Disease Identification and Classification

Indolent systemic mastocytosis can be identified using several medical coding systems. These codes help healthcare providers classify and document the disease properly.

D47.0
2A21.0Y; XH2Y59
C0272203
10056452

This disease is also known by other names in medical literature.

ISM, Indolent SM

What Is Indolent Systemic Mastocytosis?

Indolent systemic mastocytosis is a rare, usually benign, chronic form of systemic mastocytosis (a disease where abnormal mast cells accumulate in various body tissues). Mast cells are a type of white blood cell that are part of your immune system. When they work normally, mast cells help defend your body against intruders like allergens by releasing histamine, a chemical that triggers an allergic response.^[1][2]

In indolent systemic mastocytosis, abnormal mast cells accumulate mainly in the bone marrow but also in other organs or tissues, particularly the skin. These abnormal cells continue to release histamine and other chemicals long after they should stop, creating a continuous allergic response that can affect multiple parts of your body.^[1][3]

The growth and replication of normal mast cells is controlled by a membrane protein named KIT, which can be turned on and off like a switch. In mastocytosis, mutations in the KIT gene keep the switch “on,” resulting in continuous growth and activation of mast cells.^[3]

• Bone marrow
• Skin
• Liver
• Spleen
• Gastrointestinal tract

How Common Is This Disease?

Indolent systemic mastocytosis is the most common form of systemic mastocytosis, representing about 90% of all systemic mastocytosis cases. The prevalence of systemic mastocytosis in Europe is estimated between 1 in 7,700 and 1 in 10,400 people.^[1]

Overall, systemic mastocytosis is rare, affecting about 13 out of every 100,000 people worldwide. It affects about 1 in 10,000 to 20,000 individuals globally.^[2][4]

This disease mainly affects adults and elderly people. While mastocytosis can occur in children, indolent systemic mastocytosis typically develops in adulthood.^[1]

Symptoms and Clinical Presentation

Indolent systemic mastocytosis typically presents with skin lesions, usually in the form of urticaria pigmentosa (dark, itchy bumps on the skin). Most patients have these skin lesions, though some patients may have no skin lesions at all.^[1][2]

When you touch or stroke the affected area of skin, it may turn red and start to itch or swell. This reaction is known as Darier’s sign and can help doctors identify the condition.^[2][5]

Patients frequently suffer from symptoms related to the release of mast cell chemicals. These symptoms can include:^[1][2][6]

• Pruritus (itching)
• Flushing (reddening of the skin)
• Syncope (fainting)
• Headache
• Fatigue
• Vomiting
• Diarrhea
• Abdominal pain
• Bone pain
• Mood changes or depression
• Heart palpitations
• Hives

People with indolent systemic mastocytosis may suddenly develop several symptoms all at once. Healthcare providers may refer to this as a mastocytosis attack or flare.^[2]

Patients have a high risk of developing severe anaphylactic reactions (life-threatening allergic reactions) to various substances such as insect bites, foods, alcohol, spicy foods, certain medications, and other triggers. Some patients may also develop severe osteoporosis or even spontaneous fractures.^[1][6]

Common Triggers for Symptoms

Many patients find that certain things can trigger their symptoms. These triggers can differ from person to person, but common ones include:^[6][7]

• Alcohol
• Spicy foods
• Insect stings
• Changes in temperature
• Anxiety and stress
• Skin irritation
• Certain medications
• Exercise
• Physical exertion

Isolated Bone Marrow Mastocytosis

A provisional subcategory of indolent systemic mastocytosis is isolated bone marrow mastocytosis. This form is typically characterized by the absence of skin lesions and normal to slightly elevated basal tryptase levels (a marker that can be measured in blood). In most patients with this form, the KIT D816V mutation burden in the peripheral blood is low, and a bone marrow examination typically reveals small-sized clusters and aggregates of mast cells.^[1]

What Causes This Disease?

