151
Views
11
CrossRef citations to date
0
Altmetric
Reviews

Investigational drugs targeting FLT3 for leukemia

, MD, , PharmD BCOP, , MD & , MD
Pages 1445-1456 | Published online: 12 Aug 2009

Bibliography

  • Rosnet O, Birnbaum D. Hematopoietic receptors of class III receptor-type tyrosine kinases. Crit Rev Oncog 1993;4:595-613
  • Mackarehtschian K, Hardin JD, Moore KA, et al. Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Immunity 1995;3:147-61
  • McKenna HJ, Stocking KL, Miller RE, et al. Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood 2000;95:3489-97
  • Kikushige Y, Yoshimoto G, Miyamoto T, et al. Human Flt3 is expressed at the hematopoietic stem cell and the granulocyte/macrophage progenitor stages to maintain cell survival. J Immunol 2008;180:7358-67
  • Rusten LS, Lyman SD, Veiby OP, et al. 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
  • Lyman SD, James L, Vanden BOS, et al. Molecular cloning of a ligand for the flt3/flk-2 tyrosine kinase receptor: a proliferative factor for primitive hematopoietic cells. Cell 1993;75:1157-67
  • Hannum C, Culpepper J, Campbell D, et al. Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs. Nature 1994;368:643-8
  • Lyman SD, James L, Johnson L, et al. Cloning of the human homologue of the murine flt3 ligand: a growth factor for early hematopoietic progenitor cells. Blood 1994;83:2795-801
  • Namikawa R, Muench MO, de Vries JE, et al. The FLK2/FLT3 ligand synergizes with interleukin-7 in promoting stromal-cell-independent expansion and differentiation of human fetal pro-B cells in vitro. Blood 1996;87:1881-90
  • 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
  • Drexler HG. Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells. Leukemia 1996;10:588-99
  • Carow CE, Levenstein M, Kaufmann SH, et al. Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood 1996;87:1089-96
  • Allampallam K, Shetty V, Hussaini S, et al. Measurement of mRNA expression for a variety of cytokines and its receptors in bone marrows of patients with myelodysplastic syndromes. Anticancer Res 1999;19:5323-8
  • Lin P, Jones D, Medeiros LJ, et al. Activating FLT3 mutations are detectable in chronic and blast phase of chronic myeloproliferative disorders other than chronic myeloid leukemia. Am J Clin Pathol 2006;126:530-3
  • Armstrong SA, Mabon ME, Silverman LB, et al. FLT3 mutations in childhood acute lymphoblastic leukemia. Blood 2004;103:3544-6
  • Mizuki M, Fenski R, Halfter H, et al. Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood 2000;96:3907-14
  • Abu-Duhier FM, Goodeve AC, Wilson GA, et al. Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br J Haematol 2001;113:983-8
  • Thiede C, Steudel C, Mohr B, et al. 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
  • Yamamoto Y, Kiyoi H, Nakano Y, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 2001;97:2434-9
  • Spiekermann K, Bagrintseva K, Schoch C, et al. A new and recurrent activating length mutation in exon 20 of the FLT3 gene in acute myeloid leukemia. Blood 2002;100:3423-5
  • Sritana N, Auewarakul CU. KIT and FLT3 receptor tyrosine kinase mutations in acute myeloid leukemia with favorable cytogenetics: two novel mutations and selective occurrence in leukemia subtypes and age groups. Exp Mol Pathol 2008;85:227-31
  • Zhang S, Mantel C, Broxmeyer HE. Flt3 signaling involves tyrosyl-phosphorylation of SHP-2 and SHIP and their association with Grb2 and Shc in Baf3/Flt3 cells. J Leukoc Biol 1999;65:372-80
  • Abrams SLEC, Chiarini F, Misaghian N, et al. Roles of Raf/MEK/ERK and PI3K/Akt/mTOR pathways in prevention of apoptosis and induction of drug resistance in myeloid hematopoietic cells. Blood (ASH Meeting Abstracts) 2007;110:4202
  • Kiyoi H, Shiotsu Y, Ozeki K, et al. A novel FLT3 inhibitor FI-700 selectively suppresses the growth of leukemia cells with FLT3 mutations. Clin Cancer Res 2007;13:4575-82
  • Hayakawa F, Towatari M, Kiyoi H, et al. Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines. Oncogene 2000;19:624-31
