Acute myeloid leukemia (AML) is a
hematologic malignancy that carries a poor prognosis and has garnered few treatment advances in the last few decades. Mutation of the internal tandem duplication (ITD) region of
fms-like tyrosine kinase (FLT3) is considered high risk for decreased response and overall survival.
Midostaurin is a Type III
receptor tyrosine kinase inhibitor found to inhibit FLT3 and other
receptor tyrosine kinases, including
platelet-derived growth factor receptors,
cyclin-dependent kinase 1, src, c-kit, and
vascular endothelial growth factor receptor. In preclinical studies,
midostaurin exhibited broad-spectrum antitumor activity toward a wide range of
tumor xenografts, as well as an FLT3-ITD-driven mouse model of
myelodysplastic syndrome (MDS).
Midostaurin is orally administered and generally well tolerated as a single agent; hematologic toxicity increases substantially when administered in combination with standard
induction chemotherapy. Clinical trials primarily have focused on relapsed/refractory AML and MDS and included single- and combination-agent studies. Administration of
midostaurin to relapsed/refractory MDS and AML patients confers a robust anti-blast response sufficient to bridge a minority of patients to transplant. In combination with
histone deacetylase inhibitors, responses appear comparable to historic controls, while the addition of
midostaurin to standard
induction chemotherapy may prolong survival in FLT3-ITD mutant patients. The response of some wild-type (WT)-FLT3 patients to
midostaurin therapy is consistent with
midostaurin's ability to inhibit WT-FLT3 in vitro, and also may reflect overexpression of WT-FLT3 in those patients and/or off-target effects such as inhibition of
kinases other than FLT3.
Midostaurin represents a well-tolerated, easily administered oral agent with the potential to bridge mutant and WT-FLT3 AML patients to transplant and possibly deepen response to
induction chemotherapy. Ongoing studies are investigating
midostaurin's role in pretransplant induction and posttransplant consolidation
therapy.