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The clinical development of FLT3 inhibitors in acute myeloid leukemia

, DM BMBCh FRCPath MRCP
Pages 1377-1395 | Published online: 06 Sep 2011

Bibliography

  • Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer 2003;3:650-65
  • Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood 2002;100:1532-42
  • Kottaridis PD, Gale RE, Linch DC. Flt3 mutations and leukaemia. Br J Haematol 2003;122:523-38
  • Knapper S. FLT3 inhibition in acute myeloid leukaemia. Br J Haematol 2007;138:687-99
  • Levis M, Small D. Novel FLT3 tyrosine kinase inhibitors. Expert Opin Investig Drugs 2003;12:1951-62
  • Kindler T, Lipka DB, Fischer T. FLT3 as a therapeutic target in AML: still challenging after all these years. Blood 2010;116:5089-102
  • Small D, Levenstein M, Kim E, STK-1, the human homolog of Flk-2/Flt-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells. Proc Natl Acad Sci USA 1994;91:459-63
  • Gotze KS, Ramirez M, Tabor K, Flt3high and Flt3low CD34+ progenitor cells isolated from human bone marrow are functionally distinct. Blood 1998;91:1947-58
  • Rusten LS, Lyman SD, Veiby OP, Jacobsen SE. The FLT3 ligand is a direct and potent stimulator of the growth of primitive and committed human CD34+ bone marrow progenitor cells in vitro. Blood 1996;87:1317-25
  • McKenna HJ, Stocking KL, Miller RE, Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood 2000;95:3489-97
  • Rosnet O, Buhring HJ, Marchetto S, Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells. Leukemia 1996;10:238-48
  • Nakao M, Yokota S, Iwai T, Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 1996;10:1911-18
  • Yamamoto Y, Kiyoi H, Nakano Y, Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 2001;97:2434-9
  • Griffith J, Black J, Faerman C, The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Mol Cell 2004;13:169-78
  • Levis M, Small D. FLT3: ITDoes matter in leukemia. Leukemia 2003;17:1738-52
  • Meshinchi S, Alonzo TA, Stirewalt DL, Clinical implications of FLT3 mutations in pediatric AML. Blood 2006;108:3654-61
  • Kottaridis PD, Gale RE, Frew ME, 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;98:1752-9
  • Thiede C, Steudel C, Mohr B, 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;99:4326-35
  • Ravandi F, Kantarjian H, Faderl S, Outcome of patients with FLT3-mutated acute myeloid leukemia in first relapse. Leuk Res 2010;34:752-6
  • Whitman SP, Archer KJ, Feng L, 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;61:7233-9
  • Stirewalt DL, Kopecky KJ, Meshinchi S, Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia. Blood 2006;107:3724-6
  • Ponziani V, Gianfaldoni G, Mannelli F, The size of duplication does not add to the prognostic significance of FLT3 internal tandem duplication in acute myeloid leukemia patients. Leukemia 2006;20:2074-6
  • Breitenbuecher F, Schnittger S, Grundler R, Identification of a novel type of ITD mutations located in nonjuxtamembrane domains of the FLT3 tyrosine kinase receptor. Blood 2009;113:4074-7
  • Kayser S, Schlenk RF, Londono MC, Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood 2009;114:2386-92
  • Falini B, Mecucci C, Tiacci E, Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 2005;352:254-66
  • Schnittger S, Schoch C, Kern W, Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 2005;106:3733-9
  • Gale RE, Green C, Allen C, 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;111:2776-84
  • Mead AJ, Linch DC, Hills RK, 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;110:1262-70
  • Whitman SP, Ruppert AS, Radmacher MD, FLT3 D835/I836 mutations are associated with poor disease-free survival and a distinct gene-expression signature among younger adults with de novo cytogenetically normal acute myeloid leukemia lacking FLT3 internal tandem duplications. Blood 2008;111:1552-9
  • Frohling S, Schlenk RF, Breitruck J, 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;100:4372-80