Although the exact cause of indolent systemic mastocytosis is not fully understood, an activating mutation of the KIT gene is found in virtually all cases. The most common mutation, called KIT D816V, is found in the mast cells of about 95% of patients with indolent systemic mastocytosis.^[1][7]

This mutation makes the KIT protein remain constantly activated, resulting in continuous growth and activation of mast cells. The mutation probably accounts for the abnormal accumulation of mast cells in organs and tissues.^[1][3]

In some cases, the mutation is found primarily in the abnormal mast cells. In other cases, the mutation may be detected in other mature bone marrow and peripheral blood cells such as basophils, eosinophils, neutrophils, as well as B- and T-lymphocytes. Furthermore, precursors of red blood cells and other blood cells, as well as CD34+ progenitor cells, may carry the KIT D816V mutation, suggesting the involvement of a pluripotent stem cell (an early cell that can develop into many different cell types).^[1]

The disease is not typically inherited. In most cases, the KIT mutation happens for no apparent reason. In very few cases, it appears the KIT mutation may be passed down through families.^[5]

How Is It Diagnosed?

A physical examination of the skin is the first stage in diagnosing mastocytosis. Your doctor may rub the affected areas of skin to see if they become red, inflamed and itchy, which is known as Darier’s sign.^[5]

The diagnosis of systemic mastocytosis is established using the World Health Organization (WHO) consensus criteria. After confirming systemic mastocytosis, it is subsequently categorized according to the presence of specific findings. In indolent systemic mastocytosis and isolated bone marrow mastocytosis, there are neither B-findings (signs of a high burden of mast cells) nor C-findings (signs of organ damage).^[1]

Diagnostic Tests

Several tests are commonly used to diagnose and evaluate systemic mastocytosis:^[5][12]

• Blood tests – including a full blood count and measuring blood tryptase levels (tryptase is a chemical released by mast cells)
• Bone marrow biopsy – a test where a local anesthetic is used and a long needle is inserted through the skin into the bone underneath to obtain a sample. A diagnosis of systemic mastocytosis is usually made by finding typical changes on a bone marrow biopsy
• Skin biopsy – a small skin sample is taken and checked for mast cells
• Ultrasound scan – to look for enlargement of the liver and spleen
• DEXA scan – to measure bone density
• Genetic testing – to test for the KIT D816V gene mutation

KIT D816V Testing

A KIT D816V blood test may be helpful to aid in the diagnosis of patients who are being evaluated for indolent systemic mastocytosis. Since the gene mutation is found in approximately 95% of cases, measurement of this genetic marker can help screen for the disease. There are different types of KIT tests available that vary in sensitivity. High-sensitivity tests may be required to detect the mutation.^[7]

Related Conditions and Differential Diagnosis

Several other conditions need to be considered when diagnosing indolent systemic mastocytosis. These include:^[1]

Other forms of systemic mastocytosis, such as smoldering systemic mastocytosis, aggressive systemic mastocytosis, systemic mastocytosis with associated hematologic neoplasm, and mast cell leukemia.

Other causes of mast cell activation syndromes, including primary mast cell activation syndrome (clonal, but not fulfilling systemic mastocytosis diagnostic criteria), secondary mast cell activation syndrome where an IgE-dependent allergy or another reactive inflammatory disease process is present, and idiopathic mast cell activation syndrome where neither clonal mast cells nor an IgE-dependent allergy or another underlying condition can be documented.^[1]

Additional conditions to consider include cutaneous mastocytosis (where mast cells are found only in the skin), mast cell sarcoma, and various endocrine disorders.^[1]

Treatment and Management

There is no cure for indolent systemic mastocytosis, so the aim of treatment is to relieve symptoms and improve quality of life. Management focuses on preventing anaphylactic reactions, identifying and avoiding symptom triggers, and treating specific symptoms.^[5][8]

Managing Allergic Reactions and Anaphylaxis

Because patients with indolent systemic mastocytosis have an increased risk of developing severe and life-threatening allergic reactions, they may need to carry an adrenaline auto-injector (such as an EpiPen). This device can be used to treat the symptoms of anaphylaxis.^[1][5]

Epinephrine is used in acute anaphylaxis. For adults, the typical dose is 0.3 mL of a 1:1000 dilution of epinephrine. In children, the dose is 0.01 mL/kg (up to 0.3 mL) administered every 10-15 minutes as needed.^[14]

