Most people diagnosed with clonal mast cell diseaseMast cell disease A group of conditions in which mast cells behave abnormally by building up in excess, releasing chemicals too easily or both. Includes mastocytosis, mast cell activation syndrome and hereditary alpha-tryptasemia. had blood test levels below the cutoff used to support a systemic mastocytosis (SM) diagnosis, according to findings from the PROSPECTOR trial presented at the European Academy of Allergy and Clinical Immunology Congress 2026.
SM is the most common type of clonal mast cell disease, a group of disorders that originate from a single mutated 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.. When doctors are determining if someone has SM or another clonal mast cell disorder, they often check their baseline serum tryptaseTryptase A protein enzyme that is primarily produced by mast cells and stored in small pockets within the cells, known as granules. High levels of tryptase are a key indicator of SM. (BST) levels, which show how much of an enzyme produced by mast cells is in someone’s blood. A level of 20 ng/mL or higher is one criterion that can point to an SM diagnosis. However, the trial’s findings suggest that relying on this threshold alone could leave many cases of clonal mast cell disease undetected.
Read more about SM testing and diagnosis
Adding another layer of complexity, hereditary alpha-tryptasemia (HαT) is an inherited genetic trait that can naturally raise BST even in people without clonal mast cell disease.
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The researchers therefore examined the distribution of clonal mast cell disease cases across different BST levels and the effect of HαT on those levels. They also assessed how reliably BST could predict clonal disease and how many cases the 20 ng/mL cutoff captured in patients with anaphylaxisAnaphylaxis A severe allergic reaction that can turn fatal without treatment. Patients with SM are at a higher risk of developing anaphylaxis..
PROSPECTOR was a study of 381 adults with anaphylaxis or symptoms of systemic mast cell activationMast cell activation Describes when mast cells release histamine and other mediators into the blood stream in response to an allergen or other trigger. This leads to symptoms like fatigue, rash and, in severe cases, anaphylaxis.. All underwent blood testing for KIT D816V, a mutation that drives most clonal mast cell diseases.
What is a KIT mutation?
SM is usually caused by a sporadic mutation in the KIT gene, which codes for a protein called CD117 transmembrane tyrosine kinase. The protein is involved in the growth, survival and migration of mast cells. The most common KIT mutation associated with SM is the D816V mutation, which results in the amino acid aspartic acid being replaced by the amino acid valine in the protein chain.
The post hoc analysis presented in the poster included 79 participants who either tested positive for the KIT D816V mutation or who underwent further diagnostic evaluation. Researchers confirmed clonal mast cell disease in 46 participants; the other 33 did not have the condition.
Clonal mast cell disease was found across all BST ranges, even in patients with levels as low as 3.4 ng/mL. Among the 46 patients with confirmed disease, 37 (80%) had BST below 20 ng/mL and 10 (22%) had levels below 8 ng/mL. Using the 20 ng/mL cutoff would have identified only nine of the 46 cases.
HαT appeared to raise BST mainly among patients without clonal disease. Excluding HαT carriers lowered the median level from 15.6 to 7.8 ng/mL in that group. Among patients with clonal disease, excluding carriers changed the median only slightly, from 12.8 to 12.7 ng/mL. Overall, BST did not reliably predict who had the condition.
The researchers warned that using a single BST value or cutoff to decide who receives further testing could miss cases of clonal mast cell disease. Such an approach “could miss and delay diagnosis, particularly in anaphylaxis populations,” they wrote. Careful clinical assessment and testing for KIT mutations may help identify patients whose BST levels remain below commonly used thresholds.
