New treatments for systemic mastocytosis in 2025

To provide an accessible, comprehensive overview of past, present, imminent, and future therapies for systemic mastocytosis.

Based on recent trials, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved two drugs for treating advanced systemic mastocytosis: avapritinib and midostaurin. The FDA also approved imatinib for selected cases of aggressive systemic mastocytosis without the D816V c-Kit mutation. Moreover, for the first time, a cytoreductive molecule, avapritinib, has been approved for patients with indolent systemic mastocytosis.

Despite the considerable therapeutic progress in recent years, systemic mastocytosis is an incurable disease. In the last 20 years, the management of systemic mastocytosis has transformed from a one-size-fits-all approach, characterized by nonspecific cytoreductive drugs, to a tailored strategy focused on increasingly precise molecular targets, with the most notable example being the KIT inhibitors. Recently, the FDA and EMA have approved two drugs for treating systemic mastocytosis: avapritinib and midostaurin. Moreover, numerous trials are currently assessing the efficacy of new molecules: most are testing new-generation KIT inhibitors (ripretinib, bezuclastinib, elenestinib, masitinib, nintedanib), others focusing on Bruton's kinase (TL-895), interleukin-6 (sarilumab), sialic acid-binding immunoglobulin-like lectin-8 (lirentelimab), mTOR and CD33, among others. Real-life data are needed to confirm preliminary preclinical results.