Abstract

Midostaurin is a multikinase tyrosine kinase inhibitor acting against targets known to be expressed in hematologic malignancies, especially acute myeloid leukemia. Midostaurin combined with chemotherapy followed by single-agent maintenance therapy elicited statistically significant and clinically meaningful improvement in overall survival versus placebo in patients with newly diagnosed FLT3-mutant acute myeloid leukemia. Although gastrointestinal events were more common with midostaurin, overall the drug was relatively well tolerated. Of note, midostaurin is metabolized by cytochrome P450–3A4 (CYP3A4); therefore, concomitant strong CYP3A4 inhibitors should be used with caution. Preliminary safety results from an ongoing trial evaluating midostaurin as a single agent in the post-transplant setting are encouraging. In addition, studies have evaluated its safety and efficacy in advanced systemic mastocytosis.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1 Medinger M, Lengerke C, Passweg J. Novel therapeutic options in acute myeloid leukemia. Leuk. Res. Rep. 6, 39–49 (2016).Medline, Google Scholar
2 Swerdlow SH, Campo E, Harris NL et al. World Health Organization classification of tumours of haematopoietic and lymphoid tissues. In: WHO Classification of Tumours (4th Edition). (Volume 2). IARC, 109–138 (2008).Google Scholar
3 Arber DA, Orazi A, Hasserjian R et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127(20), 2391–2405 (2016).Crossref, Medline, CAS, Google Scholar
4 Papaemmanuil E, Gerstung M, Bullinger L et al. Genomic classification and prognosis in acute myeloid leukemia. N. Engl. J. Med. 374(23), 2209–2221 (2016).Crossref, Medline, CAS, Google Scholar
5 Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood 100(5), 1532–1542 (2002).Crossref, Medline, CAS, Google Scholar
6 Pemmaraju N, Kantarjian H, Ravandi F, Cortes J. FLT3 inhibitors in the treatment of acute myeloid leukemia: the start of an era? Cancer 117(15), 3293–3304 (2011).Crossref, Medline, CAS, Google Scholar
7 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 98(6), 1752–1759 (2001).Crossref, Medline, CAS, Google Scholar
8 Kayser S, Schlenk RF, Londono MC et al. Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood 114(12), 2386–2392 (2009).Crossref, Medline, CAS, Google Scholar
9 Konig H, Levis M. Targeting FLT3 to treat leukemia. Expert Opin. Ther. Targets 19(1), 37–54 (2015).Crossref, Medline, CAS, Google Scholar
10 Schneider F, Hoster E, Schneider S et al. Age-dependent frequencies of NPM1 mutations and FLT3-ITD in patients with normal karyotype AML (NK-AML). Ann. Hematol. 91(1), 9–18 (2012).Crossref, Medline, CAS, Google Scholar
11 Schlenk RF, Kayser S, Bullinger L et al. Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood 124(23), 3441–3449 (2014).Crossref, Medline, CAS, Google Scholar
12 Mead AJ, Linch DC, Hills RK, Wheatley K, Burnett AK, Gale RE. 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 110(4), 1262–1270 (2007).Crossref, Medline, CAS, Google Scholar
13 Moreno I, Martin G, Bolufer P et al. Incidence and prognostic value of FLT3 internal tandem duplication and D835 mutations in acute myeloid leukemia. Haematologica 88(1), 19–24 (2003).Medline, CAS, Google Scholar
14 National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: acute myeloid leukemia. V2 (2016). www.nccn.org/professionals/physician_gls/f_guidelines.aspGoogle Scholar
15 Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N. Engl. J. Med. 373(12), 1136–1152 (2015).Crossref, Medline, Google Scholar
16 Rydapt (midostaurin) [package insert]: Novartis Pharmaceuticals (NJ, USA) (April 2017).Google Scholar
17 Zwaan CM, Söderhäll S, Brethon B et al. A Phase I/II, open-label, dose-escalation study of midostaurin in pediatric patients with relapsed or refractory acute myeloid leukemia: final results of study ITCC-024 (CPKC412A2114). Presented at: American Society of Hematology. Orlando, FL, USA, 5–8 December 2015.Google Scholar
18 Backman JT, Filppula AM, Niemi M, Neuvonen PJ. Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol. Rev. 68(1), 168–241 (2016).Crossref, Medline, Google Scholar
19 Propper DJ, McDonald AC, Man A et al. Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C. J. Clin. Oncol. 19(5), 1485–1492 (2001). • Proof-of-concept study evaluating the pharmacokinetics and safety profile of midostaurin monotherapy in patients with advanced solid tumors.Crossref, Medline, CAS, Google Scholar
