Advanced Systemic Mastocytosis

What Is Advanced Systemic Mastocytosis?

Mast cells, found in connective tissue throughout the body, are a type of white blood cell that helps the immune system function properly and protect against disease. These cells are first responders when allergens and other invaders attack the body. They are essential for immune response, but when present in excess, they can cause a range of symptoms and complications.

When triggered, mast cells release chemicals like histamine and heparin, which can cause signs and symptoms similar to an allergic reaction.

In systemic mastocytosis, mast cells multiply abnormally in the skin, bone marrow, digestive tract, liver, spleen, or other organs.

Most people with systemic mastocytosis have mild symptoms that can be managed with medications and lifestyle changes.

Types of Advanced Systemic Mastocytosis

Systemic mastocytosis can be classified into three types: indolent systemic mastocytosis (ISM), bone marrow mastocytosis, and smoldering systemic mastocytosis (SSM).

When it progresses to the advanced stage, it is classified into different types based on the extent of the disease and the presence of additional conditions such as leukemia or other hematologic (blood-related) disorders.

Advanced systemic mastocytosis variants include:

Aggressive Systemic Mastocytosis (ASM) Aggressive systemic mastocytosis is characterized by an increased number of mast cells that infiltrate organs such as the liver, spleen, bone marrow, lymph nodes, and small intestine.

Mast Cell Leukemia (MCL) Mast cell leukemia is a very rare and aggressive form of systemic mastocytosis in which too many immature mast cells are found in the bone marrow and blood.

Mast Cell Sarcoma (MCS) A mast cell sarcoma is a solid tumor composed of abnormal mast cells that invades tissues in the body, most commonly the bones, digestive tract, lymph nodes, skin, spleen, and liver.

The symptoms of advanced systemic mastocytosis can vary widely and depend on the number of mast cells and where they are located, says Jason Gotlib, MD, a professor of hematology at Stanford University School of Medicine and a hematologist at Stanford Health Care, both in Stanford, California.

Common symptoms of systemic mastocytosis include:

• Anaphylaxis: Episodes of anaphylaxis, characterized by flushing, fainting, gastrointestinal symptoms, low blood pressure, and fast heart rate, are potentially life-threatening.
• Skin issues: People may experience lesions, rashes, hives, or itching, particularly on the skin. These symptoms occur because mast cells release histamine, which causes the skin to react.
• Gastrointestinal problems: Abdominal pain, nausea, vomiting, diarrhea, or acid reflux are common because of excess mast cells in the digestive tract.
• Fatigue and weakness: People may feel exhausted even after a full night’s sleep, which can interfere with daily activities.
• Respiratory issues: Wheezing, difficulty breathing, or coughing caused by excess mast cells in the lungs or airways can occur.
• Bone pain or fractures: Excessive mast cell accumulation in the bones can lead to pain or even fractures, as the bone structure becomes weakened.

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Risk factors for mastocytosis haven’t been identified.

“The bottom line is there’s no known, obvious predisposition to it,” says Dr. Gotlib.

It’s basically the random development of the KIT mutation in people who, over time, develop the overt, clinically evident disease, he says.

“It’s like many cancers. Although there are some [genetic mutations known to raise the risk of certain] cancers — such as BRCA for breast cancer — that are inherited, most cancers are basically acquired genetic mutations that ultimately cause a cell to turn from normal to malignant,” he says.

Mastocytosis is no different, meaning that a person develops a mutation, and then in some cases, there are other mutations in addition to KIT that drive the development of mastocytosis, says Gotlib.

An advanced systemic mastocytosis diagnosis can be challenging because of the broad range of symptoms that overlap with those of other conditions.

“This is a very rare disease, and many doctors aren’t familiar enough with the condition to recognize it. Because of that, many people can go undiagnosed for years,” says Gotlib.

Typically, doctors will begin with a physical exam and a thorough review of symptoms. If mastocytosis is suspected, several diagnostic tests may be used.

• Blood tests: Elevated levels of certain markers, such as tryptase (a protein released by mast cells), can suggest mastocytosis.
• Bone marrow biopsy: A sample of bone marrow is taken to check for abnormal mast cells. This is often one of the most definitive tests for diagnosing advanced systemic mastocytosis.
• Genetic testing: Tests to detect mutations in the KIT gene can help confirm a diagnosis of systemic mastocytosis.
• Bone scans: Bone densitometry can be done to detect osteoporosis, and skeletal imaging in suspected cases of advanced systemic mastocytosis can reveal other bone abnormalities.
• Imaging studies: CT scans, MRIs, or ultrasounds may be used to check for organ enlargement, particularly of the liver or spleen, which can occur in advanced cases of systemic mastocytosis.

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Treatment for advanced systemic mastocytosis focuses on managing symptoms and preventing complications rather than curing the condition. Since systemic mastocytosis is a rare and complex disease, treatment plans are highly individualized and may involve a combination of approaches, including symptom management and new targeted therapies that help people live longer and may even change the course of the disease.

Medications used to treat advanced systemic mastocytosis include:

Antihistamines: These are often prescribed to manage symptoms like itching, hives, and gastrointestinal discomfort caused by the release of histamine.

Bisphosphonates: These are used to treat osteoporosis.

Corticosteroids: These can reduce inflammation and control symptoms, especially in more severe cases.