  • Brandts CH, Sargin B, Rode M, et al. Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation. Cancer Res 2005;65:9643-50
  • Choudhary C, Schwable J, Brandts C, et al. AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations. Blood 2005;106:265-73
  • Choudhary C, Brandts C, Schwable J, et al. Activation mechanisms of STAT5 by oncogenic Flt3-ITD. Blood 2007;110:370-4
  • Kelly LM, Liu Q, Kutok JL, et al. FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood 2002;99:310-8
  • Nakao M, Yokota S, Iwai T, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 1996;10:1911-8
  • Kottaridis PD, Gale RE, Frew ME, et al. 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
  • Meshinchi S, Stirewalt DL, Alonzo TA, et al. Structural and numerical variation of FLT3/ITD in pediatric AML. Blood 2008;111:4930-3
  • Mead AJ, Linch DC, Hills RK, et al. 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
  • Emerenciano M, Menezes J, Vasquez ML, et al. Clinical relevance of FLT3 gene abnormalities in Brazilian patients with infant leukemia. Leuk Lymphoma 2008;49:2291-7
  • Breccia M, Frustaci AM, Cannella L, et al. Comorbidities and FLT3-ITD abnormalities as independent prognostic indicators of survival in elderly acute myeloid leukaemia patients. Hematol Oncol 2009 [Epub ahead of print] doi: 10.1002/hon.889
  • Schlenk RF, Dohner K, Kneba M, et al. Gene mutations and response to treatment with all-trans retinoic acid in elderly patients with acute myeloid leukemia. Results from the AMLSG trial AML HD98B. Haematologica 2009;94:54-60
  • Arrigoni P, Beretta C, Silvestri D, et al. FLT3 internal tandem duplication in childhood acute myeloid leukaemia: association with hyperleucocytosis in acute promyelocytic leukaemia. Br J Haematol 2003;120:89-92
  • Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008;358:1909-18
  • Wang L, Lin D, Zhang X, et al. Analysis of FLT3 internal tandem duplication and D835 mutations in Chinese acute leukemia patients. Leuk Res 2005;29:1393-8
  • Yoo SJ, Park CJ, Jang S, et al. Inferior prognostic outcome in acute promyelocytic leukemia with alterations of FLT3 gene. Leuk Lymphoma 2006;47:1788-93
  • Callens C, Chevret S, Cayuela JM, et al. Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): a retrospective study from the European APL Group. Leukemia 2005;19:1153-60
  • Andersson A, Johansson B, Lassen C, et al. Clinical impact of internal tandem duplications and activating point mutations in FLT3 in acute myeloid leukemia in elderly patients. Eur J Haematol 2004;72:307-13
  • Stock W, Najib K, Moser BK, et al. High incidence of FLT3 mutations in adults with acute promyelocytic leukemia (APL): correlation with diagnostic features and treatment outcome (CALGB 9710). Proc Am Soc Clin Oncol 2008;26:7002
  • Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2009;113:1875-91
  • Whitman SP, Archer KJ, Feng L, et al. 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
  • Gale RE, Green C, Allen C, et al. 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
  • Scholl S, Theuer C, Scheble V, et al. Clinical impact of nucleophosmin mutations and Flt3 internal tandem duplications in patients older than 60 yr with acute myeloid leukaemia. Eur J Haematol 2008;80:208-15
  • Meshinchi S, Woods WG, Stirewalt DL, et al. Prevalence and prognostic significance of Flt3 internal tandem duplication in pediatric acute myeloid leukemia. Blood 2001;97:89-94
  • Whitman SP, Ruppert AS, Radmacher MD, et al. 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
  • Meshinchi S, Alonzo TA, Stirewalt DL, et al. Clinical implications of FLT3 mutations in pediatric AML. Blood 2006;108:3654-61
  • Yanada M, Matsuo K, Suzuki T, et al. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia 2005;19:1345-9
  • Gale RE, Hills R, Pizzey AR, et al. Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Blood 2005;106:3768-76
