What is advanced systemic mastocytosis?

Systemic mastocytosis is a clonal mast cell disease in which abnormal mast cells accumulate in organs such as the bone marrow, liver, spleen, gastrointestinal tract and bones. Most patients have non-advanced disease, but a smaller group develop advanced systemic mastocytosis, where mast cell infiltration causes measurable organ damage.

Advanced systemic mastocytosis is defined by organ damage directly caused by mast cell infiltration. These are known as C findings. Examples include low blood counts, liver dysfunction with portal hypertension or ascites, enlarged spleen with hypersplenism, malabsorption with weight loss, and significant bone disease such as large osteolytic lesions or pathological fractures.

The key diagnostic concept: C findings

Advanced systemic mastocytosis is defined by organ damage directly caused by mast cell infiltration. These are known as C findings. Examples include low blood counts, liver dysfunction with portal hypertension or ascites, enlarged spleen with hypersplenism, malabsorption with weight loss, and significant bone disease such as large osteolytic lesions or pathological fractures.

KIT D816V: why molecular testing matters

Most adults with systemic mastocytosis carry the KIT D816V mutation, which drives abnormal mast cell growth and survival. Testing for KIT D816V helps confirm the diagnosis, assess disease burden and guide targeted treatment choices.

A standard next-generation sequencing panel may miss KIT D816V when the variant allele frequency is low. If clinical suspicion remains high, more sensitive techniques such as digital droplet PCR or allele-specific PCR may be needed, especially in patients with indolent or low-burden disease.

Current treatment options

Bezuclastinib: an emerging KIT D816V inhibitor

Bezuclastinib is an investigational, next-generation KIT D816V inhibitor being studied in systemic mastocytosis. Its key mechanistic distinction is potent activity against mutant KIT D816V while aiming to spare wild-type KIT and related kinases.

Unlike avapritinib, bezuclastinib has been described in clinical development as having minimal brain penetration. This is clinically important because it may reduce concerns about cognitive adverse effects and intracranial bleeding risk. However, all targeted therapies can still have side effects and require careful specialist monitoring.

Supportive care remains essential

Even when targeted treatment is used, patients with systemic mastocytosis usually need a personalised supportive care plan. This may include trigger avoidance, emergency medication, assessment of anaphylaxis risk, bone density monitoring, vitamin D optimisation, osteoporosis treatment when indicated, and review of gastrointestinal symptoms, nutrition and weight loss.

Practical action points for patients

• Ask whether your disease is non-advanced or advanced systemic mastocytosis.
• Confirm whether KIT D816V has been tested using a sufficiently sensitive method.
• Carry adrenaline auto-injectors if prescribed and ensure you know when and how to use them.
• Discuss bone density monitoring, calcium and vitamin D status, and osteoporosis prevention.
• Before avapritinib, platelet count and bleeding risk must be carefully reviewed by the treating specialist.
• Consider review in a centre with experience in mast cell disorders when the diagnosis or treatment plan is uncertain.

References and further reading

1. World Health Organization and international consensus classifications of systemic mastocytosis and advanced systemic mastocytosis.
2. Valent P, Akin C, Hartmann K, et al. Updated diagnostic criteria and classification of mast cell disorders.
3. DeAngelo DJ, Radia DH, George TI, et al. Avapritinib in advanced systemic mastocytosis: EXPLORER and PATHFINDER clinical trial data.
4. Gotlib J, Kluin-Nelemans HC, George TI, et al. Midostaurin in advanced systemic mastocytosis.
5. Cogent Biosciences. Bezuclastinib APEX study updates in advanced systemic mastocytosis.
6. American Academy of Allergy, Asthma and Immunology. Mastocytosis patient information and clinical resources.

What is SLIT immunotherapy?

Sublingual allergen immunotherapy (SLIT) is a specialist allergy treatment designed to gradually train the immune system to tolerate a specific allergen. It may be used for selected patients with allergic rhinitis, allergic conjunctivitis and allergic asthma caused by triggers such as grass pollen, tree pollen, house dust mite or animal dander.

Unlike standard medicines, which mainly reduce symptoms while they are being taken, SLIT aims to reduce the body’s allergic response over time. Treatment is usually administered as liquid allergen drops under the tongue according to the prescribed treatment plan.

Why is earlier treatment being discussed?

A 2026 expert review in Current Opinion in Allergy and Clinical Immunology highlights a shift in thinking. Traditionally, allergen immunotherapy was often considered only after symptoms remained troublesome despite medication. However, newer real-world evidence suggests that starting immunotherapy earlier in suitable patients may offer a “window of opportunity” to influence the natural history of allergic airway disease.

This is particularly relevant for patients with persistent allergic rhinitis, with or without mild to moderate allergic asthma. Allergic rhinitis and asthma are closely linked, and untreated or poorly controlled nasal allergy may contribute to lower airway symptoms in some patients.

What does recent evidence show?

Large real-world studies, including the REACT programme and the EfficAPSI study, suggest that adding allergen immunotherapy to standard care may reduce medication use, severe asthma exacerbations and healthcare use over long-term follow-up.

The 2026 review also highlights that younger patients may gain particular benefit when treatment is started before allergic airway disease becomes more established. This supports the idea that allergic rhinitis should not always be viewed as a minor condition, especially when symptoms are persistent, seasonal year after year, or associated with wheeze, cough or exercise-related breathing symptoms.

Who may be suitable for SLIT immunotherapy?

SLIT is not suitable for everyone. It should only be considered after specialist allergy assessment, including a careful clinical history and confirmation that symptoms match relevant IgE sensitisation on skin prick testing or blood testing.

Why accurate diagnosis matters

The success of SLIT depends on selecting the correct allergen. For example, a patient with spring symptoms may be reacting to birch pollen, grass pollen, plane tree pollen, or more than one pollen. A patient with year-round symptoms may have house dust mite allergy, animal dander allergy, mould allergy, non-allergic rhinitis, or a combination of causes.

At a consultant-led allergy clinic, testing may include skin prick testing, specific IgE blood testing and, where appropriate, molecular allergy testing. This helps confirm whether immunotherapy is likely to be clinically relevant and which allergen should be prioritised.

How long does treatment take?

SLIT immunotherapy is usually a long-term commitment. Many treatment courses continue for around three years, depending on the allergen and clinical response. The aim is to achieve sustained immune tolerance and longer-lasting benefit, rather than short-term symptom relief only.

Can SLIT replace antihistamines and nasal sprays?

Not immediately. Symptomatic treatment remains important, especially during the early stages of immunotherapy and during high pollen exposure. Many patients continue to use nasal sprays, antihistamines or eye drops as needed. Over time, some patients may need less medication, but this should be reviewed individually.

Why choose a specialist allergy clinic?

SLIT should be prescribed and monitored by clinicians experienced in allergy diagnosis, asthma assessment and immunotherapy safety. A specialist clinic can help identify the most relevant allergen, assess asthma risk and monitor response throughout the course.

Summary

SLIT immunotherapy is increasingly recognised as a treatment that may modify the course of allergic respiratory disease. For suitable patients with confirmed allergic rhinitis, and especially those at risk of asthma progression, earlier discussion of immunotherapy may be clinically valuable.

The decision should always be personalised. The most important first step is accurate diagnosis, followed by careful selection of the correct allergen treatment plan.