Keywords
FLT3 inhibitors, Sorafenib, Midostaurin, Acute myeloid leukemia
How to Cite
Fernández, I. (2019). First generation FLT3 inhibitors sorafenib and midostaurin in acute myeloid leukemia. Journal of Hematology, 21(2), 212–218. Retrieved from https://mail.revistahematologia.com.ar/index.php/Revista/article/view/156
Abstract
FLT3 is one of the most commonly mutated genes in AML, in about 30% of patients (pts). The most frequent mutation that confers poor prognosis is tandem duplication within the juxtamembrane domain of that receptor (FLT3-ITD). Less frequently, point mutations of the tyrosine kinase (TK) domain are detected. Sorafenib and midostaurin are inhibitors of multikinases, not specific for FLT3 mutations and have been evaluated as monotherapy with transient responses in relapsed or refractory (r/r), possibly due to lack of potency and specificity. The results of recent clinical trials show the potential benefit of the ITKs in pts with newly diagnosed AML in combination with standard chemotherapy for induction, consolidation, maintenance and posttransplantation.
References
1. Renneville A, Roumier C,Biggio V et al. Coo-perating gene mutations in acute myeloid leu-kemia: a review of the literature. Leukemia. 2008;22(5):915-931.
2. Downer H, Estey E, Grimwade D et al. Eu-ropean Leukemia Net. Diagnosis and mana-gement of AML in adults: 2017 ENL recom-mendations from an international expert panel. Blood. 2017;129(26):424-447.
3. Pacells BW, Ikeda AK, Simms-Waldrip T et al. FMS-like tyrosine kinase 3 in normal he-matopoiesis and acute myeloid leukemia. Stem Cells. 2006 24:1174-1184.
4. Meshinchi MP, Appelbaun FR. Structural and functional alterations of FLT3 in acute myeloid leukemia. Clin Cancer Res. 2009;15:4263-9.
5. Arber DA, Borowitz MJ, Cessna M et al. Initial diagnostic workup of acute leukemia: guideli-ne from the College of American Pathologists and the American Society of Hematology [pu-blished online February 22, 2017]. Arch Pathol Lab Med.
6. Zhang W, Konopleva M, Ruvolo VR et al. Sorafenib induce apoptosis of AML cells via Bim-mediated activation of the intrinsic apop-totic pathway. Leukemia. 2008;808-818.
7. Metzelder SK, Schroder T, Finck A et al. High activity of sorafenib in FLT3-positive acute myeloid leukemia synergizes with allo-immu-ne effects to induce sustained responses. Leu-kemia. 2012;26:2353-2359.
8. Man CH, Fung TK, Ho C et al. Sorafenib treat-ment of FLT3(+) acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent non responsiveness associated with the emergence of a D 835 mutation. Blood. 2012;119:5133-5143.
9. Ravandi F, Cortés J, Jones D et al. Phase I/II Study of Combination Therapy With Sorafe-nib, Idarubicin, and Cytarabine in Younger Pa-tients With Acute Myeloid Leukemia. J Clínl Oncol. 2010;28:1856-1862.
10. Ravandi F, Arana YC, Cortés JE, Levis M, Fa-der S et al. Final report of Phase II study of sorafenib, cytarabine and idarubicin for initial therapy in younger patients with acute myeloid leukemia. Leukemia2014;28:1543-1545.
11. Serve H, Krug U, Wagner R et al. Sorafenib in Combination with Intensive Chemotherapy in Elderly Patients With Acute Myeloid Leukemia: Results From a Randomized, Placebo-Control Trial. J Clin Onc. 2013;31:3110-3118.
12. Uy GL, Mandrekar S, Laumann K et al. Ad-dition of sorafenib to chemotherapy improves the overall survival of older adults with FLT3 -ITD mutated acute myeloid Leukemia (AML) (Alliance C11001). Blood. 2015;126.
13. Rollig C, Serve H, Huttmann A et al. Addi-tion of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leuke-mia (SORAML): a multicenter phase 2, ran-domized controlled trial. Lancet Oncology. 2015;16:1691-1699.
14. Ravandi F, Alatar LM, Grunwald MR et al. Phase II study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013;121:4655-4662.
