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Significance of FLT3-tyrosine kinase domain mutation as a prognostic factor for acute myeloid leukemia

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Abstract

The prognostic significance of FLT3-tyrosine kinase domain (TKD) mutations remains unknown. To investigate the prognostic impact of FLT3-TKD, 676 de novo acute myeloid leukemia (AML), we retrospectively analyzed cases and conducted a review of the literature. Of the 676 de novo AML cases, 34 (5.0%) were FLT3-TKD-positive; both FLT3-TKD and FLT3-ITD were noted in only two cases (0.3%). Although no significant differences in relapse-free survival (RFS) were noted, FLT3-TKD-positive cases showed better prognoses than FLT3-ITD-positive cases (FLT3-TKD versus FLT3-ITD, p = 0.152). For overall survival (OS), although FLT3-TKD-positive cases showed prognoses similar to those for FLT3-WT cases, their prognoses were significantly better than those of FLT3-ITD-positive cases (FLT3-TKD versus FLT3-ITD, p = 0.032). Moreover, the 5-year OS for FLT3-TKD-positive cases was 46.1%, indicating that this as an intermediate prognosis group. Although no reports from Asia have indicated a frequency of FLT3-TKD-positive cases > 10%, several reports from Europe and the United States have indicated frequencies > 10%. This suggests the possibility that FLT3-TKD-positive cases are less common in Asia than in Europe and the United States. We anticipate that in the future, the appearance of targeting agents, such as FLT3 inhibitors, will improve the prognosis of FLT3-TKD-positive AML relative to that of FLT3-WT AML.

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References

  1. Ohtake S, Miyawaki S, Fujita H, Kiyoi H, Shinagawa K, Usui N, et al. Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 study. Blood. 2011;117(8):2358–65.

    Article  CAS  PubMed  Google Scholar 

  2. Kurosawa S, Yakushijin K, Yamaguchi T, Atsuta Y, Nagamura-inoue T, Akiyama H, et al. Changes in incidence and causes of non-relapse mortality after allogeneic hematopoietic cell transplantation in patients with acute leukemia/myelodysplastic syndrome: an analysis of the Japan Transplant Outcome Registry. Bone Marrow Transplant. 2013;48(4):529–36.

    Article  CAS  PubMed  Google Scholar 

  3. Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–47.

    Article  PubMed  PubMed Central  Google Scholar 

  5. O’Donnell MR, Tallman MS, Abboud CN, Altman JK, Appelbaum FR, Bhatt VR et al. NCCN clinical practice guidelines in oncology (NCCN guidelines®) acute myeloid leukemia version 3.2018. Available at https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed 15 Oct 2018.

  6. Levis M. FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? Hematol Am Soc Hematol Educ Progr. 2013;2013:220–6.

    Article  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(8):2434–9.

    Article  CAS  PubMed  Google Scholar 

  8. Mead AJ, Linch DC, Hills RK, Wheatley K, Burnett AK, Gale RE. 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(4):1262–70.

    Article  CAS  PubMed  Google Scholar 

  9. Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Spiekermann K, Bagrintseva K, Schoch C, Haferlach T, Hiddemann W, Schnittger S. A new and recurrent activating length mutation in exon 20 of the FLT3 gene in acute myeloid leukemia. Blood. 2002;100(9):3423–5.

    Article  CAS  PubMed  Google Scholar 

  11. Chatain N, Perera RC, Rossetti G, Rossa J, Carloni P, Schemionek M, et al. Rare FLT3 deletion mutants may provide additional treatment options to patients with AML: an approach to individualized medicine. Leukemia. 2015;29(12):2434–8.

    Article  CAS  PubMed  Google Scholar 

  12. 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(5):2527–37.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. Thiede C, Steudel C, Mohr B, Schaich M, Schäkel 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.

    Article  CAS  PubMed  Google Scholar 

  15. Auewarakul CU, Sritana N, Limwongse C, Thongnoppakhun W, Yenchitsomanus PT. Mutations of the FLT3 gene in adult acute myeloid leukemia: determination of incidence and identification of a novel mutation in a Thai population. Cancer Genet Cytogenet. 2005;162(2):127–34.

