Page 33 - 2021_03-Haematologica-web

Targeting of FLT3 AML
sophisticated diagnostic techniques has provided us with the opportunity to make more informed treatment deci- sions, while the advent of FLT3 inhibitors has provided us with a powerful new treatment tool. These developments also demand ever more familiarity of practising clinicians with the nuances of FLT3 biology and FLT3 inhibitor phar- macology.
Disclosures
ML: Consulting/honoraria/research funding from Astellas, Fujifilm, Daiichi-Sankyo, Amgen, Agios, Novartis. AA: No dis- closures.
Contributions
AA and ML wrote the manuscript together.
References
1.Van Der Geer P, Hunter T, Lindberg RA. Receptor protein-tyrosine kinases and their signal transduction pathways. Ann Rev Cell Biol. 1994;10251-10337.
2. Beaudin AE, Boyer SW, Forsberg EC. Flk2/Flt3 promotes both myeloid and lym- phoid development by expanding non-self- renewing multipotent hematopoietic pro- genitor cells. Exp Hematol. 2014;42(3):218- 229.e4.
3.Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209-2221.
4. Dosil M, Wang S, Lemischka IR. Mitogenic signalling and substrate specificity of the Flk2/Flt3 receptor tyrosine kinase in fibrob- lasts and interleukin 3-dependent hematopoietic cells. Mol Cell Biol. 1993;13(10):6572-6585.
5. Rosnet O, Bühring HJ, De Lapeyriére O, et al. Expression and signal transduction of the FLT3 tyrosine kinase receptor. Acta Haematol. 1996;95(3-4):218-223.
6. Tsapogas P, Mooney CJ, Brown G, Rolink A. The cytokine Flt3-ligand in normal and malignant hematopoiesis. Int J Mol Sci. 2017;18(6):1115.
7. Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: Association with FAB subtypes and identifi- cation of subgroups with poor prognosis. Blood. 2002;99(12):4326-4335.
8.Schnittger S, Schoch C, Dugas M, et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: cor- relation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and useful- ness as a marker for the detection of mini- mal residual disease. Blood. 2002;100(1):59- 66.
9. Heidel F, Solem FK, Breitenbuecher F, 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.
10.Fröhling S, Scholl C, Levine RL, et al. Identification of driver and passenger muta- tions of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles. Cancer Cell. 2007;12(6): 501-513.
11. Fiskus W, Sharma S, Qi J, et al. BET protein antagonist JQ1 is synergistically lethal with FLT3 tyrosine kinase inhibitor (TKI) and overcomes resistance to FLT3-TKI in AML cells expressing FLT-ITD. Mol Cancer Ther. 2014;13(10):2315-2327.
12. Carow CE, Levenstein M, Kaufmann SH, et al. Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood 1996;87(3):1089-1096.
13. Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood. 2002;100(5):1532-1542.
14.Kuchenbauer F, Kern W, Schoch C, et al.
Detailed analysis of FLT3 expression levels in acute myeloid leukemia. Haematologica. 2005;90(12):1617-1625.
15. Tarlock K, Alonzo TA, Loken MR, et al. Disease characteristics and prognostic impli- cations of cell-surface FLT3 receptor (CD135) expression in pediatric acute myeloid leukemia: a report from the Children’s Oncology Group. Clin Cancer Res. 2017;23(14):3649-3656.
16. Cheng J, Qu L, Wang J, Cheng L, Wang Y. High expression of FLT3 is a risk factor in leukemia. Mol Med Rep. 2018;17(2):2885- 2892.
17. Kandeel EZ, El Sayed G, Elsharkawy N, et al. Impact of FLT3 receptor (CD135) Detection by Flow Cytometry on Clinical Outcome of Adult Acute Myeloid leukemia patients. Clin Lymphoma Myeloma Leuk. 2018;18(8):541-547.
18.Daver N, Strati P, Jabbour E, et al. FLT3 mutations in myelodysplastic syndrome and chronic myelomonocytic leukemia. Am J Hematol. 2013;88(1):56-59.
19. Rosenzwajg M, Camus S, Guigon M, Gluckman JC. The influence of interleukin (IL)-4, IL-13, and Flt3 ligand on human den- dritic cell differentiation from cord blood CD34+ progenitor cells. Exp Hematol. 1998;26(1):63-72.
20. McKenna HJ, Stocking KL, Miller RE, et al. Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic pro- genitor cells, dendritic cells, and natural killer cells. Blood. 2000;95(11):3489-3497.
21.Levis M. FLT3/ITD AML and the law of unintended consequences. Blood. 2011;117(26):6987-6990.
22. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464.
23. Döhner K, Thiede C, Jahn N, et al. Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia. Blood. 2020;135(5):371-380.
24. Chyla BJ, Harb J, Mantis C, et al. Response to venetoclax in combination with low intensity therapy (LDAC or HMA) in untreated patients with acute myeloid leukemia patients with IDH, FLT3 and other mutations and correlations with BCL2 family expression. Blood. 2019;134 (Supplement_1):546-546.
25. DiNardo CD, Tiong IS, Quaglieri A, et al. Molecular patterns of response and treat- ment failure after frontline venetoclax com- binations in older patients with AML. Blood. 2020;135(11):791-803.
26. Ravandi F, Alattar ML, Grunwald MR, 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):4655-4662.
27. National Comprehensive Cancer Network. Acute Myeloid Leukemia (Version 3.2020 - December 23, 2019). Available from: https://www.nccn.org/professionals/physi- cian_gls/pdf/aml.pdf (Last accessed June 16,
2020).
28. 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(7):1425-1432.
29. Ding L, Ley TJ, Larson DE, et al. Clonal evo- lution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature. 2012;481(7382):506-510.
30. 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 (4):424-447.
31. Meshinchi S, Arceci RJ, Sanders JE, et al. Role of allogeneic stem cell transplantation in FLT3/ITD-positive AML. Blood. 2006;108(1):400.
32. DeZern AE, Sung A, Kim S, 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):1404-1409.
33. Koreth J, Schlenk R, Kopecky KJ, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta- analysis of prospective clinical trials. JAMA. 2009;301(22):2349-2361.
34.Schlenk RF, Kayser S, Bullinger L, et al. Differential impact of allelic ratio and inser- tion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood. 2014;124(23):3441-3449.
35.Oran B, Cortes J, Beitinjaneh A, 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 Transplant. 2016;22(7):1218-1226.
36. Gaballa S, Saliba R, Oran B, et al. Relapse risk and survival in patients with FLT3 mutated acute myeloid leukemia undergo- ing stem cell transplantation. Am J Hematol. 2017;92(4):331-337.
37. Kayser S, Schlenk RF, Londono MC, et al. Insertion of FLT3 internal tandem duplica- tion in the tyrosine kinase domain-1 is asso- ciated with resistance to chemotherapy and inferior outcome. Blood. 2009;114(12):2386- 2392.
38. Breitenbuecher F, Schnittger S, Grundler R, et al. Identification of a novel type of ITD mutations located in nonjuxtamembrane domains of the FLT3 tyrosine kinase recep- tor. Blood. 2009;113(17):4074-4077.
39.Griffith J, Black J, Faerman C, et al. The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Mol Cell. 2004;13(2):169-178.
40. Stirewalt DL, Kopecky KJ, Meshinchi S, et al. Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia. Blood. 2006;107 (9):3724-3726.
41. Chen F, Sun J, Yin C, et al. Impact of FLT3- ITD allele ratio and ITD length on therapeu- tic outcome in cytogenetically normal AML
haematologica | 2021; 106(3)
679