemia. Haematologica, 2019, 104(1), e9-e12.
[http://dx.doi.org/10.3324/haematol.2018.191809] [PMID: 30076182]
[20]
Gale, R.E.; Green, C.; Allen, C.; Mead, A.J.; Burnett, A.K.; Hills, R.K.; Linch, D.C. Medical Research Council Adult Leukaemia Working Party. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood, 2008, 111(5), 2776-2784.
[http://dx.doi.org/10.1182/blood-2007-08-109090] [PMID: 17957027]
[21]
Kayser, S.; Schlenk, R.F.; Londono, M.C.; Breitenbuecher, F.; Wittke, K.; Du, J.; Groner, S.; Späth, D.; Krauter, J.; Ganser, A.; Döhner, H.; Fischer, T.; Döhner, K. German-Austrian AML Study Group (AMLSG). Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood, 2009, 114(12), 2386-2392.
[http://dx.doi.org/10.1182/blood-2009-03-209999] [PMID: 19602710]
[22]
Pratcorona, M.; Brunet, S.; Nomdedéu, J.; Ribera, J.M.; Tormo, M.; Duarte, R.; Escoda, L.; Guàrdia, R.; Queipo de Llano, M.P.; Salamero, O.; Bargay, J.; Pedro, C.; Martí, J.M.; Torrebadell, M.; Díaz-Beyá, M.; Camós, M.; Colomer, D.; Hoyos, M.; Sierra, J.; Esteve, J. Grupo Cooperativo Para el Estudio y Tratamiento de las Leucemias Agudas Mieloblásticas. Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy. Blood, 2013, 121(14), 2734-2738.
[http://dx.doi.org/10.1182/blood-2012-06-431122] [PMID: 23377436]
[23]
Schnittger, S.; Schoch, C.; Kern, W.; Mecucci, C.; Tschulik, C.; Martelli, M.F.; Haferlach, T.; Hiddemann, W.; Falini, B. Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood, 2005, 106(12), 3733-3739.
[http://dx.doi.org/10.1182/blood-2005-06-2248] [PMID: 16076867]
[24]
Mead, A.J.; Linch, D.C.; Hills, R.K.; Wheatley, K.; Burnett, A.K.; Gale, R.E. FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia. Blood, 2007, 110(4), 1262-1270.
[http://dx.doi.org/10.1182/blood-2006-04-015826] [PMID: 17456725]
[25]
Bacher, U.; Haferlach, C.; Kern, W.; Haferlach, T.; Schnittger, S. Prognostic relevance of FLT3-TKD mutations in AML: the combination matters--an analysis of 3082 patients. Blood, 2008, 111(5), 2527-2537.
[http://dx.doi.org/10.1182/blood-2007-05-091215] [PMID: 17965322]
[26]
Sakaguchi, M.; Yamaguchi, H.; Kuboyama, M.; Najima, Y.; Usuki, K.; Ueki, T.; Oh, I.; Mori, S.; Kawata, E.; Uoshima, N.; Kobayashi, Y.; Kako, S.; Tajika, K.; Shono, K.; Kayamori, K.; Hagihara, M.; Kanda, J.; Uchiyama, H.; Kuroda, J.; Uchida, N.; Kubota, Y.; Kimura, S.; Kurosawa, S.; Date, K.; Nakajima, N.; Marumo, A.; Omori, I.; Fujiwara, Y.; Terada, K.; Yui, S.; Wakita, S.; Arai, K.; Kitano, T.; Kakihana, K.; Kanda, Y.; Ohashi, K.; Fukuda, T.; Inokuchi, K. Significance of FLT3-tyrosine kinase domain mutation as a prognostic factor for acute myeloid leukemia. Int. J. Hematol., 2019, 110(5), 566-574.
[http://dx.doi.org/10.1007/s12185-019-02720-z] [PMID: 31432396]
[27]
Murphy, K.M.; Levis, M.; Hafez, M.J.; Geiger, T.; Cooper, L.C.; Smith, B.D.; Small, D.; Berg, K.D. Detection of FLT3 internal tandem duplication and D835 mutations by a multiplex polymerase chain reaction and capillary electrophoresis assay. J. Mol. Diagn., 2003, 5(2), 96-102.
[http://dx.doi.org/10.1016/S1525-1578(10)60458-8] [PMID: 12707374]
[28]
Duncavage, E.J.; Tandon, B. The utility of next-generation sequencing in diagnosis and monitoring of acute myeloid leukemia and myelodysplastic syndromes. Int. J. Lab. Hematol., 2015, 37(Suppl. 1), 115-121.
