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Acute myeloid leukemia

FLT3 inhibitors in acute myeloid leukemia: ten frequently asked questions

Leukemia volume 34, pages 682–696 (2020)Cite this article

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Abstract

The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in approximately one third of patients with acute myeloid leukemia (AML), either by internal tandem duplications (FLT3-ITD), or by a point mutation mainly involving the tyrosine kinase domain (FLT3-TKD). Patients with FLT3-ITD have a high risk of relapse and low cure rates. Several FLT3 tyrosine kinase inhibitors have been developed in the last few years with variable kinase inhibitory properties, pharmacokinetics, and toxicity profiles. FLT3 inhibitors are divided into first generation multi-kinase inhibitors (such as sorafenib, lestaurtinib, midostaurin) and next generation inhibitors (such as quizartinib, crenolanib, gilteritinib) based on their potency and specificity of FLT3 inhibition. These diverse FLT3 inhibitors have been evaluated in myriad clinical trials as monotherapy or in combination with conventional chemotherapy or hypomethylating agents and in various settings, including front-line, relapsed or refractory disease, and maintenance therapy after consolidation chemotherapy or allogeneic stem cell transplantation. In this practical question-and-answer-based review, the main issues faced by the leukemia specialists on the use of FLT3 inhibitors in AML are addressed.

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References

  1. Kayser S, Levis MJ. FLT3 tyrosine kinase inhibitors in acute myeloid leukemia: clinical implications and limitations. Leuk Lymphoma. 2014;55:243–55.

    Article  CAS  PubMed  Google Scholar 

  2. Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood. 2002;100:1532–42.

    Article  CAS  PubMed  Google Scholar 

  3. Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature. 2001;411:355–65.

    Article  CAS  PubMed  Google Scholar 

  4. Fathi AT, Chen YB. The role of FLT3 inhibitors in the treatment of FLT3-mutated acute myeloid leukemia. Eur J Haematol. 2017;98:330–6.

    Article  PubMed  Google Scholar 

  5. Carow CE, Levenstein M, Kaufmann SH, Chen J, Amin S, Rockwell P, et al. Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood. 1996;87:1089–96.

    Article  CAS  PubMed  Google Scholar 

  6. 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;150:264–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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;97:2434–9.

    Article  CAS  PubMed  Google Scholar 

  8. 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;13:169–78.

    Article  CAS  PubMed  Google Scholar 

  9. Mizuki M, Fenski R, Halfter H, Matsumura I, Schmidt R, Muller C, 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.

    Article  CAS  PubMed  Google Scholar 

  10. Hayakawa F, Towatari M, Kiyoi H, Tanimoto M, Kitamura T, Saito 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.

    Article  CAS  PubMed  Google Scholar 

  11. Roux PP, Blenis J. ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev. 2004;68:320–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Weisberg E, Roesel J, Furet P, Bold G, Imbach P, Florsheimer A, et al. Antileukemic effects of novel first- and second-generation FLT3 inhibitors: structure-affinity comparison. Genes Cancer. 2010;1:1021–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ke YY, Singh VK, Coumar MS, Hsu YC, Wang WC, Song JS, et al. Homology modeling of DFG-in FMS-like tyrosine kinase 3 (FLT3) and structure-based virtual screening for inhibitor identification. Sci Rep. 2015;5:11702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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;485:260–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, et al. Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem Biol. 2010;17:1241–9.

    Article  CAS  PubMed  Google Scholar 

  17. Levis MJ, Perl AE, Altman JK, Cortes JE, Ritchie EK, Larson RA, et al. Results of a first-in-human, phase I/II trial of ASP2215, a selective, potent inhibitor of FLT3/Axl in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). J Clin Oncol. 2015;33:7003.

    Article  Google Scholar 

  18. 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;88:19–24.

    CAS  PubMed  Google Scholar 

  19. Whitman SP, Ruppert AS, Radmacher MD, Mrozek K, Paschka P, Langer C, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bacher U, Haferlach C, Kern W, Haferlach T, Schnittger S. Prognostic relevance of FLT3-TKD mutations in AML: the combination matters-an analysis of 3082 patients. Blood. 2008;111:2527–37.