  • Stirewalt DL, Kopecky KJ, Meshinchi S, et al. 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, et al. 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
  • Falini B, Nicoletti I, Martelli MF, et al. Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. Blood 2007;109:874-85
  • Tse KF, Novelli E, Civin CI, et al. Inhibition of FLT3-mediated transformation by use of a tyrosine kinase inhibitor. Leukemia 2001;15:1001-10
  • Piloto O, Levis M, Huso D, et al. Inhibitory anti-FLT3 antibodies are capable of mediating antibody-dependent cell-mediated cytotoxicity and reducing engraftment of acute myelogenous leukemia blasts in nonobese diabetic/severe combined immunodeficient mice. Cancer Res 2005;65:1514-22
  • Tse KF, Allebach J, Levis M, et al. Inhibition of the transforming activity of FLT3 internal tandem duplication mutants from AML patients by a tyrosine kinase inhibitor. Leukemia 2002;16:2027-36
  • Levis M, Allebach J, Tse KF, et al. A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood 2002;99:3885-91
  • Levis M, Tse KF, Smith BD, et al. A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations. Blood 2001;98:885-7
  • O'Farrell AM, Abrams TJ, Yuen HA, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 2003;101:3597-605
  • Teller S, Kramer D, Bohmer SA, et al. Bis(1H-2-indolyl)-1-methanones as inhibitors of the hematopoietic tyrosine kinase Flt3. Leukemia 2002;16:1528-34
  • Yee KW, O'Farrell AM, Smolich BD, et al. SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase. Blood 2002;100:2941-9
  • Zheng R, Friedman AD, Small D. Targeted inhibition of FLT3 overcomes the block to myeloid differentiation in 32Dcl3 cells caused by expression of FLT3/ITD mutations. Blood 2002;100:4154-61
  • Weisberg E, Boulton C, Kelly LM, et al. 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, et al. CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Cancer Cell 2002;1:421-32
  • Auclair D, Miller D, Yatsula V, et al. Antitumor activity of sorafenib in FLT3-driven leukemic cells. Leukemia 2007;21:439-45
  • Lopes de Menezes DE, Peng J, Garrett EN, et al. CHIR-258: a potent inhibitor of FLT3 kinase in experimental tumor xenograft models of human acute myelogenous leukemia. Clin Cancer Res 2005;11:5281-91
  • Rivera V, Xu Q, Berk L, et al. Potent antitumor activity of AP24534, an orally active inhibitor of bcr-abl, flt3, and other kinases, in both in vitro and in vivo models of acute myeloid leukemia (AML). Blood (ASH Meeting Abstracts) 2008;112:2932
  • Pratz KW, Cortes J, Roboz GJ, et al. A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response. Blood 2009;113:3938-46
  • Joyce J, Pratz KW, Stine A, et al. Clinical pharmacokinetics and FLT3 phosphorylation of AC220, a highly potent and selective inhibitor of FLT3. Blood (ASH Meeting Abstracts) 2008;112:2637
  • Mahboobi S, Uecker A, Sellmer A, et al. Novel bis(1H-indol-2-yl)methanones as potent inhibitors of FLT3 and platelet-derived growth factor receptor tyrosine kinase. J Med Chem 2006;49:3101-15
  • Shankar DB, Li J, Tapang P, et al. ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia. Blood 2007;109:3400-08
  • Kancha RK, Grundler R, Peschel C, et al. Sensitivity toward sorafenib and sunitinib varies between different activating and drug-resistant FLT3-ITD mutations. Exp Hematol 2007;35:1522-6
  • Barry EV, Clark JJ, Cools J, et al. Uniform sensitivity of FLT3 activation loop mutants to the tyrosine kinase inhibitor midostaurin. Blood 2007;110:4476-9
  • Stone RM, DeAngelo DJ, Klimek V, et al. 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
  • Knapper S, Burnett AK, Littlewood T, et al. 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
  • Heidel F, Solem FK, Breitenbuecher F, et al. 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
  • Cools J, Mentens N, Furet P, et al. Prediction of resistance to small molecule FLT3 inhibitors: implications for molecularly targeted therapy of acute leukemia. Cancer Res 2004;64:6385-9