[http://dx.doi.org/10.1111/ijlh.12361] [PMID: 25976969]
[29]
Pratz, K.W.; Sato, T.; Murphy, K.M.; Stine, A.; Rajkhowa, T.; Levis, M. FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML. Blood, 2010, 115(7), 1425-1432.
[http://dx.doi.org/10.1182/blood-2009-09-242859] [PMID: 20007803]
[30]
Shih, L.Y.; Huang, C.F.; Wu, J.H.; Lin, T.L.; Dunn, P.; Wang, P.N.; Kuo, M.C.; Lai, C.L.; Hsu, H.C. Internal tandem duplication of FLT3 in relapsed acute myeloid leukemia: a comparative analysis of bone marrow samples from 108 adult patients at diagnosis and relapse. Blood, 2002, 100(7), 2387-2392.
[http://dx.doi.org/10.1182/blood-2002-01-0195] [PMID: 12239146]
[31]
Kottaridis, P.D.; Gale, R.E.; Langabeer, S.E.; Frew, M.E.; Bowen, D.T.; Linch, D.C. Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Blood, 2002, 100(7), 2393-2398.
[http://dx.doi.org/10.1182/blood-2002-02-0420] [PMID: 12239147]
[32]
Shih, L.Y.; Huang, C.F.; Wu, J.H.; Wang, P.N.; Lin, T.L.; Dunn, P.; Chou, M.C.; Kuo, M.C.; Tang, C.C. Heterogeneous patterns of FLT3 Asp(835) mutations in relapsed de novo acute myeloid leukemia: a comparative analysis of 120 paired diagnostic and relapse bone marrow samples. Clin. Cancer Res., 2004, 10(4), 1326-1332.
[http://dx.doi.org/10.1158/1078-0432.CCR-0835-03] [PMID: 14977832]
[33]
Knapper, S. The clinical development of FLT3 inhibitors in acute myeloid leukemia. Expert Opin. Investig. Drugs, 2011, 20(10), 1377-1395.
[http://dx.doi.org/10.1517/13543784.2011.611802] [PMID: 21895538]
[34]
Zorn, J.A.; Wang, Q.; Fujimura, E.; Barros, T.; Kuriyan, J. Crystal structure of the FLT3 kinase domain bound to the inhibitor Quizartinib (AC220). PLoS One, 2015, 10(4) e0121177
[http://dx.doi.org/10.1371/journal.pone.0121177] [PMID: 25837374]
[35]
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]
[36]
Stone, R.M.; DeAngelo, D.J.; Klimek, V.; Galinsky, I.; Estey, E.; Nimer, S.D.; Grandin, W.; Lebwohl, D.; Wang, Y.; Cohen, P.; Fox, E.A.; Neuberg, D.; Clark, J.; Gilliland, D.G.; Griffin, J.D. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood, 2005, 105(1), 54-60.
[http://dx.doi.org/10.1182/blood-2004-03-0891] [PMID: 15345597]
[37]
Fischer, T.; Stone, R.M.; Deangelo, D.J.; Galinsky, I.; Estey, E.; Lanza, C.; Fox, E.; Ehninger, G.; Feldman, E.J.; Schiller, G.J.; Klimek, V.M.; Nimer, S.D.; Gilliland, D.G.; Dutreix, C.; Huntsman-Labed, A.; Virkus, J.; Giles, F.J. Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild type or mutated FLT3. J. Clin. Oncol., 2010, 28(28), 4339-4345.
[http://dx.doi.org/10.1200/JCO.2010.28.9678] [PMID: 20733134]
[38]
Stone, R.M.; Fischer, T.; Paquette, R.; Schiller, G.; Schiffer, C.A.; Ehninger, G.; Cortes, J.; Kantarjian, H.M.; DeAngelo, D.J.; Huntsman-Labed, A.; Dutreix, C.; del Corral, A.; Giles, F. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia, 2012, 26(9), 2061-2068.
[http://dx.doi.org/10.1038/leu.2012.115] [PMID: 22627678]
[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]
Midostaurin (Rydapt) prescribing information. Initial US approval. 2017, Ref. 4090671.
[41]
Midostaurin (Rydapt). Summary of product characteristics. 2018.
[42]
Midostaurin for untreated acute myeloid leukaemia. Technology appraisal guidance TA523, 2018.
