title: Investigational FMS-like tyrosine kinase 3 inhibitors in treatment of acute myeloid leukemia.
abstract: BACKGROUND
  Outcomes for the majority of patients with acute myeloid leukemia (AML) remain poor. Over the past decade, significant progress has been made in the understanding of the cytogenetic and molecular determinants of AML pathogenesis. One such advance is the identification of recurring mutations in the FMS-like tyrosine kinase 3 gene (FLT3). Currently, this marker, which appears in approximately one-third of all AML patients, not only signifies a poorer prognosis but also identifies an important target for therapy. FLT3 inhibitors have now undergone clinical evaluation in Phase I, II and III clinical trials, as both single agents and in combination with chemotherapeutics. Unfortunately, to date, none of the FLT3 inhibitors have gained FDA approval for the treatment of patients with AML. Yet, several promising FLT3 inhibitors are being evaluated in all phases of drug development.
  
  
  METHODS
  This review aims to highlight the agents furthest along in their development. It also focuses on those FLT3 inhibitors that are being evaluated in combination with other anti-leukemia agents.
  
  
  CONCLUSIONS
  The authors believe that the field of research for FLT3 inhibitors remains promising, despite the historically poor prognosis of this subgroup of patients with AML. The most promising areas of research will likely be the elucidation of the mechanisms of resistance to FLT3 inhibitors, and development of potent FLT3 inhibitors alone or in combination with hypomethylating agents, cytotoxic chemotherapy or with other targeted agents.
authors.affiliation: MD Anderson Cancer Center, Department of Leukemia , 1515 Holcombe Blvd Houston, TX 77030 , USA fravandi@mdanderson.org.
authors.forename: Naveen
authors.initials: N
authors.lastname: Pemmaraju
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use; D052160:Benzothiazoles / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use; D010880:Piperidines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011724:Pyridazines / Q000627:therapeutic use; D000077157:Sorafenib; D019311:Staurosporine / Q000031:analogs & derivatives / Q000627:therapeutic use; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D052160:Benzothiazoles; D007093:Imidazoles; D010671:Phenylurea Compounds; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D009536:Niacinamide; C545373:ponatinib; C544967:quizartinib; D000077157:Sorafenib; D051941:fms-Like Tyrosine Kinase 3; D019311:Staurosporine; C059539:midostaurin; C577197:crenolanib
keywords: FMS-like tyrosine kinase 3 gene; FMS-like tyrosine kinase 3 gene inhibitor; crenolanib; quizartinib; sorafenib
references.citation: Blood. 2001 Sep 15;98(6):1752-9
references.pmid: 11535508
references.citation: Mol Cancer Ther. 2006 Dec;5(12):3113-21
references.pmid: 17172414
references.citation: Blood. 2011 Mar 24;117(12):3294-301
references.pmid: 21270442
references.citation: Clin Epigenetics. 2013 Jul 30;5(1):12
references.pmid: 23898968
references.citation: Lancet Oncol. 2009 Mar;10(3):223-32
references.pmid: 19230772
references.citation: Cancer Cell. 2002 Jun;1(5):421-32
references.pmid: 12124172
references.citation: PLoS One. 2014 Jan 08;9(1):e83160
references.pmid: 24416160
references.citation: N Engl J Med. 2008 Jul 24;359(4):378-90
references.pmid: 18650514
references.citation: Cancer Cell. 2014 Feb 10;25(2):226-42
references.pmid: 24525236
