Systemic mastocytosis: rare and aggressive

The pathogenesis of its subtypes can be traced to the chronic and episodic release of mast cell mediators and an excessive accumulation of mast cells in tissues.

The etiology of systemic mastocytosis: the activating KIT D816V mutation is the usual suspect

In most cases, systemic mastocytosis is caused by the point mutation of the tyrosine kinase KIT. This KIT-activating D816V mutation results in a clonal proliferation of atypical mast cells. Systemic mastocytosis is a rare but aggressive disease: it is characterised by excessive mast cell activity associated with the release of numerous vasoactive cell mediators. The most frequently released mediators are:

An important diagnostic factor in systemic mastocytosis is tryptase, as it is almost always secreted by mast cells.1,2

In addition, there are various triggers...

Food, infections, antigens, allergens, emotional stimuli, opioids, non-steroidal anti-inflammatory drugs (NSAIDs), heat, exercise, alcohol, cytokines, toxins and hormones can trigger uncontrolled mast cell degranulation. In the IgE-mediated activation mechanism, the allergen forms a cross-link with the IgE receptor, which in turn activates the mast cells and thus triggers degranulation.1,2

The various subtypes of systemic mastocytosis differ in their aggressiveness

The American Academy of Allergy, Asthma & Immunology distinguishes a total of five subtypes of systemic mastocytosis. Before starting treatment, determining the respective subgroup helps with treatment planning and prognosis. Indolent systemic mastocytosis is the most common and least aggressive form.

In addition to this subtype, there are smoldering systemic mastocytosis, aggressive systemic mastocytosis and systemic mastocytosis with an associated haematological neoplasm. As the order of the latter subgroups increases, so does their aggressiveness. In indolent and smoldering systemic mastocytosis, there is a low risk of progression to a more severe form of the disease. The different subtypes have a very specific age distribution.1,2

Indolent systemic mastocytosis (ISM) causes a variety of symptoms. These include:

Patients with smoldering systemic mastocytosis become symptomatic with hepato- and splenomegaly with/without lymphadenopathy.1,2

Classification according to organ invasiveness and survival

The WHO classification of systemic mastocytosis, on the other hand, divides it into two groups based on its progression behaviour (non-advanced SM / non-AdvSM vs. advanced SM / AdvSM). In non-advanced SM, there is less organ invasiveness. The survival of patients is only minimally affected by non-advanced SM. In contrast, advanced SM and its subtypes are organ-invasive. It includes aggressive SM, SM with associated haematological neoplasia and mast cell leukaemia. The survival of affected patients is also significantly affected. The median survival of patients is less than 4 years.3

Diagnostic criteria of the World Health Organisation (WHO) for systemic mastocytosis

One major and one minor criterion or three minor criteria are required to diagnose systemic mastocytosis. The World Health Organisation (WHO) diagnostic criteria for systemic mastocytosis include:

Conclusion for practitioners: avoid triggering factors when treating systemic mastocytosis

The treatment of systemic mastocytosis is primarily aimed at avoiding the triggering factors. If this is not possible, various medications can be used. Most treatment options to date have been supportive, but targeted therapies have recently been added. In more aggressive forms of systemic mastocytosis, immunomodulators or chemotherapeutic agents are used in addition to interferon. It is also advisable for mastocytosis patients to always carry two epinephrine injectors with them.1-4

The tyrosine kinase inhibitor avapritinib, which was initially used for the treatment of gastrointestinal stromal tumours, has now also been approved for systemic mastocytosis. Avapritinib has shown positive results in patients with aggressive systemic mastocytosis, systemic mastocytosis with associated haemotological neoplasia and mast cell leukaemia.5 Prerequisite for treatment with avapritinib: at least one previous systemic therapy with another drug.

At the end of last year, avapritinib was approved as the first and only treatment for indolent systemic mastocytosis - the most common and least aggressive form of SM.6-7 The type 1 kinase inhibitor avapritinib is used to treat a D842V mutation in the PDGFRA gene. This gene encodes the receptor type α of the platelet-derived growth factor (PDGF). Avapritinib specifically inhibits the mutated PDGFRA kinase and also inhibits the mutated KIT kinase.8

  1. Gangireddy M. et al. (2023). Systemic Mastocytosis. StatPearls.
  3. Reiter et al. Onkopedia-Leitlinie: Mastozytose Stand Januar 2024, abgerufen am 20.02.2024.
  4. Pardanani A. et al. (2018). Systemic mastocytosis in adults: 2019 update on diagnosis, risk stratification and management. American Journal of Hematology, 2019.