[43]
Larson, R.; Mandrekar, S.; Sanford, B.; Laumann, K.; Geyer, S.; Bloomfield, C. An analysis of maintenance therapy and post-midostaurin outcomes in the international prospective randomized, placebo-controlled, double-blind trial (CALGB 10603/RATIFY [Alliance]) for newly-diagnosed acute myeloid leukemia (AML) patients with FLT3 mutations. Blood, 2017, 145a.
[44]
Maziarz, R.; Patnaik, M.; Scott, B.; Mohan, S.; Deol, A.; Rowley, S.; Kim, D.; Haines, K.; Bonifacio, G.; Rine, P.; Purkayastha, D.; Fernandez, H. RADIUS: a phase 2 randomized trial investigating standard of care +/- midostaurin after allogeneic stem cell transplant in FLT3-ITD-mutated AML. Blood, 2018, 662a.
[45]
Schlenk, R.F.; Weber, D.; Fiedler, W.; Salih, H.R.; Wulf, G.; Salwender, H.; Schroeder, T.; Kindler, T.; Lübbert, M.; Wolf, D.; Westermann, J.; Kraemer, D.; Götze, K.S.; Horst, H.A.; Krauter, J.; Girschikofsky, M.; Ringhoffer, M.; Südhoff, T.; Held, G.; Derigs, H.G.; Schroers, R.; Greil, R.; Grießhammer, M.; Lange, E.; Burchardt, A.; Martens, U.; Hertenstein, B.; Marretta, L.; Heuser, M.; Thol, F.; Gaidzik, V.I.; Herr, W.; Krzykalla, J.; Benner, A.; Döhner, K.; Ganser, A.; Paschka, P.; Döhner, H. German-Austrian AML Study Group. Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood, 2019, 133(8), 840-851.
[http://dx.doi.org/10.1182/blood-2018-08-869453] [PMID: 30563875]
[46]
Cooper, B.W.; Kindwall-Keller, T.L.; Craig, M.D.; Creger, R.J.; Hamadani, M.; Tse, W.W.; Lazarus, H.M. A phase I study of midostaurin and azacitidine in relapsed and elderly AML patients. Clin. Lymphoma Myeloma Leuk., 2015, 15(7), 428-432.
[http://dx.doi.org/10.1016/j.clml.2015.02.017] [PMID: 25776192]
[47]
Strati, P.; Kantarjian, H.; Ravandi, F.; Nazha, A.; Borthakur, G.; Daver, N.; Kadia, T.; Estrov, Z.; Garcia-Manero, G.; Konopleva, M.; Rajkhowa, T.; Durand, M.; Andreeff, M.; Levis, M.; Cortes, J. Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome. Am. J. Hematol., 2015, 90(4), 276-281.
[http://dx.doi.org/10.1002/ajh.23924] [PMID: 25530214]
[48]
Smith, B.D.; Levis, M.; Beran, M.; Giles, F.; Kantarjian, H.; Berg, K.; Murphy, K.M.; Dauses, T.; Allebach, J.; Small, D. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood, 2004, 103(10), 3669-3676.
[http://dx.doi.org/10.1182/blood-2003-11-3775] [PMID: 14726387]
[49]
Knapper, S.; Burnett, A.K.; Littlewood, T.; Kell, W.J.; Agrawal, S.; Chopra, R.; Clark, R.; Levis, M.J.; Small, D. A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood, 2006, 108(10), 3262-3270.
[http://dx.doi.org/10.1182/blood-2006-04-015560] [PMID: 16857985]
[50]
Levis, M.; Brown, P.; Smith, B.D.; Stine, A.; Pham, R.; Stone, R.; Deangelo, D.; Galinsky, I.; Giles, F.; Estey, E.; Kantarjian, H.; Cohen, P.; Wang, Y.; Roesel, J.; Karp, J.E.; Small, D. Plasma inhibitory activity (PIA): A pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Blood, 2019, 108(10), 3477-3483.
[51]
Levis, M.; Ravandi, F.; Wang, E.S.; Baer, M.R.; Perl, A.; Coutre, S.; Erba, H.; Stuart, R.K.; Baccarani, M.; Cripe, L.D.; Tallman, M.S.; Meloni, G.; Godley, L.A.; Langston, A.A.; Amadori, S.; Lewis, I.D.; Nagler, A.; Stone, R.; Yee, K.; Advani, A.; Douer, D.; Wiktor-Jedrzejczak, W.; Juliusson, G.; Litzow, M.R.; Petersdorf, S.; Sanz, M.; Kantarjian, H.M.; Sato, T.; Tremmel, L.; Bensen-Kennedy, D.M.; Small, D.; Smith, B.D. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood, 2011, 117(12), 3294-3301.
