Subtypes of Systemic Mastocytosis
There are several types of Systemic Mastocytosis. They differ in how many mast cells build up, where they build up in the various parts of the body, and the types of symptoms that may be experienced. Importantly, all must satisfy the specific diagnostic criteria for Systemic Mastocytosis:
- Indolent Systemic Mastocytosis (ISM)
This form of Systemic Mastocytosis is the most common mildest subtype. It involves fewer than 20% mast cells in the bone marrow and does not lead to organ dysfunction. Despite this, individuals with ISM may still experience significant symptoms of mast cell activation, such as flushing, itching, abdominal pain, and in severe cases, anaphylaxis and osteoporosis.
- Smoldering Systemic Mastocytosis (SSM)
This is a higher-risk subtype that may progress to more aggressive forms. Like ISM, it involves fewer than 20% mast cells in the bone marrow and does not cause immediate organ dysfunction. However, patients may have high tryptase levels and significant infiltration of mast cells in organs, sometimes causing enlargement.
- Systemic Mastocytosis with an Associated Hematologic Neoplasm (SM-AHN)
This subtype of systemic mastocytosis occurs alongside another blood cancer, such as acute myeloid leukemia or myelodysplastic syndrome- where the bone marrow doesn’t function to make the blood cells. Though mast cell infiltration is under 20%, the presence of another blood cancer significantly affects disease progression and prognosis.
- Aggressive Systemic Mastocytosis (ASM)
Like the name suggests, this form of Systemic Mastocytosis is more severe and is marked by organ dysfunction due to mast cell infiltration, despite fewer than 20% mast cells in the bone marrow. Patients may experience impaired intestinal absorption, liver dysfunction, and bone marrow problems.
- Mast Cell Leukemia (MCL)
This is the rarest and most aggressive form of Systemic Mastocytosis that typically requires immediate treatment. It may progress quickly and has a high risk of mortality. It involves 20% or more mast cells in the bone marrow and requires urgent treatment due to a high risk of mortality
How do we treat Systemic Mastocytosis?
The treatment for Systemic Mastocytosis depends largely on the subtypes mentioned above.
Generally, ISM and SSM are considered “indolent” meaning that they do not advance over time to a more aggressive type with high risk of complications and death. In fact, life expectancy in these conditions is generally estimated in decades rather than just years, depending on your other medical conditions. The life expectancy for other subtypes –ASM and SM-AHN – on the other hand are measured more in months and years. MCL has the worst prognosis.
Regardless of the subtype, people with Systemic Mastocytosis are at risk for life threatening anaphylaxis where there is a sudden onset of difficulty breathing, severe GI symptoms, hives and/or (and most commonly) low blood pressure with a feeling of passing out. These episodes may be triggered by a bee sting or other exposures such as a medication, contrast agent used for a radiology test, or a food. A medication called epinephrine is prescribed and necessary for all patients for these emergency purposes. Usually, 2 injection pens are provided and their use will be reviewed with the prescriber. Understanding when and how to use epinephrine is critical for anyone with Systemic Mastocytosis. It is helpful to get a blood tryptase measurement within 2-6 hours (most often this is done in the Emergency Department) to confirm your flare was due to Systemic Mastocytosis. This information can be used to try to establish a trigger for the event and to potentially adjust the treatment plan.
Non-Advanced SM (ISM and SSM)
This includes Indolent Systemic Mastocytosis (ISM) and Smoldering Systemic Mastocytosis (SSM)
These are typically stable over time, and life expectancy can span decades. Treatment focuses on managing symptoms and preventing complications:
- Antihistamines: A drug or other compound that prevents the physiological effects of a compound (histamine) released by mast cells in response to injury or in allergic and inflammatory reactions. (e.g., cetirizine, fexofenadine, loratadine, hydroxyzine, famotidine) help block histamine effects. Sometimes combinations of these are required, and diphenhydramine can be added for breakthrough symptoms (as needed).
- Antileukotrienes (e.g., montelukast) reduce leukotriene-driven symptoms like flushing or cramping.
- Cromolyn sodium stabilizes mast cells, particularly for GI symptoms.
- Omalizumab and steroids may be used for frequent anaphylaxis.
