Role of FLT3 gene mutations in acute myeloid leukemia: effect on course of disease and results of therapy



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Abstract

Detection of FLT3 gene mutations in acute myeloid leukemia is now recognized as an unfavorable factor that affects the disease course, emerging the risk of relapses and overall survival shortening and disease-free survival of patients. The aim of the study was to determine the frequency of mutations of the gene FLT3 and to assess their impact on clinical indicators, overall survival and disease-free survival in patients with acute myeloid leukemia. We compared complete blood count parameters, karyotype, duration of overall survival and disease-free survival in 199 patients with acute myeloid leukemia depending on the presence or absence of mutations of the FLT3 gene. Significant differences across these groups were discovered only in WBC and blasts between the group of patients with acute myeloid leukemia (FLT3+) and without mutations in the FLT3 gene (FLT3-). The differences between two groups were also identified in patients chromosomal aberrations. Significant differences (p=0,00024) in the duration of overall survival between groups of patients with acute myeloid leukemia with mutations of FLT3-ITD+, FLT3-TKD+ and FLT3- were demonstrated. Median overall survival was: 1 6 months for patients with mutation FLT3-ITD+ and 17 months for FLT3-TKD+ patients and not achieved for FLT3- patients. The use of modern molecular genetic methods of research in acute myeloid leukemia allows to improve the diagnosis of the disease, as well as to carry out risk stratification and individualize therapy. The use of targeted therapy for FLT3-positive patients who are not candidates for hematopoietic stem cell transplantation will increase the effectiveness of the treatment and improve the performance of overall survival and disease-free survival.

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About the authors

A. M Radzhabova

Russian scientific research Institute of Hematology and Transfusiology of Federal medical-biological Agency

Email: aradzhabova91@gmail.com

S. V Voloshin

Russian scientific research Institute of Hematology and Transfusiology of Federal medical-biological Agency; S.M. Kirov Military Medical Academy; I.I. Mechnikov North-Western State Medical University

I. S Martynkevich

Russian scientific research Institute of Hematology and Transfusiology of Federal medical-biological Agency

A. A Kuzyaeva

Russian scientific research Institute of Hematology and Transfusiology of Federal medical-biological Agency

VA. Shuvaev

Russian scientific research Institute of Hematology and Transfusiology of Federal medical-biological Agency

E. V Motyko

Russian scientific research Institute of Hematology and Transfusiology of Federal medical-biological Agency

A. Y Kuvshinov

Russian scientific research Institute of Hematology and Transfusiology of Federal medical-biological Agency

M. S Fominykh

Russian scientific research Institute of Hematology and Transfusiology of Federal medical-biological Agency

A. V Schmidt

Russian scientific research Institute of Hematology and Transfusiology of Federal medical-biological Agency

L. B Polushkina

Russian scientific research Institute of Hematology and Transfusiology of Federal medical-biological Agency

M. P Bakay

Russian scientific research Institute of Hematology and Transfusiology of Federal medical-biological Agency

S. A Tiranova

Russian scientific research Institute of Hematology and Transfusiology of Federal medical-biological Agency

M. N Zenina

Russian scientific research Institute of Hematology and Transfusiology of Federal medical-biological Agency

N. A Potihonova

Russian scientific research Institute of Hematology and Transfusiology of Federal medical-biological Agency

SA. Kudryashova

Russian scientific research Institute of Hematology and Transfusiology of Federal medical-biological Agency

V. A Balashova

Russian scientific research Institute of Hematology and Transfusiology of Federal medical-biological Agency

J. V Chubukina

Russian scientific research Institute of Hematology and Transfusiology of Federal medical-biological Agency

O. S Uspenskaya

Leningrad Regional Clinical Hospital

E. V Karyagina

City Hospital № 15, Saint Petersburg

A. N Bogdanov

S.M. Kirov Military Medical Academy

A. V Chechetkin

Russian scientific research Institute of Hematology and Transfusiology of Federal medical-biological Agency