[http://dx.doi.org/10.1182/blood-2010-08-301796] [PMID: 21270442]
[52]
Knapper, S.; Russell, N.; Gilkes, A.; Hills, R.K.; Gale, R.E.; Cavenagh, J.D.; Jones, G.; Kjeldsen, L.; Grunwald, M.R.; Thomas, I.; Konig, H.; Levis, M.J.; Burnett, A.K. A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML. Blood, 2017, 129(9), 1143-1154.
[http://dx.doi.org/10.1182/blood-2016-07-730648] [PMID: 27872058]
[53]
Zhang, W.; Konopleva, M.; Shi, Y.X.; McQueen, T.; Harris, D.; Ling, X.; Estrov, Z.; Quintás-Cardama, A.; Small, D.; Cortes, J.; Andreeff, M. Mutant FLT3: A direct target of sorafenib in acute myelogenous leukemia. J. Natl. Cancer Inst., 2008, 100(3), 184-198.
[http://dx.doi.org/10.1093/jnci/djm328] [PMID: 18230792]
[54]
Pratz, K.W.; Cho, E.; Levis, M.J.; Karp, J.E.; Gore, S.D.; McDevitt, M.; Stine, A.; Zhao, M.; Baker, S.D.; Carducci, M.A.; Wright, J.J.; Rudek, M.A.; Smith, B.D. A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias. Leukemia, 2010, 24(8), 1437-1444.
[http://dx.doi.org/10.1038/leu.2010.132] [PMID: 20535150]
[55]
Borthakur, G.; Kantarjian, H.; Ravandi, F.; Zhang, W.; Konopleva, M.; Wright, J.J.; Faderl, S.; Verstovsek, S.; Mathews, S.; Andreeff, M.; Cortes, J.E. Phase I study of sorafenib in patients with refractory or relapsed acute leukemias. Haematologica, 2011, 96(1), 62-68.
[http://dx.doi.org/10.3324/haematol.2010.030452] [PMID: 20952518]
[56]
Ravandi, F.; Cortes, J.E.; Jones, D.; Faderl, S.; Garcia-Manero, G.; Konopleva, M.Y.; O’Brien, S.; Estrov, Z.; Borthakur, G.; Thomas, D.; Pierce, S.R.; Brandt, M.; Byrd, A.; Bekele, B.N.; Pratz, K.; Luthra, R.; Levis, M.; Andreeff, M.; Kantarjian, H.M. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J. Clin. Oncol., 2010, 28(11), 1856-1862.
[http://dx.doi.org/10.1200/JCO.2009.25.4888] [PMID: 20212254]
[57]
Ravandi, F.; Arana Yi, C.; Cortes, J.E.; Levis, M.; Faderl, S.; Garcia-Manero, G.; Jabbour, E.; Konopleva, M.; O’Brien, S.; Estrov, Z.; Borthakur, G.; Thomas, D.; Pierce, S.; Brandt, M.; Pratz, K.; Luthra, R.; Andreeff, M.; Kantarjian, H. Final report of phase II study of sorafenib, cytarabine and idarubicin for initial therapy in younger patients with acute myeloid leukemia. Leukemia, 2014, 28(7), 1543-1545.
[http://dx.doi.org/10.1038/leu.2014.54] [PMID: 24487412]
[58]
Röllig, C.; Serve, H.; Hüttmann, A.; Noppeney, R.; Müller-Tidow, C.; Krug, U.; Baldus, C.D.; Brandts, C.H.; Kunzmann, V.; Einsele, H.; Krämer, A.; Schäfer-Eckart, K.; Neubauer, A.; Burchert, A.; Giagounidis, A.; Krause, S.W.; Mackensen, A.; Aulitzky, W.; Herbst, R.; Hänel, M.; Kiani, A.; Frickhofen, N.; Kullmer, J.; Kaiser, U.; Link, H.; Geer, T.; Reichle, A.; Junghanß, C.; Repp, R.; Heits, F.; Dürk, H.; Hase, J.; Klut, I.M.; Illmer, T.; Bornhäuser, M.; Schaich, M.; Parmentier, S.; Görner, M.; Thiede, C.; von Bonin, M.; Schetelig, J.; Kramer, M.; Berdel, W.E.; Ehninger, G. Study Alliance Leukaemia. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): A multicentre, phase 2, randomised controlled trial. Lancet Oncol., 2015, 16(16), 1691-1699.
