The evolving role of FLT3 inhibitors in acute myeloid leukemia: Quizartinib and beyond

Therapeutic Advances in Hematology

Volumn 5, Issue 3, 2014, Pages 65-77

  Wander, Seth A ^a   Fathi, Amir T ^a   Levis, Mark J ^b  

^a MASSACHUSETTS GENERAL HOSPITAL CANCER CENTER   (United States)

^b JOHNS HOPKINS UNIVERSITY   (United States)

Author keywords

acute myeloid leukemia; FLT3; quizartinib; targeted therapies

Indexed keywords

EID: 84993736181     PISSN: 20406207     EISSN: 20406215     Source Type: Journal    
DOI: 10.1177/2040620714532123     Document Type: Review

References (75)

1. Abu-Duhier F. Goodeve A. Wilson G. Care R. Peake I. Reilly J. (2001) Identification of novel FLT-3 ASP 835 mutations in adult acute myeloid leukaemia. Br J Haematol 113: 983–988.
2. Bar-Natan M. Nelson E. Xiang M. Frank D. (2012) STAT signaling in the pathogenesis and treatment of myeloid malignancies. JAKSTAT 1: 55–64.
3. Burton E. Wong B. Zhang J. West B. Bollag G. Habets G. et al. (2011) The novel inhibitor PLX 3397 effectively inhibits FLT3-mutant AML. Blood 118: 3632.
4. Carow C. Kim E. Hawkins A. Webb H. Griffin C. Jabs E. et al. (1995) Localization of the human stem cell tyrosine kinase-1 gene (FLT3) to 13Q12–>Q13. Cytogen Cell Gen 70: 255–257.
5. Carow C. Levenstein M. Kaufmann S. Chen J. Amin S. Rockwell P. et al. (1996) Expression of the hematopoietic growth factor receptor FLT 3 (STK-1/FLK2) in human leukemias. Blood 87: 1089–1096.
6. Cortes J. Kantarjian H. Foran J. Ghirdaladze D. Zodelava M. Borthakur G. et al. (2013) Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol 31: 3681–3687.
7. Cortes J. Perl A. Dombret H. Kayser S. Steffen B. Rousselot P. et al. (2012) Final results of a phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients >= 60 years of age with FLT 3 ITD positive or negative relapsed / refractory acute myeloid leukemia. Blood 120: Abstract 48.
8. Demetri G. van Oosterom A. Garrett C. Blackstein M. Shah M. Verweij J. et al. (2006) Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368: 1329–1338.
9. Escudier B. Eisen T. Stadler W. Szczylik C. Oudard S. Siebels M. et al. (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356: 125–134.
10. Fathi A. Le L. Hasserjian R. Sadrzadeh H. Levis M. Chen Y. (2013) FLT 3 inhibitor-induced neutrophilic dermatosis. Blood 122: 239–242.
11. Fiedler W. Kayser S. Kebenko M. Krauter J. Salih H. Gotze K. et al. (2012) Sunitinib and intensive chemotherapy in patients with acute myeloid leukemia and activating FLT 3 mutations: results of the AMLSG 10–07 study (ClinicalTrials.gov No. NCT00783653). Blood 120: Abstract 1483.
12. Fiedler W. Serve H. Dohner H. Schwittay M. Ottmann O. O'Farrell A. et al. (2005) A phase 1 study of SU 11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood 105: 986–993.
13. Fischer T. Stone R. Deangelo D. Galinsky I. Estey E. Lanza C. et al. (2010) 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 28: 4339–4345.
14. Galanis A. Rajkhowa T. Muralidhara C. Ramachandran A. Levis M. (2012) Crenolanib: a next generation FLT 3 inhibitor. Cancer Res 72: abstract 3660.
15. Gale R. Green C. Allen C. Mead A. Burnett A. Hills R. et al. (2008) The impact of FLT 3 internal tandem duplication mutant level, number, size, and interaction with NPM 1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood 111: 2776–2784.
16. Gilliland D. Griffin J. (2002) The roles of FLT 3 in hematopoiesis and leukemia. Blood 100: 1532–1542.
17. Gollob J. Wilhelm S. Carter C. Kelley S. (2006) Role of RAF kinase in cancer: therapeutic potential of targeting the RAF/MEK/ERK signal transduction pathway. Semin Oncol 33: 392–406.
