Systemic Mastocytosis

Rare diseases |
Systemic Mastocytosis

Systemic Mastocytosis

Istituto Gentili is committed to the
treatment of systemic mastocytosis,
in order to improve the quality of life
of Patients suffering from this rare
and invalidating disease.

Characteristics

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Systemic mastocytosis (SM) is a rare disease resulting from the clonal expansion and accumulation of abnormal mast cells in various organs and tissues throughout the body. It is a complex and invalidating disease that has a negative impact on the Patient’s quality of life.

What are mast cells?

They are immune system cells that originate in the bone marrow from a pluripotent haematopoietic stem cell (the progenitor of all blood components). Mast cells play a crucial role in allergic reactions and inflammation.

What causes mast cell proliferation and accumulation?

Mutations in the c-KIT gene activate the KIT receptor, even in the absence of its ligand.

This mechanism:

favours cell proliferation,
reduces programmed cell death and, consequently, the accumulation of mast cells in certain organs and tissues of the human body.

What are the main forms of mastocytosis?

There are 2:

Cutaneous mastocytosis, which is usually found in children and often resolves during adolescence. The clinical picture is characterised by skin lesions that indicate infiltration and clusters of abnormal mast cells,

Systemic mastocytosis, which is chronic; it is observed mainly in adults and usually affects the bone marrow.

There are at least 4 subtypes of systemic mastocytosis: indolent systemic mastocytosis, bone marrow mastocytosis, smoldering systemic mastocytosis and advanced systemic mastocytosis.

Advanced systemic mastocytosis (or AdvSM), more impactful, can be further classified into:
- systemic mastocytosis with an associated hematological neoplasm (SM-AHN),
- mast cell leukaemia (MCL),
- aggressive systemic mastocytosis (ASM).

Symptoms

There are 3 types of symptoms that can present in a Patient with mastocytosis and they depend, at least in part, on the form of the disease in question.

Mediator-release symptoms:

flushing,
urticaria,
episodes of hypotension/anaphylaxis,
headache,
nausea, vomiting and diarrhoea,
abdominal cramps,
adverse reactions to food (e.g. peanuts, walnuts, hazelnuts),
adverse drug reactions (most commonly to β-lactam antibiotics, NSAIDs and anaesthetics),
adverse reactions to certain insect (Hymenoptera) bites,
severe osteoporosis.

Skin symptoms:

In the case of an accumulation of symptoms that are confined to the skin, as in the case of cutaneous mastocytosis:

small disseminated skin plaques (urticaria pigmentosa),
a single vesicular lesion (solitary mastocytoma),
hyperpigmentation, nodules and flushing.

Systemic symptoms:

Caused by mast cell infiltration in the internal organs, usually present in the aggressive systemic mastocytosis form:

skin involvement,
enlarged spleen,
liver disease and ascites,
osteoporosis and bone resorption,
recurrent allergic reactions,
high blood pressure and increased heart rate,
fever and night sweats,
fatigue,
neurological and psychiatric symptoms,
diarrhoea,
ulcerative gastrointestinal disease,
intestinal malabsorption,
weight loss,
abnormal blood test values.

Diagnosis

The diagnosis of systemic mastocytosis is based on the assessment of the morphological, immunophenotypical and genetic features of the mast cells, as summarised in the diagram below.

Graphic representation of the diagnosis for mastocytosis

The results of the various tests are used to evaluate consistency with the identification criteria for systemic mastocytosis.

What are the diagnostic criteria established by the World Health Organization?

A diagnosis of systemic mastocytosis is confirmed in the presence of:

the major criterion and 1 minor criterion,
at least 3 minor criteria.

*Biopsy specimens are taken from bone marrow and/or extracutaneous organ sections

⁺This parameter is not considered valid in the presence of an associated chronic myeloid condition

Let’s take a closer look at the diagnostic investigations required to diagnose systemic mastocytosis.

There are 3 laboratory tests:

1.
Bone marrow histology and
immunophenotyping

2.
Serum tryptase levels
measuring

3.
Molecular gene
testing

Once systemic mastocytosis has been diagnosed, the exact type can be defined using criteria evaluating:

the burden of the disease, using
B-findings

bone marrow biopsy showing ≥30% mast cell infiltration,
signs of dysplasia or myeloproliferation, liver enlargement and/or palpable spleen enlargement,
organomegaly.

the aggressivity of the disease, using
C-findings

the presence of ≥1 C-finding is consistent with aggressive systemic mastocytosis. In this case, cytoreduction therapy must be initiated;
the absence of C-findings is indicative of indolent systemic mastocytosis or smoldering systemic mastocytosis.

Identikit

The World Health Organization classification identifies different types of advanced systemic mastocytosis:

systemic mastocytosis with an associated hematological neoplasm (SM-AHN)

satisfies the criteria for systemic mastocytosis*,
presence of an associated clonal hematologic non-mast-cell disease,
usually observed in association with ASM or myeloid neoplasms.

aggressive systemic mastocytosis (ASM)

systemic mastocytosis* with ≥1 C-finding,
no evidence of mast cell leukaemia.

mast cell leukaemia (MCL)

mast cell diffusion consistent with leukaemia,
mast cell concentration ≥20% in bone marrow and ≥10% in peripheral blood.

*systemic mastocytosis affects ≥1 extracutaneous organ including bone marrow, gastrointestinal tract, lymph nodes and spleen, with or without skin involvement.

Treatment

The treatment of systemic mastocytosis is tailored to the individual Patient based on:

severity of the symptoms,
manifestations of the disease,
clinical evolution and prognosis.

As there is no pharmacological treatment that is able to cure mastocytosis, the therapeutic options available have three aims:

reduce the symptoms, by controlling the secretion and effects of mast cell mediators,
reduce the extent of mast cell infiltration with cytoreduction therapies,
treat the complications, such as organ dysfunction, caused by mast cell infiltration.

Given the complexity of the disease, the treatment and management of Patients with mastocytosis requires the involvement of medical specialties:

Treatment options currently available can be classified into:

anti-mediator therapy to reduce the release or the effects of mast cell mediators,
cytoreduction therapies to reduce the mast cell burden.

Therapeutic options available for advanced systemic mastocytosis include:

c-KIT receptor inhibitors,
chemotherapeutics,
anti-inflammatory therapy,
supportive therapy for the symptoms.

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