[http://dx.doi.org/10.1016/S1470-2045(15)00362-9] [PMID: 26549589]
[59]
Serve, H.; Krug, U.; Wagner, R.; Sauerland, M.C.; Heinecke, A.; Brunnberg, U.; Schaich, M.; Ottmann, O.; Duyster, J.; Wandt, H.; Fischer, T.; Giagounidis, A.; Neubauer, A.; Reichle, A.; Aulitzky, W.; Noppeney, R.; Blau, I.; Kunzmann, V.; Stuhlmann, R.; Krämer, A.; Kreuzer, K.A.; Brandts, C.; Steffen, B.; Thiede, C.; Müller-Tidow, C.; Ehninger, G.; Berdel, W.E. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J. Clin. Oncol., 2013, 31(25), 3110-3118.
[http://dx.doi.org/10.1200/JCO.2012.46.4990] [PMID: 23897964]
[60]
Ravandi, F.; Alattar, M.L.; Grunwald, M.R.; Rudek, M.A.; Rajkhowa, T.; Richie, M.A.; Pierce, S.; Daver, N.; Garcia-Manero, G.; Faderl, S.; Nazha, A.; Konopleva, M.; Borthakur, G.; Burger, J.; Kadia, T.; Dellasala, S.; Andreeff, M.; Cortes, J.; Kantarjian, H.; Levis, M. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood, 2013, 121(23), 4655-4662.
[http://dx.doi.org/10.1182/blood-2013-01-480228] [PMID: 23613521]
[61]
Metzelder, S.K.; Schroeder, T.; Finck, A.; Scholl, S.; Fey, M.; Götze, K.; Linn, Y.C.; Kröger, M.; Reiter, A.; Salih, H.R.; Heinicke, T.; Stuhlmann, R.; Müller, L.; Giagounidis, A.; Meyer, R.G.; Brugger, W.; Vöhringer, M.; Dreger, P.; Mori, M.; Basara, N.; Schäfer-Eckart, K.; Schultheis, B.; Baldus, C.; Neubauer, A.; Burchert, A. High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses. Leukemia, 2012, 26(11), 2353-2359.
[http://dx.doi.org/10.1038/leu.2012.105] [PMID: 22504140]
[62]
Burchert, A.; Metzelder, S.; Bug, G. Sorafenib as maintenance therapy after allogeneic stem cell transplantation for FLT3-ITD positive AML: results from the randomized, double blind, placebo-controlled SORMAIN trial. Blood, 2018, 661a.
[63]
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]
[64]
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]
[65]
Gunawardane, R.N.; Nepomuceno, R.R.; Rooks, A.M.; Hunt, J.P.; Ricono, J.M.; Belli, B.; Armstrong, R.C. Transient exposure to quizartinib mediates sustained inhibition of FLT3 signaling while specifically inducing apoptosis in FLT3-activated leukemia cells. Mol. Cancer Ther., 2013, 12(4), 438-447.
[http://dx.doi.org/10.1158/1535-7163.MCT-12-0305] [PMID: 23412931]
[66]
Cortes, J.E.; Tallman, M.S.; Schiller, G.J.; Trone, D.; Gammon, G.; Goldberg, S.L.; Perl, A.E.; Marie, J.P.; Martinelli, G.; Kantarjian, H.M.; Levis, M.J. Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITD-mutated, relapsed or refractory AML. Blood, 2018, 132(6), 598-607.
[http://dx.doi.org/10.1182/blood-2018-01-821629] [PMID: 29875101]
[67]
Cortes, J.E.; Khaled, S.; Martinelli, G.; Perl, A.E.; Ganguly, S.; Russell, N.; Krämer, A.; Dombret, H.; Hogge, D.; Jonas, B.A.; Leung, A.Y.; Mehta, P.; Montesinos, P.; Radsak, M.; Sica, S.; Arunachalam, M.; Holmes, M.; Kobayashi, K.; Namuyinga, R.; Ge, N.; Yver, A.; Zhang, Y.; Levis, M.J. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): A multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol., 2019, 20(7), 984-997.
[http://dx.doi.org/10.1016/S1470-2045(19)30150-0] [PMID: 31175001]
[68]
Hills, R.; Burnett, A.; Gale, R.; Linch, D.; Gilkes, A.; Russell, N. Outcomes in relapsed/refractory patients with FLT3-ITD mutated AML are poor when treated with non-targeted therapy with a potential role for stem cell transplantation. Results from the NCRI AML Trials; , 2018, p. 1392a.
[http://dx.doi.org/10.1182/blood-2018-99-116542]
[69]
Altman, J.K.; Foran, J.M.; Pratz, K.W.; Trone, D.; Cortes, J.E.; Tallman, M.S. Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Am. J. Hematol., 2018, 93(2), 213-221.
