Current Hematologic Malignancy Reports

, Volume 9, Issue 2, pp 174–185 | Cite as

FLT3 Inhibitors in AML: Are We There Yet?

Acute Leukemias (R Stone, Section Editor)


FMS-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in AML. Thirty percent of patients with acute myeloid leukemia (AML) harbor activating mutations in FLT3, either internal tandem duplication mutations in the juxtamembrane domain (FLT3-ITD) or point mutations in the tyrosine kinase domain (FLT3 TKD). Small molecule FLT3 inhibitors have emerged as an attractive therapeutic option in patients with FLT3 mutations; however, the clinical activity of early inhibitors was limited by a lack of selectivity, potency and unfavorable pharmacokinetic properties. Newer agents such as quizartinib have improved potency and selectivity associated with much higher bone marrow response rates; however, response duration is limited by the development of secondary resistance. We will review here a number of FLT3 inhibitors that have been evaluated in clinical trials and discuss challenges facing the use of these agents in AML.


AML FLT3-ITD FLT3 mutation FLT3 inhibitor Midostaurin Lestaurtinib Sunitinib Sorafenib Quizartinib PLX3397 Ponatinib Resistance 


Compliance with Ethics Guidelines

Conflict of Interest

Dr. Akshay Sudhindra declares no potential conflicts of interest relevant to this article.

Dr. Catherine Choy Smith received research funding from Plexxikon and has a patent pending for discovery of AC220-resistant mutations.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.••
    The Cancer Genome Atlas Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059–74. Identifies FLT3 has the most commonly mutated gene in de novo AML.CrossRefGoogle Scholar
  2. 2.
    Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U, 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(12):4326–35.PubMedCrossRefGoogle Scholar
  3. 3.
    Moreno I, Martin G, Bolufer P, Barragan E, Rueda E, Roman J, et al. Incidence and prognostic value of flt3 internal tandem duplication and d835 mutations in acute myeloid leukemia. Haematologica. 2003;88(1):19–24.PubMedGoogle Scholar
  4. 4.
    Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, 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(6):1752–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Frohling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K, et al. 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):4372–80.PubMedCrossRefGoogle Scholar
  6. 6.
    Schnittger S, Schoch C, Dugas M, Kern W, Staib P, Wuchter C, et al. 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.PubMedCrossRefGoogle Scholar
  7. 7.
    Bornhauser M, Illmer T, Schaich M, Soucek S, Ehninger G, Thiede C. Improved outcome after stem-cell transplantation in flt3/itd-positive aml. Blood. 2007;109(5):2264–5. author reply 2265.PubMedCrossRefGoogle Scholar
  8. 8.
    Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358(18):1909–18.PubMedCrossRefGoogle Scholar
  9. 9.•
    DeZern AE, Sung A, Kim S, Smith BD, Karp JE, Gore SD, et al. Role of allogeneic transplantation for flt3/itd acute myeloid leukemia: outcomes from 133 consecutive newly diagnosed patients from a single institution. Biol Blood Marrow Transplant. 2011;17(9):1404–9. Supports the use of allogeneic stem cell transplant in patients with FLT3 ITD mutant AML.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.•
    Lin PH, Lin CC, Yang HI, Li LY, Bai LY, Chiu CF, et al. Prognostic impact of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia patients with internal tandem duplication of flt3. Leuk Res. 2013;37(3):287–92. Illustrates the role of allogeneic HSCT in patients with FLT3 ITD mutant AML.PubMedCrossRefGoogle Scholar
  11. 11.•
    Brunet S, Labopin M, Esteve J, Cornelissen J, Socie G, Iori AP, et al. Impact of flt3 internal tandem duplication on the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first remission: a retrospective analysis. J Clin Oncol. 2012;30(7):735–41. Supports the use of allogeneic stem cell transplant in patients with FLT3 ITD mutant AML.PubMedCrossRefGoogle Scholar
  12. 12.
    Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B, et al. Ac220 is a uniquely potent and selective inhibitor of flt3 for the treatment of acute myeloid leukemia (aml). Blood. 2009;114(14):2984–92.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.••
    Tallman MS, Schiller G, Trone D, Gammon G, Goldberg S, Perl AE, et al. Results of a phase 2 randomized, open-label, study of lower doses of quizartinib (ac220; asp2689) in subjects with flt3-itd positive relapsed or refractory acute myeloid leukemia (aml). Blood. 2013;122(21):494. Randomized phase 2 study supporting the use of lower doses of quizartinib in FLT3 ITD mutant AML due to equivalent efficacy and decreased rates of QT prolongation.Google Scholar
  14. 14.••
    Cortes JE, Perl AE, Dombret H, Kayser S, Steffen B, Rousselot P, et al. Final results of a phase 2 open-label, monotherapy efficacy and safety study of quizartinib (ac220) in patients >= 60 years of age with flt3 itd positive or negative relapsed/refractory acute myeloid leukemia. ASH Ann Meet Abstr. 2012;120(21):48. Results of first phase 2 study of quizartininb in AML reporting CRc rate of 50% in patients >60 years of age with relapsed/refractory AML after at least one line of therapy.Google Scholar
  15. 15.••
    Levis MJ, Perl AE, Dombret H, Dohner H, Steffen B, Rousselot P, et al. 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. ASH Ann Meet Abstr. 2012;120(21):673. Results of first phase 2 study of quizartininb in AML reporting CRc rate of 44% in patients >18 years of age with relapased/refractory AML after two lines of therapy.Google Scholar
  16. 16.••
    Smith CC, Wang Q, Chin CS, Salerno S, Damon LE, Levis MJ, et al. Validation of itd mutations in flt3 as a therapeutic target in human acute myeloid leukaemia. Nature. 2012;485(7397):260–3. Identification of FLT3-ITD KD mutations as mechanism of resistance to quizatinib and sorafenib.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Gilliland DG, Griffin JD. The roles of flt3 in hematopoiesis and leukemia. Blood. 2002;100(5):1532–42.PubMedCrossRefGoogle Scholar
  18. 18.
    Mackarehtschian K, Hardin JD, Moore KA, Boast S, Goff SP, Lemischka IR. Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Immunity. 1995;3(1):147–61.PubMedCrossRefGoogle Scholar
  19. 19.
    Stirewalt DL, Radich JP. The role of flt3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3(9):650–65.PubMedCrossRefGoogle Scholar
  20. 20.
    Yokota S, Kiyoi H, Nakao M, Iwai T, Misawa S, Okuda T, et al. Internal tandem duplication of the flt3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines. Leukemia. 1997;11(10):1605–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996;10(12):1911–8.PubMedGoogle Scholar
  22. 22.
    Griffith J, Black J, Faerman C, Swenson L, Wynn M, Lu F, et al. The structural basis for autoinhibition of flt3 by the juxtamembrane domain. Mol Cell. 2004;13(2):169–78.PubMedCrossRefGoogle Scholar
  23. 23.
    Rocnik JL, Okabe R, Yu JC, Lee BH, Giese N, Schenkein DP, et al. Roles of tyrosine 589 and 591 in stat5 activation and transformation mediated by flt3-itd. Blood. 2006;108(4):1339–45.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Kayser S, Schlenk RF, Londono MC, Breitenbuecher F, Wittke K, Du J, et al. 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):2386–92.PubMedCrossRefGoogle Scholar
  25. 25.
    Breitenbuecher F, Schnittger S, Grundler R, Markova B, Carius B, Brecht A, et al. Identification of a novel type of itd mutations located in nonjuxtamembrane domains of the flt3 tyrosine kinase receptor. Blood. 2009;113(17):4074–7.PubMedCrossRefGoogle Scholar
  26. 26.•
    Schnittger S, Bacher U, Haferlach C, Alpermann T, Kern W, Haferlach T. Diversity of the juxtamembrane and tkd1 mutations (exons 13–15) in the flt3 gene with regards to mutant load, sequence, length, localization, and correlation with biological data. Genes Chromosome Cancer. 2012;51(10):910–24. Characterization of FLT3 TKD1 length mutations.CrossRefGoogle Scholar
  27. 27.
