Advanced Systemic Mastocytosis (AdvSM)

Systemic mastocytosis is a rare disorder that causes the body to produce too many mast cells. A mast cell, or mastocyte, is a type of blood cell that is found throughout your body that helps your immune system protect your body from disease and assists in wound healing. In systemic mastocytosis, excess mast cells (that are abnormal in both shape and function) build up in your skin, bone marrow, digestive tract, and other body organs. These abnormal mast cells may be easily triggered to activate. When mast cells are triggered, they release substances (mediators including histamine, tryptase, prostaglandins, etc) are responsible for causing signs and symptoms similar to those of an allergic reaction and sometimes severe inflammation that may result in organ damage. When there are too many of these mast cells, they can create a response that overwhelms the body.

The majority of cases of systemic mastocytosis are caused by a mutation in a gene called KIT. This gene is responsible for assisting in mast cell development, and mastocytosis can occur when mutations in KIT lead to the overproduction and accumulation of mast cells. The KIT D816V mutation occurs in the majority (>90%) of people living with systemic mastocytosis.

Systemic mastocytosis is further divided into 5 categories: smoldering systemic mastocytosis (SMM), indolent mastocytosis (ISM), aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL). Advanced Systemic Mastocytosis (AdvSM) has three subtypes: ASM, SM-AHN, and MCL.

Symptoms

Mastocytosis is associated with a variety of possible symptoms, which are related to the release of mast cell mediators. Some people with SM present with isolated symptoms, whereas others may develop a constellation of symptoms secondary to mast cell activation. The signs and symptoms that you experience depend upon the part of the body that is affected by excessive mast cells. Excess mast cells can commonly build up in the skin, liver, bone marrow, and intestines. Less often, organs such as the brain, heart, or lungs may also be affected.

Symptoms vary amongst individuals and may include flushing of the face, neck and chest, itching, hives, skin rashes, breathing difficulties, rapid heart rate, chest pain, low blood pressure, dizziness, fainting, gastric distress (diarrhea, nausea, vomiting, abdominal pain), bone pain, osteoporosis, fatigue, weakness, anxiety/depression, and cognitive difficulties.

These effects are often triggered by something and triggers for patients with mastocytosis are highly individualized. The most common triggers include alcohol, certain foods, medications, heat, cold, changes in temperature, exercise, fatigue, pressure, sunlight, perfumes, odors, infections, stress (environmental, emotional and physical), and insect stings/venom.

Diagnosis

Evaluation for SM is recommended in patients who have symptoms associated with the release of mast cell mediators or anaphylaxis, and/or increased serum tryptase levels or adult onset mastocytosis of the skin.

To diagnose SM, a patient must fulfill one major criterion and at least one minor criterion. Alternately, a diagnosis may be made if a patient fulfills three minor criteria.

Major criterion:

Multifocal, dense aggregates of ≥ 15 mast cells detected in bone marrow sections and/or other organ(s) not including the skin

Minor criterion:

In biopsy sections of bone marrow or an organ other than the skin, > 25% of the mast cells have an abnormal appearance (atypical morphology)
Presence of KIT mutation (D816V or other activating KIT mutation)
Mast cells express an atypical immunophenotype (CD25, with or without CD2), in addition to normal mast cell markers.
Serum total tryptase persistently > 20ng/dL (unless there is an associated myeloid neoplasm, in which case this parameter is not valid).

Initial evaluation should include:

History and Physical Exam. Physicians will look for things like a prior history of mast cell activation symptoms (MCAS) and potential triggers, a skin exam for cutaneous lesions, and the ability to feel spleen and liver.
Laboratory evaluation. Blood will be drawn to evaluate your complete metabolic panel (CMP), complete blood count (CBC), and a serum tryptase level. The serum tryptase level is elevated in the vast majority of people living with SM across all subtypes. Persistently elevated serum total tryptase > 20ng/dL is one of the minor criterion.
Peripheral blood smear. Physicians will review the peripheral blood to look for the presence of mast cells.

Additional evaluations should include:

Bone marrow biopsy or biopsy of organ(s) with suspected involvement. Bone marrow biopsy and aspirate is the gold standard for diagnosing SM. Bone marrow biopsy is almost always necessary to establish a diagnosis of SM.
Molecular testing. High-sensitivity mutation analysis that looks for the presence of the KIT D816V mutation. KIT D816V occurs in the majority (>90%) of people living with SM. Detection of the KIT D816V mutation in the bone marrow, blood or organs is a minor criterion for diagnosis of SM. Mutation analysis for KIT D816V may be done on the bone marrow sample or peripheral blood, but bone marrow samples are preferred.
Imaging studies to look at organ involvement to look for B- and/or C- findings. B and C findings assist in the diagnosis of the sub-categories of SM (ISM, SSM, ASM, SM-AHN and MCL).
- B findings indicate a high burden of mast cells without evidence of organ damage, and include:
  - High mast cell burden on bone marrow biopsy (> 30%) AND serum total tryptase > 200 ng/mL
  - Enlargement of the liver (hepatomegaly) without impairment of liver function, enlargement of the spleen (splenomegaly) without hypersplenism, and/or enlargement of the lymph nodes (lymphadenopathy)
- C findings indicate organ damage caused by mast cells and include:
  - Bone marrow impairment caused by mast cells of white blood cells, red blood cells, and/or platelets
  - Enlargement of the liver (hepatomegaly) with impairment of liver function
  - Evidence of involvement in the bones (with or without fractures)
  - Enlargement of the spleen with hypersplenism
  - Involvement in the gastrointestinal system causing malabsorption with weight loss secondary to mast cell involvement
- 24-hour urine studies to look for mast cell activation may be useful in select circumstances. Urine is collected over a period of 24 hours and then analyzed to measure levels of products that are associated with mast cell burden and activation.

Treatment

Treatment options are highly individualized and depend upon the specific diagnosis and presenting symptoms of each individual patient. For patients with Advanced SM, including ASM, SM-AHN, and MCL, treatment is focused on controlling symptoms with trigger avoidance and the management of the mast cell burden to prevent organ damage.

Management of mediator release symptoms: These treatments are directed at controlling the symptoms caused by the release of mast cell mediators. Typical types of medications used to control these symptoms include H1 antihistamines (such as hydroxyzine, doxepin, diphenhydramine, loratadine, fexofendadine, or cetirizine), H2 antihistamines (such as ranitidine, cimetidine, or famotidine), mast cell stabilizers (such as cromolyn sodium or ketotifen), and leukotriene inhibitors (such as montelukast, zileuton or zafirlukast). Epinephrine is prescribed for anaphylaxis. Steroids may be prescribed if a patient is unable to be stabilized with standard mast cell mediator treatments.
Cytoreductive treatments are indicated for patients with advanced mastocytosis and a large mast cell burden, involvement of multiple cell lines and/or findings that indicate organ damage. Cytoreductive agents utilized in the treatment of advanced SM include interferon alpha/beta, imatinib (only if KIT D816V negative), cladribine, midostraurin (Rydapt®) and avapritnib (Ayvakit®).

References

Rare Disorders