Pain medication: Both over-the-counter and prescription pain medicines can alleviate pain.

Proton pump inhibitors: These help with peptic ulcer disease that can occur with systemic mastocytosis.

Cromolyn sodium: This can relieve abdominal pain and diarrhea.

Epinephrine: An epinephrine self-injection kit is used to treat anaphylaxis. It’s recommended that people with mastocytosis carry two self-injectors at all times.

Monoclonal antibodies: For people with recurrent anaphylaxis or anaphylaxis that doesn’t respond to treatment, monoclonal antibodies, especially omalizumab, may be used.

Tyrosine kinase inhibitors: “These drugs are very effective in reducing and killing off the number of mast cells and reducing elevated tryptase levels, and sometimes reversing organ damage,” says Gotlib. [They] “have really transformed treatment of advanced systemic mastocytosis,” he says. Tyrosine kinase inhibitors include the following:

• Midostaurin (Rydapt) was the first drug approved by the U.S. Food and Drug Administration to treat advanced systemic mastocytosis.
• Avapritinib (Ayvakit) was approved to treat advanced systemic mastocytosis in 2021.
• Imatinib mesylate (Gleevec) may be helpful for types of systemic mastocytosis with certain rare KIT mutations.

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Bone marrow transplant: Right now, this is the only potential cure for mastocytosis. In some cases, a bone marrow transplant may be considered, if the patient has a donor and if they really need a transplant, says Gotlib.

Chemotherapy: Historically, before more targeted therapy was shown to be more effective, chemotherapy was used to try to kill off mast cells in advanced conditions.

Finding a healthcare team that is experienced in treating advanced systemic mastocytosis is essential to managing it effectively, says Gotlib. You can ask your healthcare provider to refer you to a mastocytosis center of excellence, which can provide access to the latest treatments and possibly clinical trials. Research on advanced systemic mastocytosis is ongoing, and new treatments may mean improved outcomes in the future.

The most meaningful lifestyle change for advanced systemic mastocytosis is to avoid the triggers that can lead to inflammation and organ damage.

Triggers can include:

• Rubbing or friction on your skin
• Exercise and physical activity
• Insect bites (such as ant bites) and wasp and beestings
• Alcohol
• Spicy foods
• Certain medications, including nonsteroidal anti-inflammatory drugs (NSAIDs), muscle relaxers and anesthesia.
• Sudden changes in temperature
• Stress

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Dietary Changes

Gotlib recommends following a healthy, balanced diet.

Many people who have mastocytosis that isn’t advanced can have a near-normal life expectancy, says Gotlib.

The prognosis for individuals with advanced systemic mastocytosis depends on several factors, including the extent of mast cell accumulation, the organs involved, and the person’s overall health. Depending on the type of advanced systemic mastocytosis a person has, life expectancy may range from less than six months in people with very advanced disease, to three to four years for other subtypes, says Gotlib.

The prognosis for most people is improving thanks to new therapies.

Not only do tyrosine kinase inhibitors help with symptoms, but there are also some indications that the drugs are modifying the disease trajectory, says Gotlib. “Patients who used to die within a few months or years seem to be living longer with these treatments,” he says.

Advanced systemic mastocytosis can lead to several serious complications, such as the following.

Anaphylaxis This severe allergic reaction requires immediate medical attention.

Organ Damage Over time, the accumulation of mast cells in organs like the liver, spleen, or bone marrow can lead to dysfunction and organ failure.

Bone Fractures Osteoporosis and bone weakening can result from abnormal mast cell activity.

There doesn’t seem to be a difference in the number of men versus women, and no race or ethnicity has been identified as being at higher risk, says Gotlib.

Advanced systemic mastocytosis may lead to a number of complications.

Peptic Ulcer Disease People with mastocytosis are at higher risk for peptic ulcer, possibly caused by higher levels of histamine.

Urticaria Pigmentosa This skin condition develops in many people with systemic mastocytosis. It looks like raised patches of brownish skin that sting or itch with contact or changes in temperature.

Osteoporosis Aggressive systemic mastocytosis is associated with a loss of bone tissue and osteoporosis.

Life with advanced systemic mastocytosis is extremely challenging. It often means living with fatigue, pain, and other conditions caused by the cancer, says Gotlib.

Support is available. People can benefit from connecting with others who understand their experiences. Support groups, both in-person and online, provide a sense of community and can be a valuable resource for coping strategies, emotional support, and information about new treatments.

Leukemia and Lymphoma Society

This nonprofit organization has an online tool to locate support groups in your community, as well as a peer-to-peer support program for those diagnosed with a blood cancer.

CANCERCare

This national organization provides free support services and information for people living with cancer. They offer online support groups that are open to anyone in the United States, Puerto Rico, and U.S. Territories, and live support groups (in-person or via videoconferencing) for residents of New York and New Jersey.

The Mast Cell Disease Society

The Mast Cell Disease Society offers a variety of patient support resources as well as an online tool to help you find a Center of Excellence in your area.

• Advanced systemic mastocytosis is a rare condition in which too many mast cells accumulate in the body, and it sometimes develops into cancer.
• Symptoms can range from skin reactions to abdominal pain to bone pain or fracture.
• Newer treatments and ongoing research provide hope for better symptom management, improved quality of life, and slower progression of the disease.