    Article  CAS  PubMed  Google Scholar 

  16. Rezaei N, Arandi N, Valibeigi B, Haghpanah S, Khansalar M, Ramzi M. FMS-like tyrosine kinase 3 (FLT3) and nucleophosmin 1 (NPM1) in Iranian adult acute myeloid leukemia patients with normal karyotypes: mutation status and clinical and laboratory characteristics. Turk J Haematol. 2017;34(4):300–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Elyamany G, Awad M, Fadalla K, Albalawi M, Al Shahrani M, Al AA. Frequency and prognostic relevance of FLT3 mutations in Saudi acute myeloid leukemia patients. Adv Hematol. 2014;2014:141360.

    PubMed  PubMed Central  Google Scholar 

  18. Ali A, Gale RE, Shakoori AR. Detection of FLT3/TKD and IDH1 mutations in Pakistani acute myeloid leukemia patients by denaturing HPLC. J Cell Biochem. 2017;118(5):1174–81.

    Article  CAS  PubMed  Google Scholar 

  19. Chou SC, Tang JL, Hou HA, Chou WC, Hu FC, Chen CY, et al. Prognostic implication of gene mutations on overall survival in the adult acute myeloid leukemia patients receiving or not receiving allogeneic hematopoietic stem cell transplantations. Leuk Res. 2014;38(11):1278–84.

    Article  CAS  PubMed  Google Scholar 

  20. Zaker F, Mohammadzadeh M, Mohammadi M. Detection of KIT and FLT3 mutations in acute myeloid leukemia with different subtypes. Arch Iran Med. 2010;13(1):21–5.

    CAS  PubMed  Google Scholar 

  21. Wang W, Wang XQ, Xu XP, Lin GW. Prevalence and prognostic significance of FLT3 gene mutations in patients with acute leukaemia: analysis of patients from the Shanghai Leukaemia Co-operative Group. J Int Med Res. 2010;38(2):432–42.

    Article  CAS  PubMed  Google Scholar 

  22. Gari M, Abuzenadah A, Chaudhary A, Al-Qahtani M, Banni H, Ahmad W, et al. Detection of FLT3 oncogene mutations in acute myeloid leukemia using conformation sensitive gel electrophoresis. Int J Mol Sci. 2008;9(11):2194–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Eisfeld AK, Kohlschmidt J, Mrozek K, Blachly JS, Walker CJ, Nicolet D, et al. Mutation patterns identify adult patients with de novo acute myeloid leukemia aged 60 years or older who respond favorably to standard chemotherapy: an analysis of Alliance studies. Leukemia. 2018;32(6):1338–48.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Uy GL, Mandrekar SJ, Laumann K, Marcucci G, Zhao W, Levis MJ, et al. A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Adv. 2017;1(5):331–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Boddu P, Kantarjian H, Borthakur G, Kadia T, Daver N, Pierce S, et al. Co-occurrence of FLT3-TKD and NPM1 mutations defines a highly favorable prognostic AML group. Blood Adv. 2017;1(19):1546–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Whitman SP, Ruppert AS, Radmacher MD, Mrózek 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(3):1552–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Perry M, Bertoli S, Rocher C, Hayette S, Ducastelle S, Barraco F, et al. FLT3-TKD mutations associated with NPM1 mutations define a favorable-risk group in patients with acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2018;18(12):e545–50.

    Article  PubMed  Google Scholar 

  28. Janke H, Pastore F, Schumacher D, Herold T, Hopfner KP, Schneider S, et al. Activating FLT3 mutants show distinct gain-of-function phenotypes in vitro and a characteristic signaling pathway profile associated with prognosis in acute myeloid leukemia. PLoS One. 2014;9(3):e89560.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Andersson A, Johansson B, Lassen C, Mitelman F, Billstrom R, Fioretos T. Clinical impact of internal tandem duplications and activating point mutations in FLT3 in acute myeloid leukemia in elderly patients. Eur J Haematol. 2004;72(5):307–13.

    Article  CAS  PubMed  Google Scholar 

  30. Verhaak RG, Goudswaard CS, van Putten W, Bijl MA, Sanders MA, Hugens W, et al. Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood. 2005;106(12):3747–54.

    Article  CAS  PubMed  Google Scholar 

  31. Moreno I, Martin G, Bolufer P, Barragán E, Rueda E, Román 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.

    CAS  PubMed  Google Scholar 

  32. Sheikhha MH, Awan A, Tobal K, Liu Yin JA. Prognostic significance of FLT3 ITD and D835 mutations in AML patients. Hematol J. 2003;4(1):41–6.

