Indolent Systemic Mastocytosis (ISM)

People living with ISM may experience a broad range of symptoms. Symptoms arise from mast cells releasing their mediators into the body and the effects depend upon the part of the body that is affected with the mast cell build up. While each person with ISM may experience different symptoms in different ways , common mediator release symptoms that patients may experience include potentially severe allergic reactions including anaphylaxis, skin lesions and rash, itching, diarrhea, brain fog, fatigue, and bone pain, and these symptoms often persist despite treatment with multiple therapies aimed at improving symptoms. Symptoms of mastocytosis are more likely to occur in response to a trigger. Common triggers may include alcohol, surgery, spicy foods, exercise, insect stings or bites, and certain medications. These symptoms can have profound effects on people’s lives and can interfere with their ability to work and complete their normal daily activities and may even lead to patients isolating themselves to protect against possible unexpected triggers.

Systemic mastocytosis, including ISM is often diagnosed based upon signs and symptoms with a series of supporting tests. Doctors use a combination of tests to reach a diagnosis of ISM. These tests may include, but are not limited to:

• Medical History is a record of all health issues and treatments you have had in your life. Be sure to include a list of old and new medications, including over-the-counter medicines, herbals and supplements you take. Your doctor may also question you about your history of mast cell activation symptoms. Communicate any symptoms that you may have. It may also be helpful to bring pictures of allergic reactions.

• Physical Exam during which your doctor may check:

• • Vital signs, such as temperature, blood pressure, pulse and/or breathing rate
  • Weight
  • Feel parts of your body to see if organs are of normal size, are soft or hard, or cause pain when touched. Feel for enlarged lymph nodes in your neck, underarms and/or groin.
  • Conduct a skin examination

• Blood tests to check for signs of disease and how well your organs are working. They require a sample of blood which is removed from a needle placed into your vein, commonly in your arm or hand. These may include a comprehensive metabolic panel (CMP), a complete blood count, liver function tests, and a serum tryptase level.
• Biopsy (bone marrow and/or organ). A biopsy is the removal of a sample of tissue or group of cells for the purpose of testing. After obtaining a biopsy of the bone marrow or organ, your doctor will use the tissue obtained to look for evidence of abnormal mast cells using tests like flow cytometry, KIT mutation testing (see below), and/or immunohistochemistry.

• Measure signs of excessive mast cells: Tests that may demonstrate an excess of mast cells include, but are not limited, to the following.
• Blood and urine tests to find high levels of histamine (a mediator released from mast cells)
• Skin biopsy to look for high levels of mast cells or the substances they release
• Bone marrow biopsy to look for the appearance to mast cells and other blood markers that indicate an excess of mast cells
• Imaging tests such as X-ray, ultrasound, bone scan, and CT to see if organs are affected by mast cells. If your doctor suspects that organs are involved, they may order a biopsy to confirm that mast cells are affecting the organ.
• KIT Mutation Testing. A KIT D816V blood test may be ordered to assist your doctor in establishing a diagnosis of patients who are being evaluated for ISM. Since this specific gene mutation is found in 95% of ISM cases, measurement of this genetic marker can help evaluate for ISM. In the case that you test negative for having the KIT D816V mutation, other testing can be done to determine if you have another less common KIT mutation, including a test called KIT sequencing.

There are different types of KIT tests available, and high sensitivity tests may be required to accurately detect the gene mutation. It is recommended that you receive the newer, more sensitive allele-specific oligonucleotide qPCR testing when your doctor is evaluating you for an ISM diagnosis.

• Test for serum tryptase. Tryptase is an enzyme that is released with histamine and other mediators from mast cells in a normal immune response as well as an allergic reaction. This test measures the amount of tryptase that has been released from mast cells into the blood.

• Urine test. Urine tests can help to determine the presence of histamine in your body. This test consists of providing urine over a 24-hour period to evaluate histamine production over a longer time frame.

Treatment decisions should involve a treatment team of experts from different specialties who have expertise and experience with ISM. Your treatment team may include a dermatologist, a hematologist, and an allergist/immunologist.

Primary treatment options have historically centered around avoiding triggers of mediator release and blocking the symptoms caused by mast cell mediator release with anti-mediator therapy, including antihistamines, cromolyn sodium, corticosteroids, ketotifen, etc., with the goals of treatment focusing on controlling mast cell activation symptoms and improving quality of life. Treatment of ISM does not usually require cytoreductive agents, however these may be indicated for patients who continue to experience mediator released symptoms despite being optimally managed on mediator blocking therapy.

Currently, the only cytoreductive therapy that is approved by the FDA for the treatment of ISM is AYVAKIT^®. AYVAKIT^® is a kinase inhibitor designed to target the KIT D816V mutation, the primary driver of the disease. AYVAKIT^® works by selectively targeting the KIT D816V gene mutation to help slow the growth of abnormal mast cells. You do not need to have the KIT D816V gene mutation in order to be prescribed AYVAKIT^®. In the registrational clinical trial for ISM, treatment with AYVAKIT^® significantly reduced mast cell burden and improved patient symptoms.