- Proton-pump inhibitors (e.g., omeprazole, pantoprazole) treat acid reflux or ulcers.
- Bone health treatments include calcium, vitamin D, and bisphosphonates.
Non-Advanced disease (ISM and SSM)
Management for these subtypes is often focused on treating the symptoms of mast cell activation (flushing, itching, abdominal cramping, loose stools, throat tightness sensation). Additional treatments may be added to address more chronic symptoms such as fatigue and bone pain to improve quality of life. Finally, treatments may be needed for the complications of SM including bone loss and stomach ulcers.
Mast cell activation treatments include:
- Antihistamines: A drug or other compound that prevents the physiological effects of a compound (histamine) released by mast cells in response to injury or in allergic and inflammatory reactions. Some examples include cetirizine, fexofenadine, loratadine, hydroxyzine, and famotidine. Sometimes combinations of these are required, and diphenhydramine can be added for breakthrough symptoms (as needed).
- Antileukotrienes: After injury, infection, or contact with allergens your body produces a chemical called leukotrienes released by mast cells. Too much of this chemical can lead to a number of disorders with the most common being asthma and allergies. Antileukotrienes help regulate this chemical. Montelukast is an example, particularly if there is flushing, itching, or abdominal cramping that persists.
- Cromolyn sodium: A medication that is used as a mast cell stabilizer, meaning it prevents the release of inflammatory chemicals from the mast cells including histamine but many others as well. This is used more commonly for gastrointestinal symptoms.
- Omalizumab and steroids: these may be considered if there are recurrent episodes of emergency anaphylaxis requiring epinephrine.
Systemic Mastocytosis treatments to prevent complications may include:
- Proton-pump inhibitors: Medications that reduce stomach acid production such as omeprazole, esomeprazole, pantoprazole. These may be used if there are persistent symptoms of heartburn, acid reflux, and nausea and to heal ulcers if these are identified (by endoscopy)
- Medications to prevent and treat bone loss: Calcium and vitamin D supplementation is often needed to prevent bone loss and specific medications including the bisphosphonates may be prescribed once significant bone loss is detected. People with SM are often referred to a bone specialist.
If episodes of emergency anaphylaxis or mast cell activation symptoms persist despite current treatment, then it is best to speak to your healthcare provider for additional treatment options. Regardless, your physician will check blood work and other tests every 6-12 months to monitor disease progression, at which point treatment options would change.
***In 2023, the Food and Drug Administration approved avapritinib (Ayvakit™) for adults with Indolent Systemic Mastocytosis (ISM). Avapritinib is in a class of medications called tyrosine kinase inhibitors. It works by blocking the action of the abnormal protein that signals mast cells to multiply. This daily medication is the only FDA approved medication for ISM. Prior, in 2023, it was approved for other types of Systemic Mastocytosis.
Advanced SM (ASM, MCL, SM-AHN)
This includes Systemic Mastocytosis with an Associated Hematologic Neoplasm (SM-AHN)
Aggressive Systemic Mastocytosis (ASM), and Mast Cell Leukemia (MCL)
These subtypes are more severe, with life expectancy measured in months to years. Treatment can involve:
- Chemotherapy-like medications to reduce mast cell counts
- Targeted therapies or stem cell transplantation
Patients are closely monitored with bloodwork every 1–3 months, periodic bone marrow biopsies, and imaging studies.
Emergency Preparedness for All SM Subtypes
All patients with SM are at risk for life-threatening anaphylaxis where there is a sudden onset of difficulty breathing, severe GI symptoms, hives and/or (and most commonly) low blood pressure with a feeling of passing out. Triggers can include insect stings, medications, contrast dyes, and foods.
If anaphylaxis occurs, every patient should:
- Carry two epinephrine pens at all times
- Know when and how to use the epinephrine
- Seek emergency care and request serum tryptase testing within 2–6 hours post-event
By understanding your specific subtype and working closely with your healthcare team, you can better manage symptoms, prevent complications, and improve your quality of life.
Adapted from IFFGD Publication #904 “Types of Systemic Mastocytosis” and IFFGD Publication #905 “Treatment of Systemic Mastocytosis”
