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Introduction to Systemic Mastocytosis
Systemic Mastocytosis: Characteristics and Emerging Therapies

Released: April 15, 2025

Expiration: April 14, 2026

Kristine J. Kucera
Kristine J. Kucera, PA-C, MPAS, DHS
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Key Takeaways
  • Systemic mastocytosis (SM) is a rare disorder characterized by an excessive number of mast cells and variable symptoms and severity.
  • Most cases of SM are caused by a gene mutation that leads to overactive KIT proteins.
  • Treatment has focused on controlling symptoms, but new and emerging therapies that target overactive KIT can reduce mast cell burden.

Systemic mastocytosis (SM) is a rare disorder where an excessive number of mast cells accumulate in various parts of the body, such as the skin, bone marrow, liver, spleen, and digestive tract. These mast cells release substances like histamine, which can trigger symptoms similar to allergic reactions, including flushing, itching, abdominal pain, severe inflammation, and even anaphylaxis. In some cases, it can lead to complications like anemia, bone pain, or organ damage.

Most cases of SM are caused by a random mutation in the KIT gene. Under normal circumstances, this gene provides instructions for making a protein that plays a crucial role in cell signaling, helping regulate processes like cell growth, division, survival, and migration. It is especially important for the development and function of certain cell types, such as mast cells, blood stem cells, melanocytes, and cells in the gastrointestinal tract. Mutations in this gene that cause SM lead to overactive signaling, resulting in increased mast cell proliferation and survival.

SM is classified into several types, each with varying severity and symptoms requiring tailored management and treatment.

Nonadvanced SM includes indolent and smoldering subtypes.

  • Indolent SM is the most common type and usually has mild symptoms that progress slowly. It often affects the skin, liver, spleen, and gastrointestinal tract but does not typically cause organ damage.
  • Smoldering SM is a more advanced form than indolent SM, with a higher burden of mast cells. It may lead to an enlarged liver or spleen but does not yet cause significant organ damage.

Advanced SM includes forms that are aggressive and associated with more pronounced neoplasms.

  • SM with Associated Hematologic Neoplasm (SM-AHN) is linked to other blood disorders, such as myelodysplastic syndromes or myeloproliferative neoplasms.
  • Aggressive SM (ASM) is a severe form of SM that can cause damage to organs, including the liver, spleen, and bones. Symptoms may include anemia, bone fractures, and malabsorption of nutrients.
  • Mast Cell Leukemia (MCL) is the rarest and most aggressive type of SM, characterized by a high number of mast cells in the blood and bone marrow. It often leads to severe organ dysfunction.

The treatment of SM has been revolutionized by the development of targeted therapies. Historically, treatment focused on controlling symptoms caused by excessive mast cell activity. This included using antihistamines for allergy-like symptoms, corticosteroids to reduce inflammation, and medications for gastrointestinal issues. Patients were also encouraged to identify and avoid factors that may trigger their disease, such as certain foods.  However, newer therapies such as midostaurin and avapritinib focus on inhibiting overactive KIT proteins, reducing the mast cell burden and improving symptoms. For many patients, these advancements can improve survival rates, particularly in patients with advanced SM, and quality of life.

To learn more about SM and increase your expertise in diagnosing and managing complex dermatologic conditions, join us on April 26, 2025, for the virtual, live educational program, “2025 Skin in the Game: Dermatology Intensive for NPs and PAs.” 

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