18. Haidar J. Bazarbachi A. Mahfouz R. Haidar H. Jaafar H. Daher R. (2002) Serum FLT 3 ligand variation as a predictive indicator of hematopoietic stem cell mobilization. J Hemato ther Stem Cell Res 11: 533–538.
19. Hay N. Sonenberg N. (2004) Upstream and downstream of mTOR. Genes Dev 18: 1926–1945.
20. Heidel F. Solem F. Breitenbuecher F. Lipka D. Kasper S. Thiede M. et al. (2006) Clinical resistance to the kinase inhibitor PKC 412 in acute myeloid leukemia by mutation of ASN-676 in the FLT 3 tyrosine kinase domain. Blood 107: 293–300.
21. Howlader N. Noone A. Krapcho M. Garshell J. Neyman N. Altekruse S. et al. (2013) SEER Stat Fact Sheets: Acute Myeloid Leukemia. http://seer.cancer.gov/csr/1975_2010/
22. Kampa-Schittenhelm K. Heinrich M. Akmut F. Dohner H. Dohner K. Schittenhelm M. (2013) Quizartinib (AC220) is a potent second generation class III tyrosine kinase inhibitor that displays a distinct inhibition profile against mutant-FLT3, -PDGFRA and -Kit isoforms. Mol Cancer 12: 19.
23. Kayser S. Levis M. (2013) FLT 3 tyrosine kinase inhibitors in acute myeloid leukemia: clinical implications and limitations. Leuk Lymphoma, in press.
24. Kayser S. Schlenk R. Londono M. Breitenbuecher F. Wittke K. Du J. et al. (2009) Insertion of FLT 3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood 114: 2386–2392.
25. Kelly L. Gilliland D. (2002) Genetics of myeloid leukemias. Annu Rev Genomics Hum Genet 3: 179–198.
26. Kiyoi H. Towatari M. Yokota S. Hamaguchi M. Ohno R. Saito H. et al. (1998) Internal tandem duplication of the FLT 3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia 12: 1333–1337.
27. Knapper S. Burnett A. Littlewood T. Kell W. Agrawal S. Chopra R. et al. (2006) A phase 2 trial of the FLT 3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood 108: 3262–3270.
28. Levis M. Perl A. Dombret H. Dohner H. Steffen B. Rousselot P. et al. (2012) Final results of a phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients with FLT3-ITD positive or negative relapsed / refractory acute myeloid leukemia after second-line chemotherapy or hematopoietic stem cell transplantation Blood 120: abstract 673.
29. Levis M. Ravandi F. Wang E. Baer M. Perl A. Coutre S. et al. (2011) Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT 3 mutant AML in first relapse. Blood 117: 3294–3301.
30. Levis M. Small D. (2003) FLT3: it does matter in leukemia. Leukemia 17: 1738–1752.
31. Ley T. Miller C. Ding L. Raphael B. Mungall A. Robertson A. et al. (2013) Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 368: 2059–2074.
32. Llovet J. Ricci S. Mazzaferro V. Hilgard P. Gane E. Blanc J. et al. (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359: 378–390.
33. Lowenberg B. Downing J. Burnett A. (1999) Acute myeloid leukemia. N Engl J Med 341: 1051–1062.
34. Lyman S. James L. Johnson L. Brasel K. de Vries P. Escobar S. et al. (1994) Cloning of the human homologue of the murine FLT 3 ligand: a growth factor for early hematopoietic progenitor cells. Blood 83: 2795–2801.
35. Manning B. Cantley L. (2007) AKT / PKB signaling: navigating downstream. Cell 129: 1261–1274.
36. Marcucci G. Haferlach T. Dohner H. (2011) Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol 29: 475–486.
37. Markman B. Atzori F. Perez-Garcia J. Tabernero J. Baselga J. (2009) Status of PI3K inhibition and biomarker development in cancer therapeutics. Ann Oncol 21: 683–691.
38. Metzelder S. Schroeder T. Finck A. Scholl S. Fey M. Gotze K. et al. (2012) High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses. Leukemia 26: 2353–2359.
