Advancing Treatment in Indolent Systemic Mastocytosis: Updates at EAACI 2025 - Episode 10
Pipeline Therapies for Indolent Systemic Mastocytosis: Growing Confidence in the Treatment Landscape of Indolent Systemic Mastocytosis
A panelist discusses how they have growing confidence in pipeline therapies for indolent systemic mastocytosis based on their experience with the PIONEER trials, particularly noting improvements in patient symptoms and quality of life, while expressing hope for additional data on the drug's effects on bone health and anaphylactic events, and describing other investigational treatments including selective inhibitors and Bruton tyrosine kinase inhibitors currently in clinical trials.
Expanding Treatment Options: Pipeline Therapies and Growing Confidence in ISM Management
The clinical experience with avapritinib has generated substantial confidence in targeted therapy approaches for indolent systemic mastocytosis (ISM), based on documented patient improvements in symptoms and quality of life. Health care providers who have participated in the PIONEER trial from its inception have witnessed firsthand the transformative effects of KIT inhibition on patient outcomes. This growing body of evidence is expected to encourage broader adoption among health care providers who may have been hesitant to prescribe newer targeted therapies for patients with persistent symptoms despite standard treatments. Future research priorities include investigating avapritinib's effects on osteoporosis, which affects approximately one-third of ISM patients and could represent a major disease-modifying benefit, as well as studying its impact on anaphylactic events, whether triggered by identifiable allergens like insect stings or occurring as idiopathic episodes.
The therapeutic landscape for ISM is expanding with several promising pipeline treatments currently under investigation. Two additional selective KIT D816V inhibitors, bezuclastinib and elenestinib, are advancing through clinical trials, offering potentially similar mechanisms of action to avapritinib. Bezuclastinib is being evaluated in the SUMMIT trial for ISM patients, though enrollment has closed, while elenestinib is being tested for both ISM and advanced mastocytosis populations. Notably, these alternative KIT inhibitors do not cross the blood-brain barrier, which may offer different safety profiles compared to avapritinib. An expanded access program for bezuclastinib provides treatment options for ISM patients outside of clinical trial enrollment, though neither drug currently holds FDA approval for ISM treatment.
Beyond KIT inhibition, novel therapeutic approaches are exploring alternative pathways involved in mast cell activation. A particularly interesting development is TLR-895, a small molecule inhibitor targeting Bruton tyrosine kinase (BTK), which plays a crucial role in mast cell activation. Unlike KIT inhibitors that reduce mast cell burden, BTK inhibition primarily focuses on preventing mast cell activation without significantly impacting overall mast cell numbers. This mechanism offers a complementary approach to disease management and is currently being evaluated in clinical trials for ISM. The diversification of therapeutic targets and mechanisms represents a promising evolution in ISM treatment, potentially offering patients multiple effective options tailored to their specific disease characteristics and treatment responses.