[http://dx.doi.org/10.1002/ajh.24974] [PMID: 29139135]
[70]
Bowen, D.; Russell, N.; Knapper, S.; Milligan, D.; Hunter, A.; Khwaja, A. AC220 (quizartinib) can be safely combined with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukaemia; , 2013, p. 622a.
[71]
Swaminathan, M.; Kantarjian, H.; Daver, N.; Borthakur, G.; Ohanian, M.; Kadia, T. The combination of quizartinib with azacitidine or low dose cytarabine is highly active in patients with FLT3-ITD mutated myeloid leukemias: interim report of a phase I/II trial; , 2017, p. 723a.
[72]
Sandmaier, B.M.; Khaled, S.; Oran, B.; Gammon, G.; Trone, D.; Frankfurt, O. Results of a phase 1 study of quizartinib as maintenance therapy in subjects with acute myeloid leukemia in remission following allogeneic hematopoietic stem cell transplant. Am. J. Hematol., 2018, 93(2), 222-231.
[http://dx.doi.org/10.1002/ajh.24959] [PMID: 29090473]
[73]
Lee, L.Y.; Hernandez, D.; Rajkhowa, T.; Smith, S.C.; Raman, J.R.; Nguyen, B.; Small, D.; Levis, M. Preclinical studies of gilteritinib, a next-generation FLT3 inhibitor. Blood, 2017, 129(2), 257-260.
[http://dx.doi.org/10.1182/blood-2016-10-745133] [PMID: 27908881]
[74]
Park, I.K.; Mishra, A.; Chandler, J.; Whitman, S.P.; Marcucci, G.; Caligiuri, M.A. Inhibition of the receptor tyrosine kinase Axl impedes activation of the FLT3 internal tandem duplication in human acute myeloid leukemia: implications for Axl as a potential therapeutic target. Blood, 2013, 121(11), 2064-2073.
[http://dx.doi.org/10.1182/blood-2012-07-444018] [PMID: 23321254]
[75]
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]
[76]
Perl, A.E.; Martinelli, G.; Cortes, J.E.; Neubauer, A.; Berman, E.; Paolini, S.; Montesinos, P.; Baer, M.R.; Larson, R.A.; Ustun, C.; Fabbiano, F.; Erba, H.P.; Di Stasi, A.; Stuart, R.; Olin, R.; Kasner, M.; Ciceri, F.; Chou, W.C.; Podoltsev, N.; Recher, C.; Yokoyama, H.; Hosono, N.; Yoon, S.S.; Lee, J.H.; Pardee, T.; Fathi, A.T.; Liu, C.; Hasabou, N.; Liu, X.; Bahceci, E.; Levis, M.J. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N. Engl. J. Med., 2019, 381(18), 1728-1740.
[http://dx.doi.org/10.1056/NEJMoa1902688] [PMID: 31665578]
[77]
FDA approves gilteritinib for relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation 2018.
[78]
Pratz, K.; Cherry, M.; Altman, J.K.; Cooper, B.W.; Cruz, J.C.; Jurcic, J.G.; Levis, M.J. Updated results from a phase I study of gilteritinib in combination with induction and consolidation chemotherapy in subjects with newly-diagnosed acute myeloid leukemia (AML); , 2018, p. 564a.
[http://dx.doi.org/10.1182/blood-2018-99-110975]
[79]
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]
[80]
Cortes, J.E.; Kantarjian, H.M.; Kadia, T.M.; Borthakur, G.; Konopleva, M.; Garcia-Manero, G. Crenolanib besylate, a type I pan-FLT3 inhibitor, to demonstrate clinical activity in multiply relapsed FLT3-ITD and D835 AML 2016, 3983a.
[http://dx.doi.org/10.1200/JCO.2016.34.15_suppl.7008]
[81]
Iyer, S.P.; Jethava, Y.; Karanes, C.; Eckardt, J.R.; Collins, R. Safety study of salvage chemotherapy high-dose Ara-C/mitoxantrone (HAM) and type I FLT3-TKI crenolanib in first relapsed/primary refractory AML 2016.
[http://dx.doi.org/10.1182/blood.V128.22.3983.3983]
[82]
Wang, E.S.; Stone, R.M.; Tallman, M.S. Crenolanib, a type I FLT3 TKI, can be safely combined with cytarabine and anthracycline induction chemotherapy and results in high response rates in patients with newly-diagnosed FLT3 mutant acute myeloid leukemia (AML) 2016, 1071a.