references.citation: Proc Natl Acad Sci U S A. 2014 Apr 8;111(14):5319-24
references.pmid: 24623852
references.citation: Blood. 2013 Jun 6;121(23):4655-62
references.pmid: 23613521
references.citation: Cancer Cell. 2002 Jun;1(5):413-5
references.pmid: 12124170
references.citation: Br J Haematol. 2007 Sep;138(6):687-99
references.pmid: 17655729
references.citation: J Clin Oncol. 2007 May 10;25(14):1908-15
references.pmid: 17488990
references.citation: Leukemia. 2010 Aug;24(8):1437-44
references.pmid: 20535150
references.citation: Clin Cancer Res. 2013 Oct 15;19(20):5758-68
references.pmid: 23969938
references.citation: J Clin Oncol. 2011 Feb 10;29(5):591-9
references.pmid: 21220598
references.citation: Br J Haematol. 2013 Aug;162(4):548-52
references.pmid: 23691988
references.citation: Blood. 2014 Mar 6;123(10):1525-34
references.pmid: 24408321
references.citation: J Clin Oncol. 2010 Apr 10;28(11):1856-62
references.pmid: 20212254
references.citation: Br J Haematol. 2012 May;157(4):483-92
references.pmid: 22409268
references.citation: Clin Cancer Res. 2004 Sep 15;10(18 Pt 2):6388S-92S
references.pmid: 15448036
references.citation: Blood. 2007 Dec 15;110(13):4476-9
references.pmid: 17827387
references.citation: N Engl J Med. 2002 Feb 28;346(9):645-52
references.pmid: 11870241
references.citation: Clin Epigenetics. 2013 Aug 01;5(1):13
references.pmid: 23915396
references.citation: Haematologica. 2011 Jan;96(1):62-8
references.pmid: 20952518
references.citation: Leuk Lymphoma. 2012 Jun;53(6):1062-7
references.pmid: 22054287
references.citation: Blood. 2013 Nov 21;122(22):3547-8
references.pmid: 24263951
references.citation: Blood. 2011 Mar 24;117(12):3286-93
references.pmid: 21263155
references.citation: Leukemia. 2012 Sep;26(9):2061-8
references.pmid: 22627678
references.citation: Blood Cancer J. 2011 Nov;1(11):e44
references.pmid: 22829080
references.citation: Biol Blood Marrow Transplant. 2011 Dec;17(12):1874-7
references.pmid: 21767516
references.citation: Clin Cancer Res. 2012 Aug 15;18(16):4375-84
references.pmid: 22745105
references.citation: Expert Opin Investig Drugs. 2013 Nov;22(11):1365-70
references.pmid: 24099404
references.citation: Blood. 2001 Sep 1;98(5):1312-20
references.pmid: 11520776
references.citation: J Clin Oncol. 2010 Feb 1;28(4):562-9
references.pmid: 20026804
references.citation: Oncogene. 2000 Feb 3;19(5):624-31
references.pmid: 10698507
references.citation: Cancer Cell. 2002 Jun;1(5):433-43
references.pmid: 12124173
references.citation: Curr Drug Targets. 2010 Jul;11(7):781-9
references.pmid: 20370649
references.citation: Mol Cancer Ther. 2011 Jun;10(6):1028-35
references.pmid: 21482694
references.citation: J Clin Oncol. 2013 Oct 10;31(29):3681-7
references.pmid: 24002496
references.citation: Nature. 2012 Apr 15;485(7397):260-3
references.pmid: 22504184
references.citation: Blood. 2006 Nov 15;108(10):3477-83
references.pmid: 16857987
references.citation: Leuk Lymphoma. 2010 Feb;51(2):252-60
references.pmid: 20109071
references.citation: Blood. 2012 May 31;119(22):5133-43
references.pmid: 22368270
references.citation: Hematology Am Soc Hematol Educ Program. 2006;:178-84
references.pmid: 17124058
references.citation: Blood. 2001 Aug 1;98(3):885-7
references.pmid: 11468194
references.citation: Blood. 2014 Jan 2;123(1):94-100
references.pmid: 24227820
references.citation: Hematology Am Soc Hematol Educ Program. 2013;2013:220-6
references.pmid: 24319184
references.citation: Blood. 2012 Nov 15;120(20):4205-14