For patients with a proven allergy to insect venom (such as bee or wasp stings), venom immunotherapy is mandatory. This treatment can help reduce the risk of severe reactions to future stings.^[8]

Antihistamines

Antihistamines are part of the initial treatment for indolent systemic mastocytosis. H1 antagonists (blockers) are used to treat pruritus (itching), flushing, and skin redness. Nonsedating antihistamines such as cetirizine or desloratadine may be recommended for daytime use, and sedating ones such as diphenhydramine or hydroxyzine for nighttime use.^[8][14]

H2 receptor blockers have been used to treat gastric hypersecretion (excessive stomach acid production) and peptic ulcer disease associated with systemic mastocytosis. Proton pump inhibitors are also useful for these symptoms.^[8][14]

Other Symptom Management

Various medications can be used to manage specific symptoms:^[5][8][11]

• Steroid cream (topical corticosteroids) can be applied to the skin for a limited time for mild to moderate skin symptoms
• Cromolyn sodium (sodium cromoglicate) is a mast cell stabilizer that reduces the amount of chemicals released by mast cells. It has proved useful for relieving abdominal pain and diarrhea, pruritus, whealing, and flushing, as well as impaired cognition
• Leukotriene antagonists, such as zafirlukast and montelukast, may be added when skin symptoms are not adequately controlled
• Aspirin can be used in patients with flushing that is unresponsive to antihistamines
• Psoralen plus ultraviolet A therapy (PUVA) may provide relief of pruritus and may cause fading of skin lesions in some patients
• Anticholinergics have been used in the treatment of diarrhea
• Corticosteroids may be used to control malabsorption, ascites, abdominal pain that doesn’t respond to cromolyn, bone pain, and severe skin disease

Bone Health Management

If you have weakened bones (osteoporosis) resulting from abnormal mast cell activity in your bones, you may be given a medicine called bisphosphonates. Bisphosphonates slow the process of bone breakdown while allowing production of new bone to continue as normal, which improves your bone density. You may also be given calcium supplements, as calcium helps strengthen bones.^[5][11]

Omalizumab

Omalizumab is an anti-immunoglobulin E (anti-IgE) humanized monoclonal antibody that inhibits the binding of IgE to mast cells. In patients with anaphylaxis that is recurrent or does not respond to conventional therapies, omalizumab reduced the frequency of anaphylaxis in some patients with systemic mastocytosis. Omalizumab appears to be effective on vasomotor symptoms (including anaphylaxis), but not on respiratory, musculoskeletal, and neuropsychiatric symptoms.^[8][13][14]

Targeted Therapy

Historically, patients managed and addressed individual symptoms with various medications. However, a targeted treatment called avapritinib (marketed as AYVAKIT) is now the only FDA-approved treatment for adults with indolent systemic mastocytosis. This medication targets the underlying cause of the disease by blocking the abnormal KIT D816V protein.^[7]

Masitinib, another targeted therapy, has shown positive results in clinical trials for indolent systemic mastocytosis. It works by inhibiting wild-type c-Kit, Lyn, and Fyn tyrosine kinases, reducing mast cell activity. Masitinib received orphan drug designation for mastocytosis from both the European Medicine Agency and the U.S. Food and Drug Administration.^[4]

A cytoreductive treatment (treatment that reduces the number of cells) is not recommended for indolent systemic mastocytosis unless anti-mediator therapy has failed.^[8]

Outlook and Disease Progression

Indolent systemic mastocytosis is a lifelong condition associated with reduced quality of life. However, patients with indolent systemic mastocytosis have a nearly normal life expectancy.^[4]

In most patients, symptoms usually develop over several years. The average delay to diagnosis is about 58 months (nearly 5 years), with patients often seeing multiple providers across many subspecialties and care sites before receiving a correct diagnosis.^[19]

While indolent systemic mastocytosis is generally considered the most common and least severe form of systemic mastocytosis, it’s possible for a small number of cases to progress to more advanced forms. Studies have reported that indolent systemic mastocytosis may progress to advanced systemic mastocytosis in approximately 3-4% of patients.^[7][19]

Healthcare providers can’t cure the condition, but treatment can ease symptoms and help patients maintain their quality of life.^[2]