    Abu-Duhier FM, Goodeve AC, Wilson GA, Care RS, Peake IR, Reilly JT. Identification of novel flt-3 asp835 mutations in adult acute myeloid leukaemia. Br J Haematol. 2001;113(4):983–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, et al. Activating mutation of d835 within the activation loop of flt3 in human hematologic malignancies. Blood. 2001;97(8):2434–9.PubMedCrossRefGoogle Scholar
  29. 29.•
    Opatz S, Polzer H, Herold T, Konstandin NP, Ksienzyk B, Zellmeier E, et al. Exome sequencing identifies recurring flt3 n676k mutations in core-binding factor leukemia. Blood. 2013;122(10):1761–9. Identifies activating FLT3 N676K mutations in AML with core binding factor mutations.PubMedCrossRefGoogle Scholar
  30. 30.
    Razumovskaya E, Masson K, Khan R, Bengtsson S, Ronnstrand L. Oncogenic flt3 receptors display different specificity and kinetics of autophosphorylation. Exp Hematol. 2009;37(8):979–89.PubMedCrossRefGoogle Scholar
  31. 31.
    Zhang Y, Askenazi M, Jiang J, Luckey CJ, Griffin JD, Marto JA. A robust error model for itraq quantification reveals divergent signaling between oncogenic flt3 mutants in acute myeloid leukemia. Mol Cell Proteomics. 2010;9(5):780–90.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Choudhary C, Schwable J, Brandts C, Tickenbrock L, Sargin B, Kindler T, et al. Aml-associated flt3 kinase domain mutations show signal transduction differences compared with flt3 itd mutations. Blood. 2005;106(1):265–73.PubMedCrossRefGoogle Scholar
  33. 33.
    Choudhary C, Olsen JV, Brandts C, Cox J, Reddy PN, Bohmer FD, et al. Mislocalized activation of oncogenic rtks switches downstream signaling outcomes. Mol Cell. 2009;36(2):326–39.PubMedCrossRefGoogle Scholar
  34. 34.
    Grundler R, Miething C, Thiede C, Peschel C, Duyster J. Flt3-itd and tyrosine kinase domain mutants induce 2 distinct phenotypes in a murine bone marrow transplantation model. Blood. 2005;105(12):4792–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Li L, Piloto O, Nguyen HB, Greenberg K, Takamiya K, Racke F, et al. Knock-in of an internal tandem duplication mutation into murine flt3 confers myeloproliferative disease in a mouse model. Blood. 2008;111(7):3849–58.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Stirewalt DL, Kopecky KJ, Meshinchi S, Appelbaum FR, Slovak ML, Willman CL, et al. Flt3, ras, and tp53 mutations in elderly patients with acute myeloid leukemia. Blood. 2001;97(11):3589–95.PubMedCrossRefGoogle Scholar
  37. 37.
    Levis M. Flt3 mutations in acute myeloid leukemia: what is the best approach in 2013? Hematol Am Soc Hematol Educ Prog. 2013;2013:220–6.CrossRefGoogle Scholar
  38. 38.
    Ravandi F, Kantarjian H, Faderl S, Garcia-Manero G, O'Brien S, Koller C, et al. Outcome of patients with flt3-mutated acute myeloid leukemia in first relapse. Leuk Res. 2010;34(6):752–6.PubMedCrossRefGoogle Scholar
  39. 39.•
    Levis M, Ravandi F, Wang ES, Baer MR, Perl A, Coutre S, et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with flt3 mutant aml in first relapse. Blood. 2011;117(12):3294–301. Randomized trial of salvage chemotherapy in combination of with lestaurtinib or placebo in relapsed AML shows no benefit for the addtion of lestaurtinib.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Gale RE, Hills R, Kottaridis PD, Srirangan S, Wheatley K, Burnett AK, et al. No evidence that flt3 status should be considered as an indicator for transplantation in acute myeloid leukemia (aml): an analysis of 1135 patients, excluding acute promyelocytic leukemia, from the uk mrc aml10 and 12 trials. Blood. 2005;106(10):3658–65.PubMedCrossRefGoogle Scholar
  41. 41.•
    Laboure G, Dulucq S, Labopin M, Tabrizi R, Guerin E, Pigneux A, et al. Potent graft-versus-leukemia effect after reduced-intensity allogeneic sct for intermediate-risk aml with flt3-itd or wild-type npm1 and cebpa without flt3-itd. Biol Blood Marrow Transplant. 2012;18(12):1845–50. Shows benefit for reduced intensity allogeneic stem cell transplant in patients with FLT3-ITD mutations.PubMedCrossRefGoogle Scholar
  42. 42.