  • Kelly LM, Liu Q, Kutok JL, FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood 2002;99:310-18
  • Grundler R, Miething C, Thiede C, FLT3-ITD and tyrosine kinase domain mutants induce 2 distinct phenotypes in a murine bone marrow transplantation model. Blood 2005;105:4792-9
  • Choudhary C, Schwable J, Brandts C, AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations. Blood 2005;106:265-73
  • Kantarjian H, Sawyers C, Hochhaus A, Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002;346:645-52
  • Hortobagyi GN. Overview of treatment results with trastuzumab (Herceptin) in metastatic breast cancer. Semin Oncol 2001;28:43-7
  • Liu Y, Gray NS. Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol 2006;2:358-64
  • Grundler R, Thiede C, Miething C, Sensitivity toward tyrosine kinase inhibitors varies between different activating mutations of the FLT3 receptor. Blood 2003;102:646-51
  • Clark JJ, Cools J, Curley DP, Variable sensitivity of FLT3 activation loop mutations to the small molecule tyrosine kinase inhibitor MLN518. Blood 2004;104:2867-72
  • Knapper S, Mills KI, Gilkes AF, The effects of lestaurtinib (CEP701) and PKC412 on primary AML blasts: the induction of cytotoxicity varies with dependence on FLT3 signaling in both FLT3-mutated and wild-type cases. Blood 2006;108:3494-503
  • Levis M, Allebach J, Tse KF, A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood 2002;99:3885-91
  • Levis M, Brown P, Smith BD, Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Blood 2006;108:3477-83
  • Smith BD, Levis M, Beran M, Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood 2004;103:3669-76
  • Knapper S, Burnett AK, Littlewood T, 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;108:3262-70
  • Ravandi F, Cortes JE, Jones D, Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol 2010;28:1856-62
  • Stone R, Fischer T, Paquette R, A phase 1b study of Midostaurin (PKC412) in combination with Daunorubicin and Cytarabine induction and HIgh-dose Cytarabine consolidation in patients under age 61 with newly diagnosed de novo acute myeloid leukemia: overall survival of patients whose blasts have FLT3 mutations is similar to those with wild-type FLT3. Blood 2009;114:634a
  • Fiedler W, Mesters R, Tinnefeld H, A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia. Blood 2003;102:2763-7
  • Giles FJ, Stopeck AT, Silverman LR, SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. Blood 2003;102:795-801
  • O'Farrell AM, Yuen HA, Smolich B, Effects of SU5416, a small molecule tyrosine kinase receptor inhibitor, on FLT3 expression and phosphorylation in patients with refractory acute myeloid leukemia. Leuk Res 2004;28:679-89
  • O'Farrell AM, Abrams TJ, Yuen HA, SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 2003;101:3597-605
  • Motzer RJ, Hutson TE, Tomczak P, Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115-24
  • Demetri GD, van Oosterom AT, Garrett CR, Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006;368:1329-38
  • O'Farrell AM, Foran JM, Fiedler W, An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. Clin Cancer Res 2003;9:5465-76
  • Fiedler W, Serve H, Dohner H, A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood 2005;105:986-93
  • Yee KW, Schittenhelm M, O'Farrell AM, Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3 ITD-positive leukemic cells. Blood 2004;104:4202-9
  • Fiedler W, Krauter J, Gotze K, A phase I/II study combining Sunitinib with standard Ara-C/Daunorubicin chemotherapy in patients 60 years or older with FLT3 mutated AML. Blood 2010;116:3285a
  • Marshall JL, Kindler H, Deeken J, Phase I trial of orally administered CEP-701, a novel neurotrophin receptor-linked tyrosine kinase inhibitor. Invest New Drugs 2005;23:31-7
  • Hexner EO, Serdikoff C, Jan M, Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood 2008;111:5663-71