    Article  CAS  PubMed  Google Scholar 

  21. Port M, Bottcher M, Thol F, Ganser A, Schlenk R, Wasem J, et al. Prognostic significance of FLT3 internal tandem duplication, nucleophosmin 1, and CEBPA gene mutations for acute myeloid leukemia patients with normal karyotype and younger than 60 years: a systematic review and meta-analysis. Ann Hematol. 2014;93:1279–86.

    Article  CAS  PubMed  Google Scholar 

  22. 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;100:59–66.

    Article  CAS  PubMed  Google Scholar 

  23. Pratz KW, Sato T, Murphy KM, Stine A, Rajkhowa T, Levis M. FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML. Blood. 2010;115:1425–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Schlenk RF, Kayser S, Bullinger L, Kobbe G, Casper J, Ringhoffer M, et al. Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood. 2014;124:3441–9.

    Article  CAS  PubMed  Google Scholar 

  25. Garg M, Nagata Y, Kanojia D, Mayakonda A, Yoshida K, Haridas Keloth S, et al. Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse. Blood. 2015;126:2491–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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;99:4326–35.

    Article  CAS  PubMed  Google Scholar 

  27. Linch DC, Hills RK, Burnett AK, Khwaja A, Gale RE. Impact of FLT3(ITD) mutant allele level on relapse risk in intermediate-risk acute myeloid leukemia. Blood. 2014;124:273–6.

    Article  CAS  PubMed  Google Scholar 

  28. Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. www.nccn.org. NCCN Clinical Oncology guidelines. Acute Myeloid Leukemia (version 2.2018). 2018.

  30. Schnittger S, Bacher U, Kern W, Alpermann T, Haferlach C, Haferlach T. Prognostic impact of FLT3-ITD load in NPM1 mutated acute myeloid leukemia. Leukemia. 2011;25:1297–304.

    Article  CAS  PubMed  Google Scholar 

  31. Boddu PC, Kadia TM, Garcia-Manero G, Cortes J, Alfayez M, Borthakur G, et al. Validation of the 2017 European LeukemiaNet classification for acute myeloid leukemia with NPM1 and FLT3-internal tandem duplication genotypes. Cancer. 2019;125:1091–100.

    Article  CAS  PubMed  Google Scholar 

  32. Sakaguchi M, Yamaguchi H, Najima Y, Usuki K, Ueki T, Oh I, et al. Prognostic impact of low allelic ratio FLT3-ITD and NPM1 mutation in acute myeloid leukemia. Blood Adv. 2018;2:2744–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ravandi F, Cortes JE, Jones D, Faderl S, Garcia-Manero G, Konopleva MY, et al. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ravandi F, Arana YiC, Cortes JE, Levis M, Faderl S, Garcia-Manero G, et al. Final report of phase II study of sorafenib, cytarabine and idarubicin for initial therapy in younger patients with acute myeloid leukemia. Leukemia. 2014;28:1543–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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;31:3110–8.

    Article  CAS  PubMed  Google Scholar 

  36. Rollig C, Serve H, Huttmann A, Noppeney R, Muller-Tidow C, Krug U, et al. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015;16:1691–9.

    Article  CAS  PubMed  Google Scholar 

  37. Rollig C, Serve H, Hüttmann A, Noppeney R, Müller-Tidow C, Krug U, et al. The addition of sorafenib to standard AML treatment results in a substantial reduction in relapse risk and improved survival. Updated results from long-term follow-up of the randomized-controlled Soraml trial. Blood. 2017;130:721–721.

    Google Scholar 

  38. Knapper S, Russell N, Gilkes A, Hills RK, Gale RE, Cavenagh JD, et al. A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML. Blood. 2017;129:1143–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer SM, Bloomfield CD, et al. The addition of midostaurin to standard chemotherapy decreases cumulative incidence of relapse (CIR) in the international prospective randomized, placebo-controlled, double-blind trial (CALGB 10603/RATIFY [Alliance]) for newly diagnosed acute myeloid leukemia (AML) patients with FLT3 mutations. Blood. 2017;130:2580.

    Google Scholar 

  40. Schlenk RF, Weber D, Fiedler W, Salih HR, Wulf G, Salwender H, et al. Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood. 2019;133:840–51.