39. Moore A. Faisal A. Gonzalez de Castro D. Bavetsias V. Sun C. Atrash B. et al. (2012) Selective FLT 3 inhibition of FLT3-ITD+ acute myeloid leukaemia resulting in secondary D835Y mutation: a model for emerging clinical resistance patterns. Leukemia 26: 1462–1470.
40. Moreno I. Martin G. Bolufer P. Barragan E. Rueda E. Roman J. et al. (2003) Incidence and prognostic value of FLT 3 internal tandem duplication and D 835 mutations in acute myeloid leukemia. Haematologica 88: 19–24.
41. Motzer R. Hutson T. Tomczak P. Michaelson M. Bukowski R. Rixe O. et al. (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356: 115–124.
42. Nakao M. Yokota S. Iwai T. Kaneko H. Horiike S. Kashima K. et al. (1996) Internal tandem duplication of the FLT 3 gene found in acute myeloid leukemia. Leukemia 10: 1911–1918.
43. O'Farrell A. Foran J. Fiedler W. Serve H. Paquette R. Cooper M. et al. (2003) An innovative phase I clinical study demonstrates inhibition of FLT 3 phosphorylation by SU 11248 in acute myeloid leukemia patients. Clin Cancer Res 9: 5465–5476.
44. Parmar A. Marz S. Rushton S. Holzwarth C. Lind K. Kayser S. et al. (2011) Stromal niche cells protect early leukemic FLT3-ITD+ progenitor cells against first-generation FLT 3 tyrosine kinase inhibitors. Cancer Res 71: 4696–4706.
45. Piloto O. Wright M. Brown P. Kim K. Levis M. Small D. (2007) Prolonged exposure to FLT 3 inhibitors leads to resistance via activation of parallel signaling pathways. Blood 109: 1643–1652.
46. Pratz K. Cho E. Levis M. Karp J. Gore S. McDevitt M. et al. (2010 a) A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias. Leukemia 24: 1437–1444.
47. Pratz K. Sato T. Murphy K. Stine A. Rajkhowa T. Levis M. (2010 b) FLT3-mutant allelic burden and clinical status are predictive of response to FLT 3 inhibitors in AML. Blood 115: 1425–1432.
48. Ravandi F. Alattar M. Grunwald M. Rudek M. Rajkhowa T. Richie M. et al. (2013) Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood 121: 4655–4662.
49. Ravandi F. Cortes J. Jones D. Faderl S. Garcia-Manero G. Konopleva M. et al. (2010) Phase I / II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol 28: 1856–1862.
50. Rosnet O. Buhring H. Marchetto S. Rappold I. Lavagna C. Sainty D. et al. (1996) Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells. Leukemia 10: 238–248.
51. Roux P. Blenis J. (2004) ERK and P 38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev 68: 320–344.
52. Sato T. Yang X. Knapper S. White P. Smith B. Galkin S. et al. (2011) FLT 3 ligand impedes the efficacy of FLT 3 inhibitors in vitro and in vivo. Blood 117: 3286–3293.
53. Schnittger S. Bacher U. Haferlach C. Alpermann T. Kern W. Haferlach T. (2012) Diversity of the juxtamembrane and TKD 1 mutations (exons 13–15) in the FLT 3 gene with regards to mutant load, sequence, length, localization, and correlation with biological data. Genes Chromosomes Cancer 51: 910–924.
54. Schnittger S. Bacher U. Kern W. Alpermann T. Haferlach C. Haferlach T. (2011) Prognostic impact of FLT3-ITD load in NPM 1 mutated acute myeloid leukemia. Leukemia 25: 1297–1304.
55. Serve H. Wagner R. Sauerland C. Brunnberg U. Krug U. Schaich M. et al. (2010) Sorafenib in combination with standard induction and consolidation therapy in elderly AML patients: results from a randomized, placebo-controlled phase II trial. Blood (ASH Annual Meeting Abstracts) 116: abstract 333.
56. Sexauer A. Perl A. Yang X. Borowitz M. Gocke C. Rajkhowa T. et al. (2012) Terminal myeloid differentiation in vivo is induced by FLT 3 inhibition in FLT3/ITD AML. Blood 120: 4205–4214.
57. Sharma M. Ravandi F. Bayraktar U. Chiattone A. Bashir Q. Giralt S. et al. (2011) Treatment of FLT3-ITD-positive acute myeloid leukemia relapsing after allogeneic stem cell transplantation with sorafenib. Biol Blood Marrow Transplant 17: 1874–1877.
