KIT Targeting: A New Frontier in ISM Management, With Cem Akin, MD

Indolent systemic mastocytosis (ISM) is a rare, chronic condition characterized by the accumulation of abnormal mast cells that drive a range of often debilitating symptoms, including flushing, gastrointestinal distress, fatigue, musculoskeletal pain, and in some cases, life-threatening anaphylaxis. Although the risk of progression to advanced disease is low, many patients live with persistent symptoms that substantially impair quality of life. Current management strategies rely heavily on antihistamines, leukotriene blockers, and other symptom-suppressing therapies, yet these do not always achieve adequate control. For individuals whose symptoms remain refractory, targeted therapies such as tyrosine kinase inhibitors have begun to reshape the treatment landscape.

The field has recently seen pivotal advances. In 2023, the FDA approved avapritinib, the first selective KIT D816V inhibitor for ISM, marking a turning point in precision treatment.1 Alongside this, investigational therapies are emerging, including elenestinib, a KIT inhibitor designed to avoid central nervous system penetration—an attribute intended to mitigate certain risks observed in earlier trials with other agents. Data from the Harbor trial suggest encouraging efficacy and safety signals, while also highlighting the importance of evaluating endpoints beyond symptom control, such as bone mineral density and anaphylaxis, which remain under-addressed clinical challenges.2

As the therapeutic landscape evolves, questions remain about long-term disease management, trial design for broader patient subsets, and strategies to address key unmet needs such as reproductive safety and the identification of surrogate markers of mast cell activation. HCPLive spoke with Cem Akin, MD, about the state of ISM care, the emerging role of KIT inhibitors, and how upcoming data may shape the future of treatment for patients living with this lifelong condition.

References

1. Conroy S. FDA Approves Avapritinib in Indolent Systemic Mastocytosis. Article. Cancer Network. May 22, 2023. https://www.cancernetwork.com/view/fda-approves-avapritinib-in-indolent-systemic-mastocytosis

2. Castells M, Akin C, Hartmann K, et al. Continued symptom and quality of life improvement with favorable safety shown with long-term avapritinib in indolent systemic mastocytosis. J Allergy Clin Immunol.: In Practice. 2025;13(8):2194-2196.e1. doi: 10.1016/j.jaip.2025.05.026

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