20 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 108(10), 3477–3483 (2006). • A description of the assay used to measure inhibition of FLT3 phosphorylation in patients receiving midostaurin.Crossref, Medline, CAS, Google Scholar
21 Yin OQ, Wang Y, Schran H. A mechanism-based population pharmacokinetic model for characterizing time-dependent pharmacokinetics of midostaurin and its metabolites in human subjects. Clin. Pharmacokinet. 47(12), 807–816 (2008).Crossref, Medline, CAS, Google Scholar
22 Wang Y, Yin OQ, Graf P, Kisicki JC, Schran H. Dose- and time-dependent pharmacokinetics of midostaurin in patients with diabetes mellitus. J. Clin. Pharmacol. 48(6), 763–775 (2008).Crossref, Medline, CAS, Google Scholar
23 Dutreix C, Huntsman Labed A, Roesel J, Lanza C, Wang Y. Midostaurin: review of pharmacokinetics (PK) and PK/pharmacodynamic (PD) relationship in AML/MDS patients. J. Clin. Oncol. 27(15S), e14540 (2009).Crossref, Google Scholar
24 Fabbro D, Ruetz S, Bodis S et al. PKC412 – a protein kinase inhibitor with a broad therapeutic potential. Anticancer Drug Des. 15(1), 17–28 (2000).Medline, CAS, Google Scholar
25 Dutreix C, Munarini F, Lorenzo S, Roesel J, Wang Y. Investigation of CYP3A4-mediated drug–drug interactions on midostaurin in healthy volunteers. Cancer Chemother. Pharmacol. 72(6), 1223–1234 (2013). • Evaluated the effects of CYP3A4 inhibition and induction, using ketoconazole and rifamicin, respectively, on midostaurin exposure in healthy volunteers.Crossref, Medline, CAS, Google Scholar
26 Chau MM, Kong DC, van Hal SJ et al. Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy, 2014. Intern. Med. J. 44(12b), 1364–1388 (2014).Crossref, Medline, CAS, Google Scholar
27 Karaman MW, Herrgard S, Treiber DK et al. A quantitative analysis of kinase inhibitor selectivity. Nat. Biotechnol. 26(1), 127–132 (2008). • A summary of the in vitro targets of midostaurin, including FLT3, PKC, KIT and PDGFR.Crossref, Medline, CAS, Google Scholar
28 Zarrinkar PP, Gunawardane RN, Cramer MD et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood 114(14), 2984–2992 (2009).Crossref, Medline, CAS, Google Scholar
29 Schlenk RF, Döhner K, Salih H et al. Midostaurin in combination with intensive induction and as single agent maintenance therapy after consolidation therapy with allogeneic hematopoietic stem cell transplantation or high-dose cytarabine (NCT01477606). Presented at: American Society of Hematology. Orlando, FL, USA, 5–8 December 2015.Crossref, Google Scholar
30 Theis F, Paschka P, Weber D et al. Pharmacodynamic monitoring of the efficacy of targeted therapy with midostaurin by plasma inhibitor activity (PIA) analysis in FLT3-ITD positive AML patients within the AMLSG 16–10 trial: a study of the AML Study Group (AMLSG). Presented at: American Society of Hematology. Orlando, FL, USA, 5–8 December 2015.Crossref, Google Scholar
31 Schlenk RF, Fiedler W, Salih HR et al. Impact of age and midostaurin-dose on response and outcome in acute myeloid leukemia with FLT3-ITD: Interim-analyses of the AMLSG 16–10 trial. Presented at: American Society of Hematology. San Diego, CA, USA, 9–12 December 2016.Crossref, Google Scholar
32 Stone RM, Mandrekar S, Sandord BL et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N. Engl. J. Med. doi:10.1056/NEJMoa1614359 (2017) (Epub ahead of print). • First report of the Phase III RATIFY trial, demonstrating improved survival with midostaurin in patients with FLT3-mutated acute myeloid leukemia (AML).Crossref, Google Scholar
33 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 26(9), 2061–2068 (2012). • First trial to show high rates of complete remission in patients with newly diagnosed AML, including both FLT3-WT and FLT3-mutated AML, upon treatment with midostaurin in combination with chemotherapy.Crossref, Medline, CAS, Google Scholar
34 Maziarz RT, Patnaik MM, Scott BL et al. RADIUS: a Phase II, randomized trial of standard of care with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant in patients with FLT3-ITD–mutated acute myeloid leukemia. Presented at: American Society of Hematology. San Diego, CA, USA, 9–12 December 2016. • Interim safety analysis of the ongoing RADIUS trial, the first trial to evaluate midostaurin in the post-transplant setting.Crossref, Google Scholar
