Cem Akin, MD 

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.

 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.

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. 

 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.

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

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. 

. 2025;13(8):2194-2196.e1. doi: 10.1016/j.jaip.2025.05.026

Videos

Akin discussed updated data on elenestinib from the HARBOR trial in indolent systemic mastocytosis.

Pipeline Therapies for Indolent Systemic Mastocytosis: Growing Confidence in the Treatment Landscape of Indolent Systemic Mastocytosis

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 

 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.

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.

Looking Ahead in Indolent Systemic Mastocytosis Treatment: Data Gaps and Hope for a Cure

Multiorgan Relief with KIT Inhibition: Broad Symptom Relief for Patients

Comprehensive Multiorgan Symptom Relief Through KIT Inhibition

Avapritinib demonstrates remarkable efficacy across multiple organ systems affected by indolent systemic mastocytosis (ISM), providing patients with comprehensive symptom relief that extends well beyond traditional treatment approaches. The medication shows particularly impressive effects on skin manifestations, significantly reducing urticaria pigmentosa lesions and in some cases causing complete disappearance of these characteristic skin changes. Additionally, avapritinib effectively addresses skin-related symptoms including itching and flushing, providing patients with relief from some of the most visible and socially impactful aspects of their disease. This multidomain effectiveness represents a significant advancement over conventional antihistamine treatments that typically target only specific symptom categories.

The therapeutic benefits extend to gastrointestinal and neurocognitive domains, areas where patients often experience severe impairment that significantly affects daily functioning. Patients frequently suffer from debilitating abdominal pain and diarrhea, along with neurocognitive symptoms such as brain fog and memory issues that can substantially impact work performance and quality of life. Avapritinib has proven effective in reducing these diverse symptoms, offering patients comprehensive relief across the spectrum of ISM manifestations. However, important knowledge gaps remain regarding the medication's effects on osteoporosis, a major concern affecting approximately one-third of ISM patients, and its impact on anaphylactic presentations, particularly in high-risk situations such as venom allergies.

The quality of life improvements achieved with avapritinib treatment are substantial and sustained over the long term, paralleling the documented improvements in symptom scores. While the PIONEER trial enrolled patients with ECOG scores of 0-1, excluding severely disabled individuals, the overall impact on quality of life has been consistently positive. Patient testimonials provide compelling evidence of the medication's transformative effects, with individuals reporting newfound confidence to engage in previously avoided activities, such as removing shirts at the beach without embarrassment about skin lesions or enjoying occasional celebratory drinks. These anecdotal reports underscore the profound impact that effective ISM treatment can have on patients' ability to participate fully in life activities they previously avoided due to their condition.

A panelist discusses how avapritinib provides broad, multi-organ symptom relief in indolent systemic mastocytosis—improving skin, gastrointestinal, and neurocognitive symptoms—leading to significant quality-of-life gains, though its effects on osteoporosis and anaphylaxis remain under investigation.

Cem Akin, MD

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