  • Lierman E, Lahortiga I, Van Miegroet H, et al. The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. Haematologica 2007;92:27-34
  • Zhou J, Bi C, Janakakumara JV, et al. Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML. Blood 2009;113(17):4052-62
  • Breitenbuecher F, Markova B, Kasper S, et al. A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in acute myeloid leukemia. Blood 2009;113(17):4063-73
  • Piloto O, Wright M, Brown P, et al. Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways. Blood 2007;109:1643-52
  • Siendones E, Barbarroja N, Torres LA, et al. Inhibition of Flt3-activating mutations does not prevent constitutive activation of ERK/Akt/STAT pathways in some AML cells: a possible cause for the limited effectiveness of monotherapy with small-molecule inhibitors. Hematol Oncol 2007;25:30-7
  • Levis M, Pham R, Smith BD, et al. 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
  • Hu S, Niu H, Orwick S, et al. Preclinical evaluation of sorafenib in combination with cytarabine and clofarabine in acute myeloid leukemia (AML). Blood (ASH Meeting Abstracts) 2007;110:4202
  • Fiedler W, Serve H, Dohner H, et al. 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
  • Delmonte J, Kantarjian HM, Andreeff M, et al. Update of a phase I study of sorafenib in patients with refractory/relapsed acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood (ASH Meeting Abstacts) 2007;110:893
  • Ravandi F, Cortes J, Faderl S, et al. Combination of sorafenib, idarbucin, and cytarabine has a high response rate in patients with newly diagnosed acute myeloid leukemia (AML) younger than 65 years. Blood (ASH Meeting Abstracts) 2008;112:768
  • Stock W, Yee K, Wang ES, et al. Pharmacokinetics results from a phase I study of a multi-targeted tyrosine kinase inhibitor, ABT-869, in patients with refractory or relapsed acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Blood (ASH Meeting Abstacts) 2008;112:4008
  • Cortes JE, Ghirdaladze D, Foran JM, et al. Phase 1 AML study of AC220, a potent and selective second generation FLT3 receptor tyrosine kinase inhibitor. Blood (ASH Meeting Abstacts) 2008;112:767
  • Smith BD, Levis M, Beran M, et al. 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
  • Fiedler W, Mesters R, Tinnefeld H, et al. A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia. Blood 2003;102:2763-7
  • Levis M, Smith BD, Beran M, et al. A randomized, open-label study of lestaurtinib (CEP-701), an oral FLT3 inhibitor, administered in sequence with chemotherapy in patients with relapsed AML harboring FLT3 activating mutations: Clinical response correlates with succesful FLT3 inhibition. Blood (ASH Meeting Abstacts) 2005;106:403
  • Stone RM, Fischer T, Paquette RL, et al. Phase IB study of PKC412, an oral FLT3 kinase inhibitor, in sequential and simultaneous combinations with daunorubicin and cytarabine (DA) induction and high-dose cytarabine consolidation in newly diagnosed adult patients (pts) with acute myeloid leukemia (AML) under age 61. Blood (ASH Meeting Abstacts) 2006;108:157
  • Deangelo DJ, Amrein PC, Kovacsovics TJ, et al. Phase 1/2 study of tandutinib (MLN518) plus standard induction chemotherapy in newly diagnosed acute myelogenous leukemia (AML). Blood (ASH Meeting Abstacts) 2006;108:158
  • George P, Bali P, Cohen P, et al. Cotreatment with 17-allylamino-demethoxygeldanamycin and FLT-3 kinase inhibitor PKC412 is highly effective against human acute myelogenous leukemia cells with mutant FLT-3. Cancer Res 2004;64:3645-52
  • Mohi MG, Boulton C, Gu TL, et al. 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
  • Mollgard L, Deneberg S, Nahi H, et al. The FLT3 inhibitor PKC412 in combination with cytostatic drugs in vitro in acute myeloid leukemia. Cancer Chemother Pharmacol 2008;62:439-48
  • George P, Bali P, Annavarapu S, et al. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood 2005;105:1768-76

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.