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Challenges and Burdens of Indolent Systemic Mastocytosis
Challenges and Burdens of Indolent Systemic Mastocytosis: Symptoms, Diagnosis, and Treatment

Released: October 01, 2024

Expiration: September 30, 2025

Matthew Giannetti
Matthew Giannetti, MD
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Key Takeaways
  • The diagnosis and treatment of indolent systemic mastocytosis (ISM) are challenging and burdensome for both healthcare professionals and patients.
  • Patients with ISM may face many challenges in addition to living with symptoms, including feelings of anxiety, depression, and isolation.

The following is a recap of 2 interviews conducted with a patient with indolent systemic mastocytosis (ISM) and a physician who specializes in the disorder, Matthew P. Giannetti, MD. They discuss the challenges and burdens of symptoms, diagnosis, and treatment.

Symptomatic Burden

Patient With ISM
Prior to my diagnosis of indolent systemic mastocytosis (ISM), for nearly 10 years I experienced significant allergic reactions to things that did not make sense to me. I would be covered head to toe in brown spots that turned into hives and became really itchy and affected by various environmental factors or foods I encountered each day. The differences in my appearance were noticed by everyone, young and old, and they often made comments about my spots. I was taking anti-inflammatories and allergy medications to try to mitigate the reactions, but my greatest concern was my energy level—it was super low and impacting my career and my relationship. I had maybe 4 or 5 hours of stamina a day to focus and navigate my career and personal life. I was also dealing with some anxiety and depression just not knowing what was happening to my body. No one understood what was going on. It was one of the most difficult times of my life. 

Matthew P. Giannetti, MD
When I think about ISM and its symptoms, I try to separate them into buckets: cutaneous, gastrointestinal, anaphylaxis, and all others. Cutaneous symptoms are the hallmark of the disease. The data vary, but approximately 80% of patients develop spots and generally present with what we call maculopapular cutaneous mastocytosis. These spots can really affect quality of life, particularly when a person is trying to sleep. Gastrointestinal symptoms (abdominal pain, cramping, and diarrhea) are probably the second most common and can be highly variable. Another symptom, and probably the most feared complication of systemic mastocytosis, is anaphylaxis, which can be life-threatening. Many things can cause anaphylaxis, but the anaphylaxis we usually see in patients with mastocytosis is quite profound and often involves cardiovascular collapse. 

Diagnostic Burden

Patient With ISM
I was visiting my primary care physician (PCP) for a regular checkup. At the visit, my spots were very inflamed and itchy. My PCP referred me to a dermatologist who worked at a teaching hospital. There they performed the scratch test for Darier’s sign, to which I had a very quick response. The students who were working under the dermatologist had actually just reviewed various mast cell disorders, including ISM, in class that week. My dermatologist then told me I would need to go through additional diagnostic testing and referred me to an oncologist. I immediately went from feeling hopeful to panicked. The oncologist ordered a bone marrow biopsy. It turned out that I have a KIT mutation, which explained why my tryptase levels were consistently high. A few days later I was diagnosed with ISM.

Matthew P. Giannetti, MD
The diagnosis of ISM is definitely burdensome and challenging. Basically, everything is a symptom. Mast cells are present in almost every organ in the body, so many patients have disparate symptoms. Most patients with ISM have many, many meetings with healthcare professionals (HCPs). In fact, Blueprint Medicines Corporation reported significantly more specialist physician office visits per patient than patients without ISM before receiving an appropriate diagnosis. A formal diagnosis requires a bone marrow biopsy, placing much emphasis on accurate screening. The 2 primary screening tests HCPs use are baseline tryptase levels and the KIT D816V mutation. Both are excellent, but neither is perfect. 

Regarding tryptase levels, most patients (80%-90%) with mastocytosis have a tryptase level greater than 20 ng/mL, but approximately 6% of the US population has a genetic trait called hereditary alpha tryptasemia that causes elevated tryptase levels. What this means is that hereditary alpha tryptasemia is a major confounding factor that could affect one of our best screening tests. 

Now, the KIT D816V mutation is the hallmark for a clonal disorder like ISM. As recently as 4 or 5 years ago, we used next-generation sequencing and polymerase chain reaction (PCR) to test for this mutation, but because of their limited sensitivity, some tests would come back as false negative. Further, mast cells do not really circulate in peripheral blood; they grow and develop in the bone marrow, briefly leave the bone marrow, circulate in the blood, and end up in mature and peripheral organs, meaning there is a very short time window in which mast cells are present in the blood. If an HCP orders a test that includes a peripheral blood draw, there are going to be some diagnostic concerns because there are simply not enough mast cells in peripheral blood for a positive result. This places even more importance on the bone marrow biopsy, because the bone marrow population is enriched in mast cells and is more accurate in detecting the KIT D816V mutation. 

Treatment Burden

Patient With ISM
At one point prior to my diagnosis, I was self-medicating with ibuprofen, acetaminophen, diphenhydramine, and loratadine. Then my allergist prescribed me an H1 blocker, an H2 blocker, and 2 EpiPens that I had to take with me everywhere I went. Taking these plus my other daily medications became unsustainable, and since many were over the counter, I was unable to work with insurance companies to help cover the costs. 

Matthew P. Giannetti, MD  
ISM is a very rare disease with specialized therapies. Patients really benefit from seeing an immunologist who specializes in mast cell disorders because there are a lot of nuances to its treatment. For example, it was previously reported that imatinib may be helpful for the treatment of ISM. It was subsequently determined that people with the KIT D816V mutation are resistant to imatinib. I think there should be a strong emphasis on seeing a specialist who is familiar with the clinical presentation and data, but unfortunately, there are very few of us. With all that being said, I think it is becoming increasingly important to get the knowledge out there, understand what to look for, how to look for it, and what medications to take (and when and why). 

Takeaways From a Patient Perspective
I want HPCs to know that a diagnosis of ISM is intimidating and scary, because there is not a lot of information available to patients or their families or accessible to those outside the medical profession. It is also really challenging to find providers who are knowledgeable about the disorder and can support patients holistically. For me, it is more than just pharmaceutical—it is about making sure I know the full impact of this illness and the small things I can do to support my health. The other thing I really want HCPs to know is that ISM is an isolating illness, and anybody who is going through a diagnosis or beginning treatment feels isolated and has not had opportunities to engage with other people with this diagnosis.  

Patient Update
I have been taking medication for just over 5 years now, and my life is completely different. I have not had to take an anti-inflammatory or antihistamine in over a year. One of my biggest reliefs was that my energy came back, and my physical ability to go and do things came back. I am happily partnered. I am working in education doing a job that I love. I get to hike, bike, kayak, and paddle board—things I could only dream of prior to starting this treatment. This medication has simplified my life in more ways than I could have ever imagined.

Your Thoughts?
In your practice, what has been the most challenging or burdensome part of the diagnostic process of ISM? Join the discussion by posting a comment below.

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