    Article  CAS  PubMed  Google Scholar 

  41. Wang ES, Tallman MS, Stone RM, Walter RB, Karanes C, Jain V, et al. Low relapse rate in younger patients ≤ 60 years old with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) treated with crenolanib and cytarabine/anthracycline chemotherapy. Blood. 2017;130:566–566.

    Google Scholar 

  42. Goldberg AD, Collins RH, Stone RM, Walter RB, Karanes C, Vigil CE, et al. Addition of crenolanib to induction chemotherapy overcomes the poor prognostic impact of co- occurring driver mutations in patients with newly diagnosed FLT3-mutated AML. Blood 2018;132(Suppl 1):1436.

  43. Altman JK, Foran JM, Pratz KW, Trone D, Cortes JE, Tallman MS. Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Am J Hematol. 2018;93:213–21.

    Article  CAS  PubMed  Google Scholar 

  44. Pratz KW, Cherry M, Altman JK, Cooper B, Cruz JC, Jurcic JG, et al. Updated results from a phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in subjects with newly diagnosed acute myeloid leukemia (AML). Blood. 2018;132:564–564.

    Article  Google Scholar 

  45. 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;121:4655–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Strati P, Kantarjian H, Ravandi F, Nazha A, Borthakur G, Daver N, et al. Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome. Am J Hematol. 2015;90:276–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Swaminathan M, Kantarjian HM, Daver N, Borthakur G, Ohanian M, Kadia T, et al. The combination of quizartinib with azacitidine or low dose cytarabine is highly active in patients (Pts) with FLT3-ITD mutated myeloid leukemias: interim report of a phase I/II Trial. Blood. 2017;130:723.

    Google Scholar 

  48. Esteve J, Schots R, Bernal Del Castillo T, Lee J-H, Wang ES, Dinner S, et al. Multicenter, open-label, 3-arm study of gilteritinib, gilteritinib plus azacitidine, or azacitidine alone in newly diagnosed FLT3 mutated (FLT3 mut+) acute myeloid leukemia (AML) patients ineligible for intensive induction chemotherapy: findings from the safety cohort. Blood. 2018;132:2736.

    Article  Google Scholar 

  49. 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;30:735–41.

    Article  PubMed  Google Scholar 

  50. Schmid C, Labopin M, Socie G, Daguindau E, Volin L, Huynh A, et al. Outcome of patients with distinct molecular genotypes and cytogenetically normal AML after allogeneic transplantation. Blood. 2015;126:2062–9.

    Article  CAS  PubMed  Google Scholar 

  51. Bazarbachi AH, Al Hamed R, Malard F, Mohty M, Bazarbachi A. Allogeneic transplant for FLT3-ITD mutated AML: a focus on FLT3 inhibitors before, during, and after transplant. Ther Adv Hematol. 2019;10:2040620719882666.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 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 Transpl. 2011;17:1404–9.

    Article  Google Scholar 

  53. Oran B, Cortes J, Beitinjaneh A, Chen HC, de Lima M, Patel K, et al. Allogeneic transplantation in first remission improves outcomes irrespective of FLT3-ITD allelic ratio in FLT3-ITD-positive acute myelogenous leukemia. Biol Blood Marrow Transpl. 2016;22:1218–26.

    Article  CAS  Google Scholar 

  54. Gaballa S, Saliba R, Oran B, Brammer JE, Chen J, Rondon G, et al. Relapse risk and survival in patients with FLT3 mutated acute myeloid leukemia undergoing stem cell transplantation. Am J Hematol. 2017;92:331–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 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;26:2353–9.

    Article  CAS  PubMed  Google Scholar 

  56. Sato T, Yang X, Knapper S, White P, Smith BD, Galkin S, et al. FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo. Blood. 2011;117:3286–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Chen YB, Li S, Lane AA, Connolly C, Del Rio C, Valles B, et al. Phase I trial of maintenance sorafenib after allogeneic hematopoietic stem cell transplantation for fms-like tyrosine kinase 3 internal tandem duplication acute myeloid leukemia. Biol Blood Marrow Transpl. 2014;20:2042–8.

    Article  CAS  Google Scholar 

  58. Antar A, Kharfan-Dabaja MA, Mahfouz R, Bazarbachi A. Sorafenib maintenance appears safe and improves clinical outcomes in FLT3-ITD acute myeloid leukemia after allogeneic hematopoietic cell transplantation. Clin Lymphoma Myeloma Leuk. 2015;15:298–302.

