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ISM Treatment

CE / CME

The Treatment of ISM: An Expert’s Review

ABIM MOC: maximum of 0.25 Medical Knowledge MOC point

Physician Assistants/Physician Associates: 0.25 AAPA Category 1 CME credit

Nurses: 0.25 Nursing contact hour

Physicians: maximum of 0.25 AMA PRA Category 1 Credit™

Pharmacists: 0.25 contact hour (0.025 CEUs)

Released: November 14, 2023

Expiration: November 13, 2024

Mariana Castells
Mariana Castells, MD, PhD
CME/CE Information

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Key Takeaways
  • The treatment approach for indolent systemic mastocytosis (ISM) is personalized, and based on patient‑specific trigger avoidance.
  • Due to increased anaphylaxis risk, education on injectable epinephrine and the need to carry 2 devices is recommended for all pediatric and adult patients with ISM.
  • Avapritinib 25 mg PO once daily is the first KIT D816V-targeted therapy FDA approved for adults with ISM, including those unresponsive to standard supportive care medications.

Initial Treatment
The approach to treatment of indolent systemic mastocytosis (ISM) is personalized, with patient‑specific avoidance of triggers. Not all patients are intolerant of nonsteroidals, it can happen to 30% of patients. Vancomycin and quinolones are medications that activate mast cells through the MRGPRX2 receptor; patients with ISM may have overexpression of this receptor and these medications should be avoided. Other triggers such as stress, lack of sleep, and emotions can induce mast cell activation in patients with ISM. Premedication is recommended for surgery, radiologic procedures, travel, dental procedures, and vaccinations. Steroids are not recommended for all patients or procedures. Nonsedating antihistamine H1 and H2 receptor blockers and leukotriene receptor blockade medications are commonly recommended as premedication.

Treatment of Systems and Symptoms
The symptoms of ISM are driven by mediators released from mast cells located in skin, gastrointestinal, and other tissues and are targeted with antihistamines H1 and H2 receptors blockers, leukotriene blockers, aspirin to block prostaglandins and for severe symptoms, and intermittent steroids. Because of increased risk for anaphylaxis, it is very important for patients with ISM to be educated on the indications and technique of injectable epinephrine and to always carry 2 devices. Omalizumab, an anti-IgE, has been used for patients with frequent and/or severe episodes of mast cell activation and anaphylaxis and patients with hymenoptera venom anaphylaxis. Sodium cromolyn, a mast cell stabilizer, helps with symptoms targeting the skin, central nervous system, and gastrointestinal system.

Targeted Therapy
Because more than 90% of patients with ISM have a mutation in KIT, specifically the D816V mutation, which is thought to drive the disease by promoting the proliferation and activation of mast cells, KIT-targeted treatments could decrease mast cell burden and mediator-related symptoms.

Avapritinib is the first KIT D816V-targeted tyrosine kinase inhibitor FDA approved in the spring of 2023 for ISM. It was approved earlier for advanced mastocytosis and was shown to significantly decrease the mast cell burden and the number and severity of symptoms. In the PIONEER study in patients with ISM, more than 141 patients were treated with avapritinib and 71 with placebo. Avapritinib was able to significantly decrease all the symptoms—from fatigue to brain fog, flushing spots, bone pain, itching, headache, abdominal pain, dizziness, nausea, and diarrhea—compared to placebo. In addition, avapritinib was able to decrease the serum tryptase by 50% or more, decrease the bone marrow mast cell mass, and the allele fraction burden of the KIT D816V mutation in peripheral blood. In this study, avapritinib was able to clear the skin of patients with urticaria pigmentosa lesions at 24 weeks.

The current treatment of ISM includes managing the symptoms of mast cell activation with antimediator therapy, which requires polypharmacy and carrying epinephrine injectable devices. Targeted therapy such as avapritinib should be considered for patients with unresponsive or severe symptoms and to address cutaneous mastocytosis lesions, which are not addressed by antimediator therapy. Avapritinib 25 mg once daily is approved as the first targeted therapy for ISM. It is contraindicated in pregnancy. Other tyrosine kinase inhibitors are in clinical trials and information is available to patients for enrollment through their providers and the Mast Cell Disease Society.

Your Thoughts?
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