    Stone RM, DeAngelo DJ, Klimek V, Galinsky I, Estey E, Nimer SD, 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(1):54–60.PubMedCrossRefGoogle Scholar
  43. 43.
    Fischer T, Stone RM, Deangelo DJ, Galinsky I, Estey E, Lanza C, et al. 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):4339–45.PubMedCrossRefGoogle Scholar
  44. 44.
    Stone RM, Fischer T, Paquette R, Schiller G, Schiffer CA, Ehninger G, et al. 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):2061–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Smith BD, Levis M, Beran M, Giles F, Kantarjian H, Berg K, 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(10):3669–76.PubMedCrossRefGoogle Scholar
  46. 46.
    DeAngelo DJ, Stone RM, Heaney ML, Nimer SD, Paquette RL, Klisovic RB, et al. 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(12):3674–81.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    De Angelo DJ, Stone RM, Heaney ML, Nimer SD, Paquette R, Bruner-Klisovic R, et al. Phase ii evaluation of the tyrosine kinase inhibitor mln518 in patients with acute myeloid leukemia (aml) bearing a flt3 internal tandem duplication (itd) mutation. ASH Ann Meet Abstr. 2004;104 (11 %U;104/11/1792 %8 November 16, 2004):1792
  48. 48.
    DeAngelo DJ, Amrein PC, Kovacsovics TJ, Klisovic RB, Powell BL, Cooper M, et al. Phase 1/2 study of tandutinib (mln518) plus standard induction chemotherapy in newly diagnosed acute myelogenous leukemia (aml). ASH Ann Meet Abstr. 2006;108(11):158.Google Scholar
  49. 49.
    Pratz KW, Cortes J, Roboz GJ, Rao N, Arowojolu O, Stine A, et al. A pharmacodynamic study of the flt3 inhibitor kw-2449 yields insight into the basis for clinical response. Blood. 2009;113(17):3938–46.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Fiedler W, Serve H, Dohner H, Schwittay M, Ottmann OG, O'Farrell AM, 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(3):986–93.PubMedCrossRefGoogle Scholar
  51. 51.
    Fiedler W, Kayser S, Kebenko M, Krauter J, Salih HR, Gotze K, et al. Sunitinib and intensive chemotherapy in patients with acute myeloid leukemia and activating flt3 mutations: results of the amlsg 10–07 study (clinicaltrials.Gov no. Nct00783653). ASH Ann Meet Abstr. 2012;120(21):1483.Google Scholar
  52. 52.
    Zhang W, Konopleva M, Shi YX, McQueen T, Harris D, Ling X, et al. Mutant flt3: a direct target of sorafenib in acute myelogenous leukemia. J Natl Cancer Inst. 2008;100(3):184–98.PubMedCrossRefGoogle Scholar
  53. 53.••
    Metzelder SK, Schroeder T, Finck A, Scholl S, Fey M, Gotze K, et al. High activity of sorafenib in flt3-itd-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses. Leukemia. 2012;26(11):2353–9. Sorafenib can achieve remisions in FLT3-ITD+ AML patients relapsed after chemotherapy or stem cell transplant.Google Scholar
  54. 54.
