title: Antileukemic effects of midostaurin in acute myeloid leukemia - the possible importance of multikinase inhibition in leukemic as well as nonleukemic stromal cells.
abstract: Midostaurin is a multikinase inhibitor that inhibits receptor tyrosine kinases (Flt3, CD117/c-kit, platelet-derived growth factor receptor, vascular endothelial growth factor receptor 2) as well as non-receptor tyrosine kinases (Frg, Src, Syk, Protein kinase C). Combination of midostaurin with conventional intensive chemotherapy followed by one year maintenance monotherapy was recently reported to improve the survival of acute myeloid leukemia (AML) patients with Flt3 mutations. Areas covered: Relevant publications were identified through literature searches in the PubMed database. We searched for (i) original articles describing the results from clinical studies; (ii) published articles describing the importance of midostaurin-inhibited kinases for leukemogenesis and chemosensitivity. Expert opinion: Midostaurin monotherapy is well tolerated, combined with conventional chemotherapy gastrointestinal toxicity increases significantly. Midostaurin alters anthracycline pharmacokinetics. Furthermore, its antileukemic effects may not only be mediated through Flt3 inhibition alone; the inhibition of other kinases may also be important for the overall antileukemic effect. Midostaurin may then have direct effects on the leukemic cells but also indirect antileukemic effects through inhibition of the AML-supporting effects of neighboring stromal cells in the bone marrow microenvironment. Midostaurin may thus be used in combination with intensive chemotherapy, as maintenance treatment or as disease-stabilizing treatment for elderly unfit patients.
authors.affiliation: a Section for Hematology, Department of Medicine , Haukeland University Hospital , Bergen , Norway.
authors.forename: Tor Henrik
authors.initials: TH
authors.lastname: Tvedt
authors.affiliation: b Section for Hematology , Institute of Clinical Science, University of Bergen , Bergen , Norway.
authors.forename: Ina
authors.initials: I
authors.lastname: Nepstad
authors.affiliation: a Section for Hematology, Department of Medicine , Haukeland University Hospital , Bergen , Norway.|b Section for Hematology , Institute of Clinical Science, University of Bergen , Bergen , Norway.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Bruserud
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019311:Staurosporine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D015996:Survival Rate
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D019311:Staurosporine; C059539:midostaurin
keywords: 4ʹ-N-benzoylstaurosporine; Flt3 ligand; Platelet derived growth factor; Protein kinase c; Protein tyrosine kinase; acute myeloid leukemia; vascular endothelia growth factor