  • Santos FP, Kantarjian HM, Jain N, Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Blood 2010;115:1131-6
  • Levis M, Pham R, Smith BD, Small D. In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects. Blood 2004;104:1145-50
  • Levis M, Ravandi F, Wang ES, Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood 2011;117:3294-301
  • Knapper S, Burnett A, Hills R, Lestaurtinib FLT3 inhibitory activity is modulated by concomitant azole therapy and may influence relapse risk. Blood 2009;114:789a
  • Stone RM, DeAngelo DJ, Klimek V, Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 2005;105:54-60
  • Fischer T, Stone RM, DeAngelo DJ, 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;28:4339-45
  • DeAngelo DJ, Stone RM, Heaney ML, Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. Blood 2006;108:3674-81
  • Lehky TJ, Iwamoto FM, Kreisl TN, Neuromuscular junction toxicity with tandutinib induces a myasthenic-like syndrome. Neurology 2011;76:236-41
  • De Angelo D, Stone R, Heaney H. Phase II evaluation of the tyrosine kinase inhibitor MLN518 in patients with acute myeloid leukemia (AML) bearing a FLT3 internal tandem duplication (ITD) mutation. Blood 2004;104:1792a
  • Schittenhelm MM, Kampa KM, Yee KW, Heinrich MC. The FLT3 inhibitor tandutinib (formerly MLN518) has sequence-independent synergistic effects with cytarabine and daunorubicin. Cell Cycle 2009;8:2621-30
  • DeAngelo D, Amrein P, Kovacsovics T, Phase 1/2 study of Tandutinib (MLN518) plus standard induction chemotherapy in newly diagnosed acute myelogenous leukemia (AML). Blood 2006;108:158a
  • Escudier B, Eisen T, Stadler WM, Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125-34
  • Llovet JM, Ricci S, Mazzaferro V, Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-90
  • Pratz KW, Cho E, Levis MJ, A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias. Leukemia 2010;24:1437-44
  • Zhang W, Konopleva M, Shi YX, Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. J Natl Cancer Inst 2008;100:184-98
  • Delmonte J, Kantarjian H, Andreeff M, Update of a phase I study of Sorafenib in patients with refractory/relapsed acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood 2007;110:893a
  • Safaian NN, Czibere A, Bruns I, Sorafenib (Nexavar) induces molecular remission and regression of extramedullary disease in a patient with FLT3-ITD+ acute myeloid leukemia. Leuk Res 2009;33:348-50
  • Lee SH, Paietta E, Racevskis J, Wiernik PH. Complete resolution of leukemia cutis with sorafenib in an acute myeloid leukemia patient with FLT3-ITD mutation. Am J Hematol 2009;84:701-2
  • Metzelder S, Wang Y, Wollmer E, Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. Blood 2009;113:6567-71
  • Metzelder S, Finck A, Fey M, Sorafenib monotherapy is effective in relapsed and refractory Flt3-ITD positive acute myeloid leukemia, particularly after allogeneic stem cell transplantation. Blood 2010;116:3314a
  • Serve H, Wagner R, Sauerland C, Sorafenib in combination with standard induction and consolidation therapy in elderly AML patients: results from a randomized, placebo-controlled phase II trial. Blood 2010;116:333a
  • Pratz KW, Sato T, Murphy KM, FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML. Blood 2010;115:1425-32
  • Shiotsu Y, Kiyoi H, Ishikawa Y, KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation. Blood 2009;114:1607-17
  • Cortes J, Roboz G, Kantarjian H, A phase I dose escalation study of KW-2449, an oral multi-kinase inhibitor against FLT3, Abl, FGFR1 and Aurora in patients with relapsed/ refractpry AML, ALL and MDS or resistant/intolerant CML. Blood 2008;112:2967a
  • Pratz KW, Cortes J, Roboz GJ, A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response. Blood 2009;113:3938-46
