Midostaurin for the treatment of adult patients with newly diagnosed acute myeloid leukemia that is FLT3 mutation-positive

Abstract

Midostaurin is a multitargeted tyrosine kinase inhibitor (TKI) that potently inhibits activated fms-related tyrosine kinase 3 (FLT3) in the nanomolar range and other kinases including platelet-derived growth factor receptors α (PDGFR- α) and β (PDGFR- β), cyclin-dependent kinase, proto-oncogene tyrosine-protein kinase Src, tyrosine-protein kinase Fgr, spleen tyrosine kinase (Syk), KIT proto-oncogene receptor tyrosine kinase and the major vascular endothelial growth factor receptor (VEGFR). Activating mutations in FLT3, which is one of the more common acute myeloid leukemia (AML) mutations, particularly those that result in an FLT3-ITD (internal tandem duplication) mutation, confer poor prognosis and represent a therapeutic target. Small molecule TKIs that vary in potency and selectivity for FLT3 are under investigation. Here, we provide a comprehensive review of the preclinical and clinical activity of midostaurin, a recently approved drug indicated to be used in combination with cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy for the treatment of AML featuring an FLT3 mutation.

Multi-parametric single cell evaluation defines distinct drug responses in healthy hematologic cells that are retained in corresponding malignant cell types

“…In our primary screen, we observed selective depletion of B and NK cells in PB samples (n=3) treated with midostaurin ( Figure 2A and Supplementary Figure S8A), which is approved for treating FLT3 mutated AML and systemic mastocytosis 24,25 Figure 4A). CD34+CD38+/blast cells from all FLT3-ITD mutated AML samples were sensitive (median IC 50, 554 nM) ( Figure 4B).…”

Molecular Mechanisms of Anticancer Activity of N-Glycosides of Indolocarbazoles LCS-1208 and LCS-1269

“…The second branch is the inhibition of serine/threonine and tyrosine protein kinases that implies direct modulation of the key signal transduction pathways in cancer cells [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. This molecular mechanism is mainly realized by staurosporine and its derivatives.…”