Clinical Validation of KIT Inhibition in Advanced Systemic Mastocytosis.

PURPOSE OF REVIEW: We discuss recent developments in the treatment of advanced systemic mastocytosis (advSM) with inhibitors of the KIT receptor tyrosine kinase.

RECENT FINDINGS: advSM is a heterogeneous group of neoplasms of poor prognosis characterized by the accumulation of neoplastic mast cells. The canonical KIT D816V mutation is present in approximately 90% of SM patients, and its detection is critical for both diagnosis and therapeutic decision-making. The multikinase/KIT inhibitor midostaurin was recently approved for advSM. This agent can reverse SM-related organ damage and disease symptoms, and decrease the bone marrow mast cell burden and splenomegaly. However, complete remissions are rare and durability of responses is variable. Potent and selective KIT D816V inhibitors including avapritinib (BLU-285) and DCC-2618 have entered clinical trials, and rational combination strategies are under development. The clinical efficacy of KIT inhibitors validate KIT as a key oncogenic driver in mast cell neoplasms. An improved understanding of the genetic heterogeneity beyond KIT will help inform the dynamics of response and relapse.