    Article  PubMed  Google Scholar 

  59. Brunner AM, Li S, Fathi AT, Wadleigh M, Ho VT, Collier K, et al. Haematopoietic cell transplantation with and without sorafenib maintenance for patients with FLT3-ITD acute myeloid leukaemia in first complete remission. Br J Haematol. 2016;175:496–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Battipaglia G, Ruggeri A, Massoud R, El Cheikh J, Jestin M, Antar A, et al. Efficacy and feasibility of sorafenib as a maintenance agent after allogeneic hematopoietic stem cell transplantation for Fms-like tyrosine kinase 3-mutated acute myeloid leukemia. Cancer. 2017;123:2867–74.

    Article  CAS  PubMed  Google Scholar 

  61. Battipaglia G, Massoud R, Ahmed SO, Legrand O, El Cheikh J, Youniss R, et al. Efficacy and feasibility of sorafenib as a maintenance agent after allogeneic hematopoietic stem cell transplantation for FMS-like tyrosine kinase 3 mutated acute myeloid leukemia: an update. Clin Lymphoma Myeloma Leuk. 2019;19:506–8.

  62. Bazarbachi A, Labopin M, Battipaglia G, Djabali A, Passweg J, Socie G, et al. Sorafenib improves survival of FLT3-mutated acute myeloid leukemia in relapse after allogeneic stem cell transplantation: a report of EBMT acute leukemia Working Party. Haematologica. 2019;104:e398–401.

  63. Burchert A, Bug G, Finke J, Stelljes M, Rollig C, Wäsch R, et al. Sorafenib as maintenance therapy post allogeneic stem cell transplantation for FLT3-ITD positive AML: results from the randomized, double-blind, placebo-controlled multicentre sormain trial. Blood. 2018;132(Suppl 1):661.

  64. Larson RA, Mandrekar SJ, Sanford BL, Laumann K, Geyer SM, Bloomfield CD, et al. An analysis of maintenance therapy and post-midostaurin outcomes in the international prospective randomized, placebo-controlled, double-blind trial (CALGB 10603/RATIFY [alliance]) for newly diagnosed acute myeloid leukemia (AML) patients with FLT3 mutations. Blood. 2017;130:145.

    Google Scholar 

  65. Maziarz RTT, Patnaik MM, Scott BL, Mohan SR, Deol A, Rowley SD, et al. Radius: a phase 2 randomized trial investigating standard of care ± midostaurin after allogeneic stem cell transplant in FLT3-ITD-mutated AML. Blood. 2018;132:662.

    Article  Google Scholar 

  66. Sandmaier BM, Khaled S, Oran B, Gammon G, Trone D, Frankfurt O. Results of a phase 1 study of quizartinib as maintenance therapy in subjects with acute myeloid leukemia in remission following allogeneic hematopoietic stem cell transplant. Am J Hematol. 2018;93:222–31.

  67. Cortes J, Perl AE, Döhner H, Kantarjian H, Martinelli G, Kovacsovics T, et al. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2018;19:889–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cortes JE, Tallman MS, Schiller GJ, Trone D, Gammon G, Goldberg SL, et al. Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITD-mutated, relapsed or refractory AML. Blood. 2018;132:598–607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Cortes J, Khaled S, Martinelli G, Perl A, Ganguly S, Russell N, et al. Quizartinib significantly prolongs overall survival in patients with flt3-internal tandem duplication–mutated (mut) relapsed/refractory aml in the phase 3, randomized, controlled quantum-r trial. Eur Hematol Assos. 2018;218882:LB2600.

    Google Scholar 

  70. Cortes J, Khaled S, Martinelli G, Perl A, Ganguly S, Russell N, et al. Quizartinib significantly prolongs overall survival in patients with flt3-internal tandem duplication–mutated (mut) relapsed/refractory aml in the phase 3, randomized, controlled quantum-r trial. European Hematology Association (EHA) 2018;218882;LB2600.

  71. Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 2017;18:1061–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, et al. Gilteritinib or Chemotherapy for Relapsed or Refractory -Mutated AML. N. Eng. J. Med. 2019;381:1728–40.