  • Chao Q, Sprankle KG, Grotzfeld RM, Identification of N-(5-tert-butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2, 1-b][1,3]benzothiazol-2-yl]phenyl}urea dihydrochloride (AC220), a uniquely potent, selective, and efficacious FMS-like tyrosine kinase-3 (FLT3) inhibitor. J Med Chem 2009;52:7808-16
  • Zarrinkar PP, Gunawardane RN, Cramer MD, AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood 2009;114:2984-92
  • Cortes J, Foran J, Ghirdaladze D, AC220, a potent, selective, second generation FLT3 receptor tyrosine kinase (RTK) inhibitor, in a first-in-human (FIH) phase 1 AML study. Blood 2009;114:636a
  • Brown P, Meshinchi S, Levis M, Pediatric AML primary samples with FLT3/ITD mutations are preferentially killed by FLT3 inhibition. Blood 2004;104:1841-9
  • Cools J, Mentens N, Furet P, Prediction of resistance to small molecule FLT3 inhibitors: implications for molecularly targeted therapy of acute leukemia. Cancer Res 2004;64:6385-9
  • Wadleigh M, DeAngelo DJ, Griffin JD, Stone RM. After chronic myelogenous leukemia: tyrosine kinase inhibitors in other hematologic malignancies. Blood 2005;105:22-30
  • Heidel F, Solem FK, Breitenbuecher F, Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain. Blood 2006;107:293-300
  • Sato T, Yang X, Knapper S, FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo. Blood 2011;117:3286-93
  • Piloto O, Wright M, Brown P, Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways. Blood 2007;109:1643-52
  • Breitenbuecher F, Markova B, Kasper S, A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML. Blood 2009;113:4063-73
  • Zhou J, Bi C, Janakakumara JV, Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML. Blood 2009;113:4052-62
  • Kohl TM, Hellinger C, Ahmed F, BH3 mimetic ABT-737 neutralizes resistance to FLT3 inhibitor treatment mediated by FLT3-independent expression of BCL2 in primary AML blasts. Leukemia 2007;21:1763-72
  • Chen W, Drakos E. Grammatikakis I, et al. mTOR signaling is activated by FLT3 kinase and promotes survival of FLT3-mutated acute myeloid leukemia cells. Mol Cancer 2010;9:292
  • Mohi MG, Boulton C, Gu TL, Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc Natl Acad Sci USA 2004;101:3130-5
  • Nishioka C, Ikezoe T, Yang J, Blockade of MEK/ERK signaling enhances sunitinib-induced growth inhibition and apoptosis of leukemia cells possessing activating mutations of the FLT3 gene. Leuk Res 2008;32:865-72
  • Nishioka C, Ikezoe T, Yang J, MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells. Leuk Res 2008;32:1382-92
  • Ahmad R, Liu S, Weisberg E, Combining the FLT3 inhibitor PKC412 and the triterpenoid CDDO-Me synergistically induces apoptosis in acute myeloid leukemia with the internal tandem duplication mutation. Mol Cancer Res 2010;8:986-93
  • Rombouts EJ, Pavic B, Lowenberg B, Ploemacher RE. Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia. Blood 2004;104:550-7
  • Zeng Z, Shi YX, Samudio IJ, Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML. Blood 2009;113:6215-24
  • Piloto O, Nguyen B, Huso D, IMC-EB10, an anti-FLT3 monoclonal antibody, prolongs survival and reduces nonobese diabetic/severe combined immunodeficient engraftment of some acute lymphoblastic leukemia cell lines and primary leukemic samples. Cancer Res 2006;66:4843-51
  • Levis M, Murphy KM, Pham R, Internal tandem duplications of the FLT3 gene are present in leukemia stem cells. Blood 2005;106:673-80
  • Kern W, Haferlach C, Haferlach T, Schnittger S. Monitoring of minimal residual disease in acute myeloid leukemia. Cancer 2008;112:4-16
  • Shih LY, Huang CF, Wu JH, 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;10:1326-32
  • Yee KW, O'Farrell AM, Smolich BD, SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase. Blood 2002;100:2941-9
  • Weisberg E, Boulton C, Kelly LM, Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell 2002;1:433-43
  • Kelly LM, Yu JC, Boulton CL, CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Cancer Cell 2002;1:421-32

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