[http://dx.doi.org/10.1182/blood.V128.22.1071.1071]
[83]
Jetani, H.; Garcia-Cadenas, I.; Nerreter, T.; Thomas, S.; Rydzek, J.; Meijide, J.B.; Bonig, H.; Herr, W.; Sierra, J.; Einsele, H.; Hudecek, M. CAR T-cells targeting FLT3 have potent activity against FLT3-ITD+ AML and act synergistically with the FLT3-inhibitor crenolanib. Leukemia, 2018, 32(5), 1168-1179.
[http://dx.doi.org/10.1038/s41375-018-0009-0] [PMID: 29472720]
[84]
Dutreix, C.; Munarini, F.; Lorenzo, S.; Roesel, J.; Wang, Y. Investigation into CYP3A4-mediated drug-drug interactions on midostaurin in healthy volunteers. Cancer Chemother. Pharmacol., 2013, 72(6), 1223-1234.
[http://dx.doi.org/10.1007/s00280-013-2287-6] [PMID: 24085261]
[85]
Levis, M. FLT3/ITD AML and the law of unintended consequences. Blood, 2011, 117(26), 6987-6990.
[http://dx.doi.org/10.1182/blood-2011-03-340273] [PMID: 21586749]
[86]
Sato, T.; Yang, X.; Knapper, S.; White, P.; Smith, B.D.; Galkin, S.; Small, D.; Burnett, A.; Levis, M. FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo. Blood, 2011, 117(12), 3286-3293.
[http://dx.doi.org/10.1182/blood-2010-01-266742] [PMID: 21263155]
[87]
Piloto, O.; Wright, M.; Brown, P.; Kim, K.T.; Levis, M.; Small, D. Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways. Blood, 2007, 109(4), 1643-1652.
[http://dx.doi.org/10.1182/blood-2006-05-023804] [PMID: 17047150]
[88]
Zhang, W.; Borthakur, G.; Gao, C.; Chen, Y.; Mu, H.; Ruvolo, V.R.; Nomoto, K.; Zhao, N.; Konopleva, M.; Andreeff, M. the dual mek/flt3 inhibitor e6201 exerts cytotoxic activity against acute myeloid leukemia cells harboring resistance-conferring FLT3 mutations. Cancer Res., 2016, 76(6), 1528-1537.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-1580] [PMID: 26822154]
[89]
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]
[90]
Kohl, T.M.; Hellinger, C.; Ahmed, F.; Buske, C.; Hiddemann, W.; Bohlander, S.K.; Spiekermann, K. BH3 mimetic ABT-737 neutralizes resistance to FLT3 inhibitor treatment mediated by FLT3-independent expression of BCL2 in primary AML blasts. Leukemia, 2007, 21(8), 1763-1772.
[http://dx.doi.org/10.1038/sj.leu.2404776] [PMID: 17554384]
[91]
Yoshimoto, G.; Miyamoto, T.; Jabbarzadeh-Tabrizi, S.; Iino, T.; Rocnik, J.L.; Kikushige, Y.; Mori, Y.; Shima, T.; Iwasaki, H.; Takenaka, K.; Nagafuji, K.; Mizuno, S.; Niiro, H.; Gilliland, G.D.; Akashi, K. FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation. Blood, 2009, 114(24), 5034-5043.
[http://dx.doi.org/10.1182/blood-2008-12-196055] [PMID: 19808698]
[92]
Cools, J.; Mentens, N.; Furet, P.; Fabbro, D.; Clark, J.J.; Griffin, J.D.; Marynen, P.; Gilliland, D.G. Prediction of resistance to small molecule FLT3 inhibitors: implications for molecularly targeted therapy of acute leukemia. Cancer Res., 2004, 64(18), 6385-6389.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-2148] [PMID: 15374944]
[93]
Heidel, F.; Solem, F.K.; Breitenbuecher, F.; Lipka, D.B.; Kasper, S.; Thiede, M.H.; Brandts, C.; Serve, H.; Roesel, J.; Giles, F.; Feldman, E.; Ehninger, G.; Schiller, G.J.; Nimer, S.; Stone, R.M.; Wang, Y.; Kindler, T.; Cohen, P.S.; Huber, C.; Fischer, T. Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain. Blood, 2006, 107(1), 293-300.