15. Muppidi MR, Portwood S, Griffiths EA et al. Decitabine and sorafenib therapy in FLT-3 ITD-mutant acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2015;15:573:579.
16. Metzelder SK, Michel C, Burchert A et al. High activity of sorafenib in FLT3-ITD-posi-tive acute myeloid leukemia synergizes with allo-immune effects to induce sustained res-ponses. Leukemia. 2012;26:2353-2359.
17. Dato T, Yang X, Knapper S et al. FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo. Blood. 2011;117:3285-3293.
18. Chen YB, Li S, Lane AA et al. Phase I trial of maintenance sorafenib after allogeneic hema-topoietic stem cell transplantation for fms-like tyrosine kinase 3 internal tandem duplication acute myeloid leukemia. Biol Blood Marrow Transplant. 2014;20:2042-2048.
19. Antár A, Kharfan–Dabaja MA, Mahfouz R et al. Sorafenib maintenance appear safe and improves clinical outcomes in FLT3-ITD acu-te myeloid leukemia after allogeneic hemato-poietic cell transplantation. Clin Lymphoma Myeloma Leuk 2015;15:298-302).
20. Brunner A, Li S, Fathi A 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 Nov;175(3):496-504.
21. Battipaglia G, Ruggeri A, Massoud R et al. Efficacy and feasibility as a maintenance agent after allogeneic hematopoietic stem cell trans-plantation for Fms-like tyrosine kinase3-muta-ted acute myeloid leukemia. Cancer. 2017:1-8.
22. Stone RM, DeAngelo DJ, Klimek V et al: Pa-tients with acute myeloid leukemia and an ac-tivating mutation in FLT3 respond to a sma-ll-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005;105:54-60.
23. Fisher T, Stone RM, Deangelo DJ et al. Pha-se IIB trial of oral Midostaurin (PKC412),the FMS-liketyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor in patients with acute myeloid leukemia and high–risk myelod-ysplastic syndrome with either wild-type or mu-tated FLT3. J Clin Oncol. 2010;28:4339-4345.
24. Stone RM, Fischer T,Paquete R et al. Phase 1B study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagno-sed adult patients with acute myeloid leuke-mia. Leukemia. 2012;26:2061-2068.
25. Stone RM, Mandrekar SJ, Sanford BS et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with an FLT3 mutation. N Engl J Med. 2017 Jun;23:1-10.
26 .Cooper BW, Kindwall-Keller TL, Craig MD et al. A Phase I Study of Midostaurin and Azaciti-dine in Relapsed and Elderly AML. Clin Lym-phoma Myeloma Leuk. 2015;15(7):428-432.
27. Strati P, Kantarjian H, Ravandi F 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(4):276-281.
2. Downer H, Estey E, Grimwade D et al. Eu-ropean Leukemia Net. Diagnosis and mana-gement of AML in adults: 2017 ENL recom-mendations from an international expert panel. Blood. 2017;129(26):424-447.
3. Pacells BW, Ikeda AK, Simms-Waldrip T et al. FMS-like tyrosine kinase 3 in normal he-matopoiesis and acute myeloid leukemia. Stem Cells. 2006 24:1174-1184.
4. Meshinchi MP, Appelbaun FR. Structural and functional alterations of FLT3 in acute myeloid leukemia. Clin Cancer Res. 2009;15:4263-9.
5. Arber DA, Borowitz MJ, Cessna M et al. Initial diagnostic workup of acute leukemia: guideli-ne from the College of American Pathologists and the American Society of Hematology [pu-blished online February 22, 2017]. Arch Pathol Lab Med.
6. Zhang W, Konopleva M, Ruvolo VR et al. Sorafenib induce apoptosis of AML cells via Bim-mediated activation of the intrinsic apop-totic pathway. Leukemia. 2008;808-818.
7. Metzelder SK, Schroder T, Finck A et al. High activity of sorafenib in FLT3-positive acute myeloid leukemia synergizes with allo-immu-ne effects to induce sustained responses. Leu-kemia. 2012;26:2353-2359.
8. Man CH, Fung TK, Ho C et al. Sorafenib treat-ment of FLT3(+) acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent non responsiveness associated with the emergence of a D 835 mutation. Blood. 2012;119:5133-5143.
