Vol 10, No 4 (2019)
Review paper
Published online: 2020-04-23
Role of midostaurin in treatment of acute myeloid leukemia harbouring FLT3 mutation
Hematologia 2019;10(4):163-173.
Abstract
Acute myeloid leukemia (AML) is a highly heterogeneous disease. Mutation with internal tandem duplication of fms-like tyrosine kinase-3 (FLT3-ITD) is one of the two most common driver mutations in AML, the presence of which is associated with a poor outcome. Midostaurin (Mido) is a multi-targeted tyrosine kinase inhibitor that potently inhibits kinase FLT3, other kinases including platelet-derived growth factor receptors α (PDGFR-α) and b (PDGFR-β), tyrosine-protein kinase Src, KIT receptor tyrosine kinase, and vascular endothelial growth factor receptor (VEGFR). Mido is the first targeted therapy to demonstrate improved outcome, and as such it represents a game-changer. The RATIFY study demonstrated significant improvements in overall survival, and in event-free survival, when Mido was added to standard chemotherapy in patients with newly diagnosed FLT3-mutated AML. This paper reviews the current clinical evidence regarding Mido and its use in the induction and treatment of relapsed or refractory disease, and maintenance setting.
Keywords: midostaurinacute myeloid leukemiafms-like tyrosine kinase 3FLT3-ITD mutationFLT3 inhibitor
References
- Yamamoto JF, Goodman MT. Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997-2002. Cancer Causes Control. 2008; 19(4): 379–390.
- 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.
- 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.
- Ley TJ, Miller C, Ding Li, et al. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013; 368(22): 2059–2074.
- Matthews W, Jordan CT, Wiegand GW, et al. A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell. 1991; 65(7): 1143–1152.
- Rosnet O, Marchetto S, deLapeyriere O, et al. Murine Flt3, a gene encoding a novel tyrosine kinase receptor of the PDGFR/CSF1R family. Oncogene. 1991; 6(9): 1641–1650.
- Rosnet O, Matteï MG, Marchetto S, et al. Isolation and chromosomal localization of a novel FMS-like tyrosine kinase gene. Genomics. 1991; 9(2): 380–385.
- Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood. 2002; 100(5): 1532–1542.
- Rosnet O, Birnbaum D. Hematopoietic receptors of class III receptor-type tyrosine kinases. Crit Rev Oncog. 1993; 4(6): 595–613.
- Tsapogas P, Mooney CJ, Brown G, et al. The cytokine Flt3-ligand in normal and malignant hematopoiesis. Int J Mol Sci. 2017; 18(6).
- Schnittger S, Schoch C, Dugas M, et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood. 2002; 100(1): 59–66.
- Fröhling S, Schlenk RF, Breitruck J, et al. AML Study Group Ulm. Acute myeloid leukemia. 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): 4372–4380.
- Kottaridis PD, Gale RE, Frew ME, 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): 1752–1759.
- Bullinger L, Döhner K, Döhner H. Genomics of acute myeloid leukemia diagnosis and pathways. J Clin Oncol. 2017; 35(9): 934–946.
- Schlenk RF, Döhner K, Krauter J, et al. German-Austrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008; 358(18): 1909–1918.
- Kiyoi H, Naoe T, Nakano Y, et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood. 1999; 93(9): 3074–3080.
- Port M, Böttcher M, Thol F, et al. Prognostic significance of FLT3 internal tandem duplication, nucleophosmin 1, and CEBPA gene mutations for acute myeloid leukemia patients with normal karyotype and younger than 60 years: a systematic review and meta-analysis. Ann Hematol. 2014; 93(8): 1279–1286.
- Kayser S, Schlenk RF, Londono MC, et al. German-Austrian AML Study Group (AMLSG). Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood. 2009; 114(12): 2386–2392.
- Bornhäuser M, Illmer T, Schaich M, et al. AML SHG 96 study group. Improved outcome after stem-cell transplantation in FLT3/ITD-positive AML. Blood. 2007; 109(5): 2264–5; author reply 2265.
- Brunet S, Labopin M, Esteve J, et al. Impact of FLT3 internal tandem duplication on the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first remission: a retrospective analysis. J Clin Oncol. 2012; 30(7): 735–741.
- Gale RE, Hills R, Kottaridis PD, et al. No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials. Blood. 2005; 106(10): 3658–3665.
- Bacher U, Haferlach C, Kern W, et al. Prognostic relevance of FLT3-TKD mutations in AML: the combination matters--an analysis of 3082 patients. Blood. 2008; 111(5): 2527–2537.
- Pratz KW, Sato T, Murphy KM, et al. FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML. Blood. 2010; 115(7): 1425–1432.