    Article  PubMed  Google Scholar 

  33. 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.

    Article  CAS  PubMed  Google Scholar 

  34. Wakita S, Yamaguchi H, Omori I, Terada K, Ueda T, Manabe E, et al. Mutations of the epigenetics-modifying gene (DNMT3a, TET2, IDH1/2) at diagnosis may induce FLT3-ITD at relapse in de novo acute myeloid leukemia. Leukemia. 2013;27(5):1044–52.

    Article  CAS  PubMed  Google Scholar 

  35. Wakita S, Yamaguchi H, Ueki T, Usuki K, Kurosawa S, Kobayashi Y, et al. Complex molecular genetic abnormalities involving three or more genetic mutations are important prognostic factors for acute myeloid leukemia. Leukemia. 2016;30(3):545–54.

    Article  CAS  PubMed  Google Scholar 

  36. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48(3):452–8.

    Article  CAS  PubMed  Google Scholar 

  37. Jahic A, Iljazovic E, Hasic S, Arnautovic AC, Sabitovic D, Mesanovic S, et al. Prognostic parameters of acute myeloid leukaemia at presentation. Med Arch. 2017;71(1):20–4.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Wang L, Lin D, Zhang X, Chen S, Wang M, Wang J. Analysis of FLT3 internal tandem duplication and D835 mutations in Chinese acute leukemia patients. Leuk Res. 2005;29(12):1393–8.

    Article  CAS  PubMed  Google Scholar 

  39. 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(8):1061–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors thank the physicians who cared for patients and collected clinical data during this study.

Author information

Author notes

  1. Masahiro Sakaguchi, Hiroki Yamaguchi, and Marika Kuboyama have contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-Ku, Tokyo, 113-8603, Japan

    Masahiro Sakaguchi, Hiroki Yamaguchi, Marika Kuboyama, Kenta Date, Nana Nakajima, Atsushi Marumo, Ikuko Omori, Yusuke Fujiwara, Kazuki Terada, Shunsuke Yui, Satoshi Wakita, Kunihito Arai, Tomoaki Kitano & Koiti Inokuchi

  2. Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan

    Yuho Najima, Kazuhiko Kakihana & Kazuteru Ohashi

  3. Department of Hematology, NTT Medical Center Tokyo, Tokyo, Japan

    Kensuke Usuki

  4. Department of Hematology, Nagano Red Cross Hospital, Nagano, Japan

    Toshimitsu Ueki

  5. Division of Hematology, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan

    Iekuni Oh & Yoshinobu Kanda

  6. Hemato-Oncology Department, St. Luke’s International Hospital, Tokyo, Japan

    Shinichiro Mori

  7. Department of Hematology, Japanese Red Cross, Kyoto Daini Hospital, Kyoto, Japan

    Eri Kawata, Nobuhiko Uoshima & Yutaka Kobayashi

  8. Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan

    Shinichi Kako & Yoshinobu Kanda

  9. Department of Hematology, Yokohama Minami Kyousai Hospital, Yokohama, Kanagawa, Japan

    Kenji Tajika

  10. Department of Hematology, Chiba Aoba Municipal Hospital, Chiba, Japan

    Katsuhiro Shono

  11. Department of Hematology, Chiba University Hospital, Chiba, Japan

    Kensuke Kayamori

  12. Department of Hematology, Eiju General Hopital, Tokyo, Japan

    Masao Hagihara

  13. Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Junya Kanda

  14. Department of Hematology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan

    Hitoji Uchiyama

  15. Division of Hematology and Oncology, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Eri Kawata & Junya Kuroda

  16. Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations, Toranomon Hospital, Tokyo, Japan

    Naoyuki Uchida

  17. Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan

    Yasushi Kubota & Shinya Kimura

  18. Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan

    Saiko Kurosawa & Takahiro Fukuda

Authors
  1. Masahiro Sakaguchi
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  2. Hiroki Yamaguchi
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Correspondence to Hiroki Yamaguchi.

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Sakaguchi, M., Yamaguchi, H., Kuboyama, M. et al. Significance of FLT3-tyrosine kinase domain mutation as a prognostic factor for acute myeloid leukemia. Int J Hematol 110, 566–574 (2019). https://doi.org/10.1007/s12185-019-02720-z

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