A recent review published in Current Allergy and Asthma Reports highlights new and emerging targeted treatment strategies for nonadvanced systemic mastocytosisMastocytosis Rare disease caused by the buildup of mast cells. Cutaneous mastocytosis primarily affects the skin and is more common in children, while systemic mastocytosis affects internal organs and is more common in adults., particularly indolent systemic mastocytosis (ISM).
Treatment for ISM has traditionally focused on managing symptoms caused by the release of mast cellMast cell A type of white blood cell produced in the bone marrow. They help defend against infections and play a key role in allergic reactions. In SM, mast cells become overactive and build up throughout the body. chemicals such as histamineHistamine A chemical released by mast cells when they are activated. Histamine causes many of the allergy-type symptoms in mastocytosis, including flushing, itching and hives.. Common medications include antihistaminesAntihistamines Medications that block the effects of histamine, the chemical found in mast cells that is responsible for many of the symptoms of SM, as well as many allergic reactions., 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 SMNonadvanced SM In these subtypes of SM, mast cells accumulate in the body but do not usually cause severe organ damage. Nonadvanced SM includes the subtypes indolent SM and smoldering 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 SMAdvanced SM In these subtypes of SM, mast cells begin to damage organs. Advanced SM includes the subtypes aggressive SM, mast cell leukemia and SM with an associated hematological neoplasm.,” the study’s authors conclude.
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