A recent review published in Current Allergy and Asthma Reports highlights new and emerging targeted treatment strategies for nonadvanced systemic mastocytosis, particularly indolent systemic mastocytosis (ISM).
Treatment for ISM has traditionally focused on managing symptoms caused by the release of mast cell chemicals such as histamine. Common medications include antihistamines, leukotriene blockers, cromolyn sodium, proton pump inhibitors and mast cell stabilizers. Avoiding triggers that lead to symptoms like flushing, itching, hives, digestive problems, bone or muscle pain and fatigue is also an important component of care.
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However, many people still have ongoing symptoms or side effects from taking several medications at once, which has led researchers to investigate treatments that target the underlying disease process.
One major target is the KIT D816V mutation, which is present in more than 90% of people with ISM and causes mast cells to grow and survive longer than normal. The drug avapritinib, which blocks this mutated receptor, became the first targeted therapy approved by the U.S. Food and Drug Administration for ISM in 2023. In a phase 2 clinical trial, people with ISM who received avapritinib had larger improvements in symptom scores than those given a placebo, along with reductions in markers linked to mast cell activity.
Researchers are currently studying several additional targeted therapies. Bezuclastinib showed significant improvements in symptom scores compared with placebo in a phase 2 trial, while elenestinib has shown preliminary evidence of symptom reduction and decreased mast cell burden in an ongoing trial. Both drugs are also designed to inhibit KIT D816V.
Other therapies being studied include treatments that target different biological pathways involved in mast cell activity. These include therapies that affect mTOR signaling, drugs that target the siglec-8 receptor on mast cells and Bruton tyrosine kinase inhibitors such as TL-895, which is currently being tested in a clinical trial. A study evaluating the interleukin-6 blocker sarilumab, however, did not show benefits for individuals with ISM.
Overall, researchers note that nonadvanced SM remains challenging to treat because of its heterogeneous symptoms and associated comorbidities. But continued investigation of targeted therapies may offer new care strategies.
“Several of these investigational approaches appear promising and potentially offer new treatment paradigms for non-advanced SM,” the study’s authors conclude.
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