references.pmid: 23012328
references.citation: Blood. 2009 Oct 1;114(14):2984-92
references.pmid: 19654408
references.citation: J Clin Oncol. 2012 Mar 1;30(7):735-41
references.pmid: 22291086
references.citation: Leukemia. 2012 Nov;26(11):2353-9
references.pmid: 22504140
references.citation: J Clin Oncol. 2003 Dec 15;21(24):4642-9
references.pmid: 14673054
references.citation: Curr Opin Oncol. 2014 Jan;26(1):36-44
references.pmid: 24240178
references.citation: J Clin Oncol. 2010 Oct 1;28(28):4339-45
references.pmid: 20733134
references.citation: Oncotarget. 2013 Jun;4(6):830-43
references.pmid: 23919981
references.citation: Blood. 2013 Apr 18;121(16):3165-71
references.pmid: 23430109
references.citation: Genes Cancer. 2012 Jul;3(7-8):503-11
references.pmid: 23264850
references.citation: J Natl Cancer Inst. 2008 Feb 6;100(3):184-98
references.pmid: 18230792
references.citation: Blood. 2006 Nov 15;108(10):3280-8
references.pmid: 16840728
references.citation: Mol Cancer. 2010 Nov 10;9:292
references.pmid: 21067588
references.citation: Br J Cancer. 2006 Oct 9;95(7):829-34
references.pmid: 16969355
references.citation: N Engl J Med. 2013 Nov 7;369(19):1783-96
references.pmid: 24180494
references.citation: Blood. 2009 Jun 11;113(24):6215-24
references.pmid: 18955566
references.citation: PLoS One. 2013 Nov 18;8(11):e79478
references.pmid: 24260231
references.citation: Clin Lymphoma Myeloma Leuk. 2013 Aug;13(4):435-40
references.pmid: 23763915
references.citation: J Clin Oncol. 2011 Aug 20;29(24):3293-300
references.pmid: 21768474
references.citation: Leuk Lymphoma. 2014 Feb;55(2):243-55
references.pmid: 23631653
references.citation: Eur J Cancer. 2004 Mar;40(5):707-21, discussion 722-4
references.pmid: 15010072
references.citation: J Clin Oncol. 2011 Feb 10;29(5):475-86
references.pmid: 21220609
references.citation: Blood. 2013 Nov 21;122(22):3607-15
references.pmid: 24046014
references.citation: Best Pract Res Clin Haematol. 2013 Sep;26(3):269-74
references.pmid: 24309529
references.citation: Leukemia. 2000 Oct;14(10):1766-76
references.pmid: 11021752
references.citation: Expert Rev Hematol. 2014 Apr;7(2):301-15
references.pmid: 24308526
references.citation: Leuk Res. 2009 Feb;33(2):348-50
references.pmid: 18573526
references.citation: N Engl J Med. 2007 Jan 11;356(2):125-34
references.pmid: 17215530
references.citation: Leukemia. 2012 Oct;26(10):2233-44
references.pmid: 22469781
references.citation: Pharmacotherapy. 2013 Dec;33(12):1341-52
references.pmid: 23798029
references.citation: N Engl J Med. 2001 Apr 5;344(14):1031-7
references.pmid: 11287972
references.citation: J Clin Oncol. 2005 Feb 10;23(5):965-72
references.pmid: 15613696
references.citation: Expert Opin Investig Drugs. 2013 Jun;22(6):775-85
references.pmid: 23442043
references.citation: Leukemia. 2008 Apr;22(4):808-18
references.pmid: 18200035
references.citation: Cancer. 2011 Aug 1;117(15):3293-304
references.pmid: 21319142
references.citation: Cancer Lett. 2013 Feb 1;329(1):45-58
references.pmid: 23036488
references.citation: Mol Cancer Ther. 2014 Apr;13(4):880-9
references.pmid: 24526162
references.citation: Drug Resist Updat. 2009 Aug-Oct;12(4-5):103-13
references.pmid: 19632887
references.citation: Blood. 2002 Jun 15;99(12):4326-35
references.pmid: 12036858
references.citation: Br J Haematol. 2014 Jan;164(2):200-11
references.pmid: 24383842
references.citation: Br J Haematol. 2013 Jun;161(5):659-66
references.pmid: 23530930