Daniel DeAngelo, MD, PhD, Chief, Division of Leukemia, Dana-Farber Cancer Institute, discusses the mechanism of action of avapritinib, a kinase inhibitor recently approved for the treatment of advanced systemic mastocytosis (SM).

SM is a rare, hematologic disorder most often caused by a mutation in the KIT D816V gene. The disorder is characterized by uncontrolled mast cell proliferation and activation across multiple organ systems, resulting in chronic, severe, and often unpredictable symptoms and extensive organ damage. A minority of SM patients have advanced SM, which encompasses a group of high-risk SM subtypes including aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).

As Dr. DeAngelo explains, avapritinib is a potent inhibitor of the KIT-D816V mutation. Another drug that has been indicated for the treatment of advanced SM is midostaurin, which is a multi-targeted protein kinase inhibitor. The two differ in that avapritinib directly targets the KIT-D816V mutation while midostaurin inhibits multiple tyrosine kinases. Avapritinib works by targeting mast cells carrying the KIT D816V mutation and inhibiting the protein kinases. This interrupts the signalling cascade which leads to uncontrolled mast cell production. As Dr. DeAngelo puts it, affected cells are “addicted” to the signal from the mutated protein and, without that signal, these cells will die. This ultimately blocks the proliferation of mast cells, which treats the disease.

To learn more about SM and other rare hematologic disorders, visit checkrare.com/diseases/hematologic-disorders/