- McCormick SR, McCormick MJ, Grutkoski PS, et al. FLT3 mutations at diagnosis and relapse in acute myeloid leukemia: cytogenetic and pathologic correlations, including cuplike blast morphology. Arch Pathol Lab Med. 2010; 134(8): 1143–1151.
- Warren M, Luthra R, Yin CC, et al. Clinical impact of change of FLT3 mutation status in acute myeloid leukemia patients. Mod Pathol. 2012; 25(10): 1405–1412.
- Wagner K, Damm F, Thol F, et al. FLT3-internal tandem duplication and age are the major prognostic factors in patients with relapsed acute myeloid leukemia with normal karyotype. Haematologica. 2011; 96(5): 681–686.
- Ke Y-Y, Singh VK, Coumar MS, et al. Homology modeling of DFG-in FMS-like tyrosine kinase 3 (FLT3) and structure-based virtual screening for inhibitor identification. Sci Rep. 2015; 5: 11702.
- Smith CC, Lin K, Stecula A, et al. FLT3 D835 mutations confer differential resistance to type II FLT3 inhibitors. Leukemia. 2015; 29(12): 2390–2392.
- Fabbro D, Ruetz S, Bodis S, et al. PKC412 — a protein kinase inhibitor with a broad therapeutic potential. Anticancer Drug Des. 2000; 15(1): 17–28.
- Weisberg E, Boulton C, Kelly LM, et al. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell. 2002; 1(5): 433–443.
- Perl AE, Altman JK, Cortes J, 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): 1061–1075.
- Levis M, Brown P, Smith BD, et al. Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Blood. 2006; 108(10): 3477–3483.
- Stone RM, DeAngelo DJ, Klimek V, et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005; 105(1): 54–60.
- Fischer T, Stone RM, Deangelo DJ, et al. Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol. 2010; 28(28): 4339–4345.
- Stone RM, 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): 2061–2068.
- 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.
- Schlenk RF, Weber D, Fiedler W, et al. German-Austrian AML Study Group. Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with -ITD. Blood. 2019; 133(8): 840–851.
- Williams CB, Kambhampati S, Fiskus W, et al. Preclinical and phase I results of decitabine in combination with midostaurin (PKC412) for newly diagnosed elderly or relapsed/refractory adult patients with acute myeloid leukemia. Pharmacotherapy. 2013; 33(12): 1341–1352.
- 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.
- Cooper BW, Kindwall-Keller TL, Craig MD, et al. A phase I study of midostaurin and azacitidine in relapsed and elderly AML patients. Clin Lymphoma Myeloma Leuk. 2015; 15(7): 428–432.e2.
- Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015; 373(12): 1136–1152.
- Lin P-H, Lin C-C, Yang H-I, et al. Prognostic impact of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia patients with internal tandem duplication of FLT3. Leuk Res. 2013; 37(3): 287–292.
- 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.
- Labouré G, Dulucq S, Labopin M, et al. Potent graft-versus-leukemia effect after reduced-intensity allogeneic SCT for intermediate-risk AML with FLT3-ITD or wild-type NPM1 and CEBPA without FLT3-ITD. Biol Blood Marrow Transplant. 2012; 18(12): 1845–1850.
- Ma Y, Wu Y, Shen Z, et al. Is allogeneic transplantation really the best treatment for FLT3/ITD-positive acute myeloid leukemia? A systematic review. Clin Transplant. 2015; 29(2): 149–160.
- Maziarz RT, Fernandez H, Patnaik M, et al. Radius: midostaurin (mido) plus standard of care (SOC) after allogeneic stem cell transplant (alloSCT) in patients (pts) with FLT3-internal tandem duplication (ITD)-mutated acute myeloid leukemia (AML). Biol Blood Marrow Transplant. 2019; 25(3): S11–S12.
- Propper DJ, McDonald AC, Man A, et al. Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C. J Clin Oncol. 2001; 19(5): 1485–1492.
- Charakterystyka produktu leczniczego. https://www.novartis.pl/system/files/product-info/rydapt_chpl_2018_04.pdf (2.01.2020).
- Dutreix C, Munarini F, Lorenzo S, et al. Investigation into CYP3A4-mediated drug-drug interactions on midostaurin in healthy volunteers. Cancer Chemother Pharmacol. 2013; 72(6): 1223–1234.
- ClinicalTrials.gov. (2.01.2020).
- Weisberg E, Barrett R, Liu Q, et al. FLT3 inhibition and mechanisms of drug resistance in mutant FLT3-positive AML. Drug Resist Updat. 2009; 12(3): 81–89.
- Assi R, Ravandi F. FLT3 inhibitors in acute myeloid leukemia: choosing the best when the optimal does not exist. Am J Hematol. 2018; 93(4): 553–563.
