38 -4 (36) 2021Egamova S.Q. — THE IMPORTANCE OF FLT-3MUTATIONAL ANALYSIS IN ACUTE MYELOID LEUKEMIA

THE IMPORTANCE OF FLT-3 MUTATIONAL ANALYSIS IN ACUTE MYELOID LEUKEMIA

Egamova S.Q. Bukhara State Medical Institute named after Abu Ali ibn Sina

Resume

Activating mutations in FMS-like tyrosine kinase 3 (FLT-3), including internal tandem duplications (ITDs) and tyrosine kinase domain (TKD) mutations, are common in patients with acute myeloid leukemia (AML). FLT-3-ITD is a negative prognostic factor that remains prognostically relevant even after intensive chemotherapy and/or stem cell transplant. FLT-3 testing was historically viewed as being purely prognostic; however, with the advent of FLT-3 inhibitors, it will likely be seen as both prognostic and predictive. First discovered 20 years ago, these mutations were identified as viable therapeutic targets, and FLT-3 tyrosine-kinase inhibitors (TKIs) have been in development for the last decade with steadily increasing potency. However, FLT3-mutated AML often acquires resistance to the growing armamentarium of FLT-3 inhibitors through a variety of mechanisms. In this review, we discuss the distinct clinical phenotype of FLT-3-mutated AML, historically and currently available therapeutics, mechanisms of resistance, ongoing trials, and future outlook at treatment strategies. In this review, I discuss the importance of mutational analysis in AML.

Key words: acute myeloid leukemia, FLT-3 testing, prognostic marker, FLT-3 tyrosinekinase inhibitor

First page

185

Last page

191

For citation: Egamova S.Q. THE IMPORTANCE OF FLT-3 MUTATIONAL ANALYSIS IN ACUTE MYELOID LEUKEMIA //New Day in Medicine 4(36)2021 185-191 https://cutt.ly/iTnPihJ

LIST OF REFERENCES:

  1. Papaemmanuil E., Gerstung M., Bullinger L., et al. Genomic classification and prognosis in acute myeloid leukemia  // N. Engl. J. Med. 2016; 374:2209–2221
  2. Levine R.L. Molecular pathogenesis of AML: translating insights to the clinic // Best Pract Res Clin Haematol. 2013; 26(3): 245– 248.
  3. Chatain N., Perera R.C., Rossetti G., et al. Rare FLT3 deletion mutants may provide additional treatment options to patients with AML: an approach to individualized medicine  // Leukemia. 2015; 29:2434–2438
  4. Opatz S., Polzer H., Herold T., et al. Exome sequencing identifies recurring FLT3 N676K mutations in core-binding factor leukemia // Blood. 2013; 122:1761–1769
  5. Döhner H., Estey E., Grimwade D., et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel // Blood. 2017; 129:424–447
  6. Koszarska M., Meggyesi N., Bors A., et al. Mediumsized FLT3 internal tandem duplications confer worse prognosis than short and long duplications in a non-elderly acute myeloid leukemia cohort // Leuk Lymphoma. 2014; 55:1510–1517.
  7. Walter R.B., Othus M., Burnett A.K., et al. Resistance prediction in AML: analysis of 4601 patients from MRC/ NCRI, HOVON/SAKK, SWOG and MD Anderson Cancer Center // Leukemia.2015; 29:312–320.
  8. Arber D.A., Borowitz M.J., Cessna M., et al. Initial diagnostic workup of acute leukemia: guideline from the College of American Pathologists and the American Society of Hematology // Arch Pathol Lab Med. 2017; 141:1342–1393.
  9. Rydapt (midostaurin) [prescribing information]. East Hanover (NJ): Novartis Pharmaceuticals Corporation; April 2017
  10. Lin T.L., Williams T., He J., et al. Rates of complete diagnostic testing for patients with acute myeloid leukemia // Cancer Med. 2015; 4:519–522.
  11. George T.I., Tworek J.A., Thomas N.E., et al. Evaluation of testing of acute leukemia samples: survey result from the College of American Pathologists // Arch Pathol Lab Med. 2017; 141:1101–1106.
  12. Altman J.K., Perl A.E., Cortes J.E., et al. Deep molecular response to gilteritinib improves survival in FLT3 mutation-positive relapsed/refractory acute myeloid leukemia. // Paper presented at: European Hematology Association 22nd Congress: 2017 Jun 22–25; Madrid, Spain.
  13. McKerrell T., Moreno T., Ponstingl H., et al. Development and validation of a comprehensive genomic diagnostic tool for myeloid malignancies // Blood. 2016; 128:1–9.
  14. Duncavage E.J., Tandon B. The utility of next-generation sequencing in diagnosis and monitoring of acute myeloid leukemia and myelodysplastic syndromes // Int J Lab Hematol. 2015;37(Suppl 1): 115–121.
  15. Au CH., Wa A., Ho D.N., et al. Clinical evaluation of panel testing by next-generation sequencing (NGS) for gene mutations in myeloid neoplasms // Diagn Pathol. 2016;11:11
  16. Liu H.E., Ko C., Lam F., et al. Establishment of a costeffective method to detect FLT-ITD and D835 mutations in acute myeloid leukemia patients in the Taiwanese population // Tzu Chi Med J. 2015; 27:18–24.
  17. Gupta A., Viswanatha D.S., Patnaik M.M. FLT3 mutation testing in acute myeloid leukemia // JAMA Oncol. 2017;3:991–992
  18. Schiller G.J., Tuttle P., Desai P. Allogeneic hematopoietic stem cell transplantation in FLT3-ITD-positive acute myelogenous leukemia: the role for FLT3 tyrosine kinase inhibitors post-transplantation // Biol Blood Marrow Transplant. 2016;22:982–990.
  19. Oran B., Cortes J., Beitinjaneh A., et al. Allogeneic transplantation in first remission improves outcomes irrespective of FLT3-ITD allelic ratio in FLT3- itdimportance of  FLT3 testing in AML 2283 positive acute myelogenous leukemia // Biol Blood Marrow Transplant. 2016;22:1218–1226.
  20. Battipaglia G., Ruggeri A., Jestin M., 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 // Poster presented at: 58th American Society of Hematology Annual Meeting and Exposition; 2016 Dec 3–6; San Diego, CA.

file

download