References

  1. Hiddemann W., Buchner T. Treatment strategies in acute myeloid leukemia (AML). B. Second line treatment. Blut 1990; 60(3): 163-71.
  2. Dohner H., Weisdorf D.J., Bloomfield C.D. Acute myeloid leukemia. N. Engl. J. Med. 2015; 373(12): 1136-52.
  3. de Souza D.S., Fernandez Cde S., Camargo A. et al. Cytogenetic as an important tool for diagnosis and prognosis for patients with hypocellular primary myelodysplastic syndrome. Biomed Res. Int. 2014; 2014: 542395.
  4. Graubert T.A., Brunner A.M., Fathi A.T. New molecular abnormalities and clonal architecture in AML: from reciprocal translocations to whole-genome sequencing. Am. Soc. Clin. Oncol. Educ. Book 2014; e334-40.
  5. Yamamoto Y., Kiyoi H., Nakano Y. et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 2001; 97(8): 2434-9.
  6. Dohner H., Estey E.H., Amadori S. et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European Leukemia Net. Blood 2010; 115(3): 453-74.
  7. Gale R.E., Green C., Allen C. et al. The impact of FLT3 internal tandem duplication mutant level, number, size and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid. Blood 2008; 111(5): 2776-84.
  8. Kottaridis P.D., Gale R.E., Frew M.E. 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.
  9. Marcucci G., Haferlach T., Dohner H. Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J. Clin. Oncol. 2011; 29(5): 475-86.
  10. Ozeki K., Kiyoi H., Hirose Y. et al. Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia. Blood 2004; 103(5): 1901-8.
  11. Cooper B.W., Kindwall-Keller T.L., Craig M.D. et al. Phase I study of midostaurin and azacitidine in relapsed and elderly AML. Clin. Lymphoma Myeloma Leuk. 2015; 15(7): 428-32.e2.
  12. Piacibello W., Fubini L., Sanavio F. et al. Effects of human FLT3 ligand on myeloid leukemia cell growth: heterogeneity in response and synergy with other hematopoietic growth factors.Blood 1995; 86(11): 4105-14.
  13. Allen C., Hills R.K., Lamb K. et al. The importance of relative mutant level for evaluating impact on outcome of KIT, FLT3 and CBL mutations in core-binding factor acute myeloid leukemia. Leukemia 2013; 27(9): 1891-901.
  14. Bains A., Luthra R., Medeiros L.J. et al. FLT3 and NPM1 mutations in myelodysplastic syndromes: frequency and potential value for predicting progression to acute myeloid leukemia. Am. J. Clin. Pathol. 2011; 135(1): 62-9.
  15. Balusu R., Fiskus W., Rao R. et al. Targeting levels or oligomerization of nucleophosmin 1 induces differentiation and loss of survival of human AML cells with mutant NPM1. Blood 2011; 118(11): 3096-106.
  16. Becker H., Marcucci G., Maharry K. et al. Favorable prognostic impact of NPM1 mutations in older patients with cytogenetically normal de novo acute myeloid leukemia and associated gene and microRNA-expression signatures: a cancer and leukemia group B study. J. Clin. Oncol. 2010; 28(4): 596-604.
  17. Bejar R., Stevenson K., Abdel-Wahab O. et al. Clinical effect of point mutations in myelodysplastic syndromes. N. Engl. J. Med. 2011; 364(26): 2496-506.
  18. Metzelder S., Wang Y., Wollmer E. 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.
  19. Петрова Е.В., Мартынкевич И.С., Полушкина Л.Б. и др. Клинические, гематологические и молекулярно-генетические особенности острых миелоидных лейкозов с мутациями в генах FLT3, CKIT, NRAS и NPM1. Гематология и трансфузиология 2016; 61(2): 72-80.
  20. Gaidzik V.I., Schlenk R.F., Paschka P. et al. Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML Study Group (AMLSG). Blood 2013; 121(23): 4769-77.
  21. Рубнитц Д. Современные стратегии лечения острого миелоидного лейкоза. Российский журнал детской гематологии и онкологии 2016; 3(3): 47-51. (Rubnitz D. Modern strategies for the treatment of acute myeloid leukemia. Russian journal of pediatric hematology and oncology 2016; 3(3): 47-51).
  22. Mead A.J., Linch D.C., Hills R.K. et al. 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.
  23. Whitman S.P., Ruppert A.S., Radmacher M.D. 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.
  24. Савченко В.Г, Паровичникова Е.Н., Клясова Г.А. и др. Итоги двух с половиной лет работы Российского многоцентрового исследования по лечению острых миелоидных лейкозов взрослых. Терапевтический архив 1995; 67(7): 8-12. (Savchenko V.G, Parovichnikova E.N., Klyasova G.A. et al. Results of two and a half years of the Russian multicenter study on the treatment of acute myeloid leukemia in adults. Therapeutic archive 1995; 67(7): 8-12).
  25. Stone R.M., Fischer T., Paquette R. 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.
  26. Ravandi F., Alattar M.L., Grunwald M.R. 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.
  27. Martinelli G., Perl A.E., Dombret H. et al. Effect of quizartinib (AC220) on response rates and long-term survival in elderly patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia. J. Clin. Oncol. 2013; 15: 7021.
  28. Perl A.E., Dohner H., Rousselot P.H. et al. Efficacy and safety of quizartinib (AC220) in patients age >70 years with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia (AML). J. Clin. Oncol. 2013; 15: 7023.
  29. Nazha A., Kantarjian H., Borthakur G. et al. A phase I/II trial of combination of PKC412 and 5-azacytidine (AZA) for the treatment of patients with refractory or relapsed (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MdS). J. Clin. Oncol. 2012; 15: 6589.

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