9. Ravandi F, Cortés J, Jones D et al. Phase I/II Study of Combination Therapy With Sorafe-nib, Idarubicin, and Cytarabine in Younger Pa-tients With Acute Myeloid Leukemia. J Clínl Oncol. 2010;28:1856-1862.
10. Ravandi F, Arana YC, Cortés JE, Levis M, Fa-der S et al. Final report of Phase II study of sorafenib, cytarabine and idarubicin for initial therapy in younger patients with acute myeloid leukemia. Leukemia2014;28:1543-1545.
11. Serve H, Krug U, Wagner R et al. Sorafenib in Combination with Intensive Chemotherapy in Elderly Patients With Acute Myeloid Leukemia: Results From a Randomized, Placebo-Control Trial. J Clin Onc. 2013;31:3110-3118.
12. Uy GL, Mandrekar S, Laumann K et al. Ad-dition of sorafenib to chemotherapy improves the overall survival of older adults with FLT3 -ITD mutated acute myeloid Leukemia (AML) (Alliance C11001). Blood. 2015;126.
13. Rollig C, Serve H, Huttmann A et al. Addi-tion of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leuke-mia (SORAML): a multicenter phase 2, ran-domized controlled trial. Lancet Oncology. 2015;16:1691-1699.
14. Ravandi F, Alatar LM, Grunwald MR et al. Phase II study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013;121:4655-4662.
15. Muppidi MR, Portwood S, Griffiths EA et al. Decitabine and sorafenib therapy in FLT-3 ITD-mutant acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2015;15:573:579.
16. Metzelder SK, Michel C, Burchert A et al. High activity of sorafenib in FLT3-ITD-posi-tive acute myeloid leukemia synergizes with allo-immune effects to induce sustained res-ponses. Leukemia. 2012;26:2353-2359.
17. Dato T, Yang X, Knapper S et al. FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo. Blood. 2011;117:3285-3293.
18. Chen YB, Li S, Lane AA et al. Phase I trial of maintenance sorafenib after allogeneic hema-topoietic stem cell transplantation for fms-like tyrosine kinase 3 internal tandem duplication acute myeloid leukemia. Biol Blood Marrow Transplant. 2014;20:2042-2048.
19. Antár A, Kharfan–Dabaja MA, Mahfouz R et al. Sorafenib maintenance appear safe and improves clinical outcomes in FLT3-ITD acu-te myeloid leukemia after allogeneic hemato-poietic cell transplantation. Clin Lymphoma Myeloma Leuk 2015;15:298-302).
20. Brunner A, Li S, Fathi A 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 Nov;175(3):496-504.
21. Battipaglia G, Ruggeri A, Massoud R et al. Efficacy and feasibility as a maintenance agent after allogeneic hematopoietic stem cell trans-plantation for Fms-like tyrosine kinase3-muta-ted acute myeloid leukemia. Cancer. 2017:1-8.
22. Stone RM, DeAngelo DJ, Klimek V et al: Pa-tients with acute myeloid leukemia and an ac-tivating mutation in FLT3 respond to a sma-ll-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005;105:54-60.
23. Fisher T, Stone RM, Deangelo DJ et al. Pha-se IIB trial of oral Midostaurin (PKC412),the FMS-liketyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor in patients with acute myeloid leukemia and high–risk myelod-ysplastic syndrome with either wild-type or mu-tated FLT3. J Clin Oncol. 2010;28:4339-4345.
24. Stone RM, Fischer T,Paquete R et al. Phase 1B study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagno-sed adult patients with acute myeloid leuke-mia. Leukemia. 2012;26:2061-2068.
25. Stone RM, Mandrekar SJ, Sanford BS et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with an FLT3 mutation. N Engl J Med. 2017 Jun;23:1-10.
26 .Cooper BW, Kindwall-Keller TL, Craig MD et al. A Phase I Study of Midostaurin and Azaciti-dine in Relapsed and Elderly AML. Clin Lym-phoma Myeloma Leuk. 2015;15(7):428-432.
27. Strati P, Kantarjian H, Ravandi F 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(4):276-281.
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