  73. Rautenberg C, Nachtkamp K, Dienst A, Schmidt PV, Heyn C, Kondakci M, et al. Sorafenib and azacitidine as salvage therapy for relapse of FLT3-ITD mutated AML after allo-SCT. Eur J Haematol. 2017;98:348–54.

    Article  CAS  PubMed  Google Scholar 

  74. Metzelder SK, Schroeder T, Lubbert M, Ditschkowski M, Gotze K, Scholl S, et al. Long-term survival of sorafenib-treated FLT3-ITD-positive acute myeloid leukaemia patients relapsing after allogeneic stem cell transplantation. Eur J Cancer. 2017;86:233–9.

    Article  CAS  PubMed  Google Scholar 

  75. Kindler T, Lipka DB, Fischer T. FLT3 as a therapeutic target in AML: still challenging after all these years. Blood. 2010;116:5089–102.

    Article  CAS  PubMed  Google Scholar 

  76. Smith CC, Lin K, Stecula A, Sali A, Shah NP. FLT3 D835 mutations confer differential resistance to type II FLT3 inhibitors. Leukemia. 2015;29:2390–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Al-Jamal HAN, Jusoh SAM, Hassan R, Johan MF. Enhancing SHP-1 expression with 5-azacytidine may inhibit STAT3 activation and confer sensitivity in lestaurtinib (CEP-701)-resistant FLT3-ITD positive acute myeloid leukemia. BMC Cancer. 2015;15:869.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Nelson EA, Walker SR, Xiang M, Weisberg E, Bar-Natan M, Barrett R, et al. The STAT5 inhibitor pimozide displays efficacy in models of acute myelogenous leukemia driven by FLT3 mutations. Genes Cancer. 2012;3:503–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Malumbres M, Harlow E, Hunt T, Hunter T, Lahti JM, Manning G, et al. Cyclin-dependent kinases: a family portrait. Nat Cell Biol. 2009;11:1275–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Mohi MG, Boulton C, Gu TL, Sternberg DW, Neuberg D, Griffin JD, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Green AS, Maciel TT, Hospital MA, Yin C, Mazed F, Townsend EC, et al. Pim kinases modulate resistance to FLT3 tyrosine kinase inhibitors in FLT3-ITD acute myeloid leukemia. Sci Adv. 2015;1:e1500221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377:454–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Williams AB, Li L, Nguyen B, Brown P, Levis M, Small D. Fluvastatin inhibits FLT3 glycosylation in human and murine cells and prolongs survival of mice with FLT3/ITD leukemia. Blood. 2012;120:3069–79.

  84. Choudhary C, Olsen JV, Brandts C, Cox J, Reddy PNG, Böhmer FD, et al. Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes. Mol Cell. 2009;36:326–39.

  85. Mathew NR, Baumgartner F, Braun L, O’Sullivan D, Thomas S, Waterhouse M, et al. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells. Nat Med. 2018;24:282–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Hematology and Oncology, Hammoud Hospital University Medical Center, Saida, Lebanon

    Ahmad I. Antar

  2. Department of Pathology and Laboratory Medicine, Henry Ford Hospital, Wayne State University, Detroit, MI, USA

    Zaher K. Otrock

  3. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Elias Jabbour

  4. Service d’hématologie clinique et thérapie cellulaire, Hôpital Saint-Antoine, INSERM UMRs 938 and université Sorbonne, Paris, France

    Mohamad Mohty

  5. Bone Marrow Transplantation Program, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon

    Ali Bazarbachi

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Correspondence to Ali Bazarbachi.

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We declare the following conflicts of interest: Elias Jabbour (Research grants and advisory roles from Abbvie, Adaptive Biotechnologies, Amgen, BMS, Pfizer and Takeda), Mohamad Mohty (Honoraria from Novartis and Daiichi Sankyo), Ali Bazarbachi (Research grants and advisory roles from Novartis and Takeda). The other authors declare no conflict of interest. No financial support was provided for this project.

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Antar, A.I., Otrock, Z.K., Jabbour, E. et al. FLT3 inhibitors in acute myeloid leukemia: ten frequently asked questions. Leukemia 34, 682–696 (2020). https://doi.org/10.1038/s41375-019-0694-3

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  • DOI: https://doi.org/10.1038/s41375-019-0694-3

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