58. Small D. Levenstein M. Kim E. Carow C. Amin S. Rockwell P. et al. (1994) 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 91: 459–463.
59. Smith B. Levis M. Beran M. Giles F. Kantarjian H. Berg K. et al. (2004) Single-agent CEP-701, a novel FLT 3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood 103: 3669–3676.
60. Smith C. Wang Q. Chin C. Salerno S. Damon L. Levis M. et al. (2012) Validation of ITD mutations in FLT 3 as a therapeutic target in human acute myeloid leukaemia. Nature 485: 260–263.
61. Stirewalt D. Kopecky K. Meshinchi S. Engel J. Pogosova-Agadjanyan E. Linsley J. et al. (2006) Size of FLT 3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia. Blood 107: 3724–3726.
62. Stone R. Deangelo D. Klimek V. Galinsky I. Estey E. Nimer S.D. et al. (2005) Patients with acute myeloid leukemia and an activating mutation in FLT 3 respond to a small-molecule FLT 3 tyrosine kinase inhibitor, PKC412. Blood 105: 54–60.
63. Stone R. Fischer T. Paquette R. Schiller G. Schiffer C. Ehninger G. et al. (2012) Phase Ib study of the FLT 3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia 26: 2061–2068.
64. Thiede C. Steudel C. Mohr B. Schaich M. Schakel U. Platzbecker U. et al. (2002) Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99: 4326–4335.
65. van der Geer P. Hunter T. Lindberg R. (1994) Receptor protein-tyrosine kinases and their signal transduction pathways. Ann Rev Cell Biol 10: 251–337.
66. von Bubnoff N. Engh R. Aberg E. Sanger J. Peschel C. Duyster J. (2009) FMS-like tyrosine kinase 3-internal tandem duplication tyrosine kinase inhibitors display a nonoverlapping profile of resistance mutations in vitro. Cancer Res 69: 3032–3041.
67. Wander S. Hennessy B. Slingerland J. (2011) Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. J Clin Invest 121: 1231–1241.
68. Weisberg E. Liu Q. Nelson E. Kung A. Christie A. Bronson R. et al. (2012) Using combination therapy to override stromal-mediated chemoresistance in mutant FLT3-positive AML: synergism between FLT 3 inhibitors, dasatinib/multi-targeted inhibitors and JAK Inhibitors. Leukemia 26: 2233–2244.
69. Weisberg E. Liu Q. Zhang X. Nelson E. Sattler M. Liu F. et al. (2013) Selective AKT inhibitors synergize with tyrosine kinase inhibitors and effectively override stroma-associated cytoprotection of mutant FLT3-positive AML cells. PloS ONE 8: e56473.
70. Yamamoto Y. Kiyoi H. Nakano Y. Suzuki R. Kodera Y. Miyawaki S. et al. (2001) Activating mutation of D 835 within the activation loop of FLT 3 in human hematologic malignancies. Blood 97: 2434–2439.
71. Yang X. Sexauer A. Levis M. (2011) Persistent ERK activation in bone marrow blasts may account for the difference in bone marrow versus peripheral blood response to FLT 3 inhibition in FLT3/ITD AML Blood 118: abstract 736.
72. Zarrinkar P. Gunawardane R. Cramer M. Gardner M. Brigham D. Belli B. et al. (2009) AC 220 is a uniquely potent and selective inhibitor of FLT 3 for the treatment of acute myeloid leukemia (AML). Blood 114: 2984–2992.
73. Zhang W. Konopleva M. Shi Y. McQueen T. Harris D. Ling X. et al. (2008) Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. J Natl Cancer Inst 100: 184–198.
74. Zhou J. Bi C. Janakakumara J. Liu S. Chng W. Tay K. et al. (2009) Enhanced activation of stat pathways and overexpression of survivin confer resistance to FLT 3 inhibitors and could be therapeutic targets in AML. Blood 113: 4052–4062.
75. Zimmerman E. Turner D. Buaboonnam J. Hu S. Orwick S. Roberts M. et al. (2013) Crenolanib is active against models of drug-resistant FLT3-ITD-positive acute myeloid leukemia. Blood, in press.