    Pratz KW, Cho E, Levis MJ, Karp JE, Gore SD, McDevitt M, et al. A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias. Leukemia. 2010;24(8):1437–44.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Kruger WH, Hirt C, Kiefer T, Neumann T, Busemann C, Dolken G. Molecular remission of flt3-itd(+) positive aml relapse after allo-sct by acute gvhd in addition to sorafenib. Bone Marrow Transplant. 2012;47(1):137–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Sharma M, Ravandi F, Bayraktar UD, Chiattone A, Bashir Q, Giralt S, et al. Treatment of flt3-itd-positive acute myeloid leukemia relapsing after allogeneic stem cell transplantation with sorafenib. Biol Blood Marrow Transplant. 2011;17(12):1874–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Metzelder S, Wang Y, Wollmer E, Wanzel M, Teichler S, Chaturvedi A, et al. Compassionate use of sorafenib in flt3-itd-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. Blood. 2009;113(26):6567–71.PubMedCrossRefGoogle Scholar
  58. 58.••
    Ravandi F, Alattar ML, Grunwald MR, Rudek MA, Rajkhowa T, Richie MA, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and flt-3 internal tandem duplication mutation. Blood. 2013;121(23):4655–62. 46% response rate achieve in relapsed/refractory FLT3-ITD+ patients with a combination of sorafenib and azacytidine.PubMedCrossRefGoogle Scholar
  59. 59.••
    Serve H, Krug U, Wagner R, Sauerland MC, Heinecke A, Brunnberg U, et al. 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):3110–8. No benefit to sorafenib added to induction chemotherapy for unselected newly diagnosed elderly patients with AML; a low percentage of patients with FLT3-ITD mutations were treated.PubMedCrossRefGoogle Scholar
  60. 60.•
    Cortes JE, Kantarjian H, Foran JM, Ghirdaladze D, Zodelava M, Borthakur G, et al. 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. 2013;31(29):3681–7. Initial report of safety and efficacy of quizartinib in a phase 1 dose-finding study.PubMedCrossRefGoogle Scholar
  61. 61.••
    Sexauer A, Perl A, Yang X, Borowitz M, Gocke C, Rajkhowa T, et al. Terminal myeloid differentiation in vivo is induced by flt3 inhibition in flt3/itd aml. Blood. 2012;120(20):4205–14. Reports differentiation response in the bone marrow associated with inflammatory infiltrates seen in patients responding to quizartinib.PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.•
    Foran JM, Pratz KW, Trone D, Gammon G, Cortes JE, Tallman MS. Results of a phase 1 study of quizartinib (ac220, asp2689) in combination with induction and consolidation chemotherapy in younger patients with newly diagnosed acute myeloid leukemia. Blood. 2013;122(21):623. Reports safety of quizartinib in combination with induction chemotherapy in younger adult patients.Google Scholar
  63. 63.•
    Bowen D, Russell N, Knapper S, Milligan D, Hunter AE, Khwaja A, et al. Ac220 (quizartinib) can be safely combined with conventional chemotherapy in older patients with newly diagnosed acute myeloid leukaemia: experience from the aml18 pilot trial. Blood. 2013;122(21):622. Reports safety of quizartinib in combination with induction chemotherapy in older adult patients.Google Scholar
  64. 64.•
    Malvar J, Cassar J, Eckroth E, Sposto R, Gaynon P, Dubois S, et al. A phase i study of ac220 (quizartinib) in combination with cytarabine and etoposide in relapsed/refractory childhood all and aml: a therapeutic advances in childhood leukemia & lymphoma (tacl) study. Blood. 2013;122(21):624. Reports safety of quizartinib in combination with salvage chemotherapy in pediatric AML.Google Scholar
  65. 65.••
    Man CH, Fung TK, Ho C, Han HH, Chow HC, Ma AC, et al. Sorafenib treatment of flt3-itd(+) acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a d835 mutation. Blood. 2012;119(22):5133–43. D835 mutations are associated with clinical relapse on sorafenib monotherapy.PubMedCrossRefGoogle Scholar
  66. 66.•