35 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. 28(28), 4339–4345 (2010). • Earlier study evaluating midostaurin monotherapy in patients with FLT3-WT or FLT3-mutated AML; results supported moving forward with trials in combination with chemotherapy.Crossref, Medline, CAS, Google Scholar
36 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 105(1), 54–60 (2005).Crossref, Medline, CAS, Google Scholar
37 del Corral A, Dutreix C, Huntsman-Labed A et al. Midostaurin does not prolong cardiac repolarization defined in a thorough electrocardiogram trial in healthy volunteers. Cancer Chemother. Pharmacol. 69(5), 1255–1263 (2012).Crossref, Medline, CAS, Google Scholar
38 Peter B, Winter GE, Blatt K et al. Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predict distinct effects on activation and growth. Leukemia 30(2), 464–472(2015).Crossref, Medline, Google Scholar
39 Stone RM, Döhner H, Ehninger G et al. CALGB 10603 (RATIFY): a randomized Phase III study of induction (daunorubicin/cytarabine) and consolidation (high-dose cytarabine) chemotherapy combined with midostaurin or placebo in treatment-naive patients with FLT3 mutated AML. Presented at: American Society of Clinical Oncology. Chicago, IL, USA, 3–7 June 2011.Crossref, Google Scholar
40 National Marrow Donor Program: Trends in HCT for Allogeneic Diseases in the U.S., 2000–2015. 15 May 2017.Google Scholar
41 Ravandi F, Ritchie EK, Sayar H et al. Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukemia (VALOR): a randomised, controlled, double-blind, multinational, Phase III study. Lancet Oncol. 16(9), 1025–1036 (2015).Crossref, Medline, CAS, Google Scholar
42 Maziarz RT, Scott BL, Mohan SR et al. A Phase II, randomized trial of standard of care with or without midostaurin to prevent relapse following allogeneic stem cell transplantation in patients with FLT3-ITD mutated acute myeloid leukemia. Presented at: American Society of Clinical Oncology. Chicago, IL, USA, 29 May–2 June 2015.Crossref, Google Scholar
43 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. 15(7), 428–432 (2015).Crossref, Medline, Google Scholar
44 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. 90(4), 276–281 (2015).Crossref, Medline, CAS, Google Scholar
45 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 33(12), 1341–1352 (2013).Crossref, Medline, CAS, Google Scholar
46 Ramsingh G, Westervelt P, McBride A et al. Phase I study of cladribine, cytarabine, granulocyte colony stimulating factor (CLAG regimen) and midostaurin and all-trans retinoic acid in relapsed/refractory AML. Int. J. Hematol. 99(3), 272–278 (2014).Crossref, Medline, Google Scholar
47 Walker AR, Wang H, Walsh K et al. Midostaurin, bortezomib and MEC in relapsed/refractory acute myeloid leukemia. Leuk. Lymphoma 57(9), 2100–2108 (2016).Crossref, Medline, CAS, Google Scholar
48 Stone RM, Driscoll C, Galinsky I et al. A Phase I trial of escalating dose of the rapamycin analog everolimus in combination with the kinase inhibitor midostaurin in patients (pts) with relapsed, refractory or poor prognosis acute myeloid leukemia (AML). Blood 120(21), 3627 (2012).Crossref, Medline, Google Scholar
49 Gotlib J, DeAngelo DJ, George TI et al. KIT inhibitor midostaurin exhibits a high rate of clinically meaningful and durable responses in advanced systemic mastocytosis: report of a fully accrued Phase II trial. American Society of Hematology. Orlando, FL, USA, 6–9 December 2010.Crossref, Google Scholar
50 Gotlib J, Kluin-Nelemans HC, George TI et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N. Engl. J. Med. 374(26), 2530–2541 (2016).Crossref, Medline, CAS, Google Scholar
51 Horny HP, Metcalfe DD, Bennet JM et al. Mastocytosis. In: WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. Swerdlow SH, Campo E, Harris NL (Eds), International Agency for Research and Cancer (IARC), Lyon, France, 54–63 (2008).Google Scholar
52 Lim KH, Tefferi A, Lasho TL et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood 113(23), 5727–5736 (2009).Crossref, Medline, CAS, Google Scholar
53 Garcia-Montero AC, Jara-Acevedo M, Teodosio C et al. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood 108(7), 2366–2372 (2006).Crossref, Medline, CAS, Google Scholar
54 Fischer T, Kantarjian H, Feldman E et al. Midostaurin (mido) demonstrates a favorable safety profile in older patients (pts) with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Presented at: 18th Congress of the European Hematology Association. Stockholm, Sweden, 13–16 June 2013.Google Scholar