[http://dx.doi.org/10.1182/blood-2005-06-2469] [PMID: 16150941]
[94]
von Bubnoff, N.; Engh, R.A.; Aberg, E.; Sänger, J.; Peschel, C.; Duyster, J. B. N. von. FMS-like tyrosine kinase 3-internal tandem duplication tyrosine kinase inhibitors display a nonoverlapping profile of resistance mutations in vitro. Cancer Res., 2009, 69(7), 3032-3041.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-2923] [PMID: 19318574]
[95]
Smith, C.C.; Wang, Q.; Chin, C.S.; Salerno, S.; Damon, L.E.; Levis, M.J.; Perl, A.E.; Travers, K.J.; Wang, S.; Hunt, J.P.; Zarrinkar, P.P.; Schadt, E.E.; Kasarskis, A.; Kuriyan, J.; Shah, N.P. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature, 2012, 485(7397), 260-263.
[http://dx.doi.org/10.1038/nature11016] [PMID: 22504184]
[96]
Perl, A.; Martinelli, G.; Cortes, J.E.; Neubauer, A.; Berman, E.; Paolini, S.; Montesinos, P.; Baer, M.R.; Larson, R.A.; Ustun, C.; Fabbiano, F.; Stasi, A.; Levis, M.J. 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. Hemasphere, 2019, 3, 392-393.
[97]
Alvarado, Y.; Kantarjian, H.M.; Luthra, R.; Ravandi, F.; Borthakur, G.; Garcia-Manero, G.; Konopleva, M.; Estrov, Z.; Andreeff, M.; Cortes, J.E. Treatment with FLT3 inhibitor in patients with FLT3-mutated acute myeloid leukemia is associated with development of secondary FLT3-tyrosine kinase domain mutations. Cancer, 2014, 120(14), 2142-2149.
[http://dx.doi.org/10.1002/cncr.28705] [PMID: 24737502]
[98]
Ivey, A.; Hills, R.K.; Simpson, M.A.; Jovanovic, J.V.; Gilkes, A.; Grech, A.; Patel, Y.; Bhudia, N.; Farah, H.; Mason, J.; Wall, K.; Akiki, S.; Griffiths, M.; Solomon, E.; McCaughan, F.; Linch, D.C.; Gale, R.E.; Vyas, P.; Freeman, S.D.; Russell, N.; Burnett, A.K.; Grimwade, D. UK National Cancer Research Institute AML Working Group. assessment of minimal residual disease in standard risk AML. N. Engl. J. Med., 2016, 374(5), 422-433.
[http://dx.doi.org/10.1056/NEJMoa1507471] [PMID: 26789727]
[99]
Ravandi, F.; Kantarjian, H.; Faderl, S.; Garcia-Manero, G.; O’Brien, S.; Koller, C.; Pierce, S.; Brandt, M.; Kennedy, D.; Cortes, J.; Beran, M. Outcome of patients with FLT3-mutated acute myeloid leukemia in first relapse. Leuk. Res., 2010, 34(6), 752-756.
[http://dx.doi.org/10.1016/j.leukres.2009.10.001] [PMID: 19878996]
[100]
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 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]
[101]
J. Lancet, G. Uy.; J, Cortes.; L, Newell.; T, Lin.; E, Ritchie.; Stuart, R.; S, Strickland.; Hogge.; S, Solomon.; R, Stone.; D, Bixby.; J, Kolitz.; G, Schiller.; M, Wieduwilt.; D, Ryan.; Hoering, Banerjee, Chiarella; A, Louie; B. Medeiros CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukaemia. J. Clin. Oncol., 2018, 36, 2684-2692.
[102]
Burnett, A.K.; Russell, N.H.; Hills, R.K. United Kingdom National Cancer Research Institute Acute Myeloid Leukemia Study Group. Higher daunorubicin exposure benefits FLT3 mutated acute myeloid leukemia. Blood, 2016, 128(3), 449-452.
[http://dx.doi.org/10.1182/blood-2016-04-712091] [PMID: 27268085]
[103]
Ehninger, A.; Kramer, M.; Röllig, C.; Thiede, C.; Bornhäuser, M.; von Bonin, M.; Wermke, M.; Feldmann, A.; Bachmann, M.; Ehninger, G.; Oelschlägel, U. Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia. Blood Cancer J., 2014, 4 e218
[http://dx.doi.org/10.1038/bcj.2014.39] [PMID: 24927407]
[104]
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]
[105]
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]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 7
Year: 2020
Published on: 17 May, 2020
Page: [513 - 531]
Pages: 19
DOI: 10.2174/1570163817666200518075820
Price: $65

Article Metrics

PDF: 63
HTML: 6
PRC: 1



Related Article(s)