    Baker SD, Zimmerman EI, Wang YD, Orwick S, Zatechka DS, Buaboonnam J, et al. Emergence of polyclonal flt3 tyrosine kinase domain mutations during sequential therapy with sorafenib and sunitinib in flt3-itd-positive acute myeloid leukemia. Clin Cancer Res. 2013;19:5758–68. D835 and F691 mutations are associated with relapse after treatment with sorafenib and chemotherapy.PubMedCrossRefGoogle Scholar
  67. 67.•
    Shah NP, Talpaz M, Deininger MW, Mauro MJ, Flinn IW, Bixby D, et al. Ponatinib in patients with refractory acute myeloid leukaemia: findings from a phase 1 study. Br J Haematol. 2013;162(4):548–52. Reports two cases of complete remission in FLT3-ITD+ patients treated with ponatinib.PubMedCrossRefGoogle Scholar
  68. 68.•
    Smith CC, Lasater EA, Zhu X, Lin KC, Stewart WK, Damon LE, et al. Activity of ponatinib against clinically-relevant ac220-resistant kinase domain mutants of flt3-itd. Blood. 2013;121:3165–71. Reports activity of ponatinib against FLT3-ITD F691 gatekeeper mutations but reveals vulnerability of ponatinib to FLT3-ITD activation loop mutations.PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.•
    Smith CC, Lin K, Lasater E, Stewart W, Damon LE, Kasarskis A, et al. Preclinical and clinical resistance mechanisms to the investigational selective flt3 inhibitor plx3397 in flt3-itd+ acute myeloid leukemia (aml). Blood. 2013;122(21):3938. Reveals activity of PLX3397 against FLT3 F691L mutation but vulnerability to FLT3 activation loop mutations.Google Scholar
  70. 70.•
    Galanis A, Ma H, Rajkhowa T, Ramachandran A, Small D, Cortes J, et al. Crenolanib is a potent inhibitor of flt3 with activity against resistance-conferring point mutants. Blood. 2014;123(1):94–100. Report of pre-clinical activity of crenolanib against FLT3 D835 mutations.PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.•
    Zimmerman EI, Turner DC, Buaboonnam J, Hu S, Orwick S, Roberts MS, et al. Crenolanib is active against models of drug-resistant flt3-itd-positive acute myeloid leukemia. Blood. 2013;122:3607–15. Report of pre-clinical activity of crenolanib against FLT3 D835 mutations.PubMedCrossRefGoogle Scholar
  72. 72.•
    Smith CC, Lasater EA, Lin KC, Wang Q, McCreery MQ, Stewart WK, et al. Crenolanib is a selective type i pan-flt3 inhibitor. Proc Natl Acad Sci USA. 2014. doi: 10.1073/pnas.1320661111. Report of pre-clinical activity of crenolanib against FLT3 D835 mutations.
  73. 73.•
    Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC, et al. The origin and evolution of mutations in acute myeloid leukemia. Cell. 2012;150(2):264–78. Reveals polyclonality of AML.PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Whitman SP, Archer KJ, Feng L, Baldus C, Becknell B, Carlson BD, 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(19):7233–9.PubMedGoogle Scholar
  75. 75.
    Williams AB, Nguyen B, Li L, Brown P, Levis M, Leahy D, Small D. Mutations of flt3/itd confer resistance to multiple tyrosine kinase inhibitors. Leuk. 2013;27:48–55.Google Scholar
  76. 76.
    Cools J, Mentens N, Furet P, Fabbro D, Clark JJ, Griffin JD, et al. Prediction of resistance to small molecule flt3 inhibitors: implications for molecularly targeted therapy of acute leukemia. Cancer Res. 2004;64(18):6385–9.PubMedCrossRefGoogle Scholar
  77. 77.
    Heidel F, Solem FK, Breitenbuecher F, Lipka DB, Kasper S, Thiede MH, 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(1):293–300.PubMedCrossRefGoogle Scholar
  78. 78.
    von Bubnoff N, Rummelt C, Menzel H, Sigl M, Peschel C, Duyster J. Identification of a secondary flt3/a848p mutation in a patient with flt3-itd-positive blast phase cmml and response to sunitinib and sorafenib. Leukemia. 2010;24(8):1523–5.CrossRefGoogle Scholar
  79. 79.
    Clark JJ, Cools J, Curley DP, Yu JC, Lokker NA, Giese NA, et al. Variable sensitivity of flt3 activation loop mutations to the small molecule tyrosine kinase inhibitor mln518. Blood. 2004;104(9):2867–72.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.University of California, San FranciscoSan FranciscoUSA

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