55 United States National Institutes of Health (NIH). www.clinicaltrials.gov.2012Google Scholar
56 Annesley CE, Brown P. The biology and targeting of FLT3 in pediatric leukemia. Front. Oncol. 4, 263 (2014).Crossref, Medline, Google Scholar
57 Armstrong SA, Staunton JE, Silverman LB et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat. Genet. 30(1), 41–47 (2002).Crossref, Medline, CAS, Google Scholar
58 Neumann M, Coskun E, Fransecky L et al. FLT3 mutations in early T-cell precursor ALL characterize a stem cell like leukemia and imply the clinical use of tyrosine kinase inhibitors. PLoS ONE 8(1), e53190 (2013).Crossref, Medline, CAS, Google Scholar
59 von Bubnoff N, Engh RA, Åberg E, Sänger J, Peschel C, Duyster J. FMS-like tyrosine kinase 3–internal tandem duplication tyrosine kinase inhibitors display a nonoverlapping profile of resistance mutations in vitro. Cancer Res 69(7), 3032–3041 (2009).Crossref, Medline, CAS, Google Scholar
60 Barry EV, Clark JJ, Cools J, Roesel J, Gilliland DG. Uniform sensitivity of FLT3 activation loop mutants to the tyrosine kinase inhibitor midostaurin. Blood 110(13), 4476–4479 (2007).Crossref, Medline, CAS, Google Scholar
61 Kindler T, Lipka DB, Fischer T. FLT3 as a therapeutic target in AML: still challenging after all these years. Blood 116(24), 5089–5102 (2010).Crossref, Medline, CAS, Google Scholar
62 Nexavar (sorafenib), package insert. Bayer HealthCare Pharmaceuticals: NJ, USA (June 2016).Google Scholar
63 Weisberg E, Barrett R, Liu Q, Stone R, Gray N, Griffin JD. FLT3 inhibition and mechanisms of drug resistance in mutant FLT3-positive AML. Drug Resist Updat 12(3), 81–89 (2009).Crossref, Medline, CAS, Google Scholar
64 Altman JK, Perl AE, Cortes JE et al. Antileukemic activity and tolerability of ASP2215 80mg and greater in FLT3 mutation-positive subjects with relapsed or refractory acute myeloid leukemia: results from a Phase I/II, open-label, dose-escalation/dose-response study. Presented at: American Society of Hematology. Orlando, FL, USA, 5–8 December 2015.Crossref, Google Scholar
65 Mori M, Kaneko N, Ueno Y et al. ASP2215, a novel FLT3/AXL inhibitor: preclinical evaluation in acute myeloid leukemia (AML). Presented at: American Society of Clinical Oncology. Chicago, IL, USA, 30 May–3 June 2014.Crossref, Google Scholar
66 Levis MJ, Perl AE, Dombret H et al. Final results of a Phase II open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia after second-line chemotherapy or hematopoietic stem cell transplantation. Presented at: American Society of Hematology. Orlando, FL, USA, 5–8 December 2012.Google Scholar
67 Schiller GJ, Tallman MS, Goldberg SL et al. Final results of a randomized Phase II study showing the clinical benefit of quizartinib (AC220) in patients with FLT3-ITD positive relapsed or refractory acute myeloid leukemia. Presented at: American Society of Clinical Oncology. Chicago, IL, USA, 30 May–3 June 2014.Google Scholar
68 Cortes JE, Ravandi F, Garcia-Manero G et al. Dose escalation study of crenolanib in combination with high dose cytarabine/idarubicin salvage chemotherapy in multiple relapsed FLT3 positive AML. Presented at: 21st Congress of the European Hematology Association. Copenhagen, Denmark, 9–12 June 2016.Google Scholar
69 Wang ES, Stone RM, Tallman MS, Walter RB, Eckardt JR, Collins R. Crenolanib, a type I FLT3 TKI, can be safely combined with cytarabine and anthracycline induction chemotherapy and results in high response rates in patients with newly diagnosed FLT3 mutant acute myeloid leukemia (AML). Presented at: American Society of Hematology. San Diego, CA, USA, 9–12 December 2016.Crossref, Google Scholar
70 Galanis A, Levis M. Inhibition of c-Kit by tyrosine kinase inhibitors. Haematologica 100(3), e77–e79 (2014).Crossref, Medline, Google Scholar

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Published online 14 June 2017

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Financial & competing interests disclosure

This review was funded by the NIH. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

The author thanks R Boehme, J Gooch and P Tuttle from ArticulateScience, LLC, for medical editorial assistance. Medical editorial assistance was supported by Novartis Pharmaceuticals.

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Midostaurin for the treatment of acute myeloid leukemia

Abstract

References