Introduction: Clonal mast cell diseases (cMCD) are driven by clonal expansion of aberrant mast cells (MC), primarily due to the gain-of-function KIT D816V mutation. Systemic mastocytosis (SM), the most common subtype of cMCD, harbors KIT D816V in approximately 95% of adult cases. SM diagnosis is defined by 1 major criterion from the World Health Organization (WHO 2023) and International Consensus Classification (ICC 2022), the presence of noncutaneous tissue MC aggregates, and 4 minor criteria including basal serum tryptase (BST) >20 ng/mL. Emerging evidence supports that SM can occur with BST levels below 20 ng/mL. Therefore, recent guidance from the American College of Allergy, Asthma, and Immunology recommends that BST >8 ng/mL should be considered suggestive of cMCD or hereditary alpha tryptasemia (HaT). BST levels below 20 ng/mL have been identified as a source of diagnostic SM/cMCD confusion. “Tryptase-gating,” using BST >20 ng/mL as a threshold for further SM/cMCD evaluation, may delay diagnosis. Here, we aim to evaluate the diagnostic utility and reliability of BST levels in predicting cMCD.

Methods: PROSPECTOR (NCT04811365) was a multicenter, prospective, screening study that evaluated the prevalence of KIT D816V mutation in peripheral blood (PB) by central laboratory testing using droplet digital PCR (limit of detection ≤0.03%) in 381 patients with anaphylaxis. Post hoc, local follow-up assessments to evaluate for the presence of cMCD were conducted in a subset of 27 patients with elevated BST (>11.4 ng/mL) in the absence of HaT. Univariate logistic regression was performed to evaluate BST as the sole predictor of cMCD. A multivariable exploratory model included age, sex, and BST as predictors of cMCD risk.

Results: In PROSPECTOR, 8% (29/381) patients had documented cMCD: 15 patients were positive for KIT D816V in central PB testing and 14 patients were KIT D816V-negative, with BST >11.4 ng/mL in the absence of HaT and subsequently diagnosed following bone marrow biopsy. Of the 15 KIT D816V-positive patients, 80% (12/15) had BST <20 ng/mL (median: 14.2 ng/mL [min, max: 7.2, 19.9]); 1 patient had HaT (BST=11.9 ng/mL). An exploratory analysis suggested comparable proportions of KIT D816V positivity across BST strata, though sample sizes are small. Local assessment in 27 patients with elevated BST (>11.4 ng/mL) without HaT led to cMCD diagnosis in 22 patients; 77% (17/22) had BST <20 ng/mL. Among these, 64% (14/22) were negative for KIT D816V by central PB testing, and 79% (11/14) had BST between 11.4 ng/mL and 20 ng/mL. In the remaining 5/27 patients without confirmed cMCD, BST levels were all <20 ng/mL. Exploratory, multivariable analyses comparing the clonal population (confirmed cMCD diagnosis and no HaT [n=28]) with the control population (unconfirmed cMCD diagnosis due to absence of bone marrow biopsy on follow-up [n=5]) showed no evidence of an association between cMCD and age, sex, or BST level, although the analysis was underpowered due to small sample size. A univariate analysis focused on BST alone revealed no significant association with cMCD (odds ratio: 0.978; 95% confidence interval: 0.868–1.102). Descriptive statistics showed similar median BST levels across groups (median: 14.9 ng/mL [min, max: 7.2, 200] vs 16.1 ng/mL [min, max: 12.0, 19.9] in the cMCD and unconfirmed cMCD cohorts, respectively), noting 1 extreme BST outlier (200 ng/mL) in the cMCD group.

Conclusions: Overall, tryptase should be obtained when looking for cMCD. In this limited study 79% of patients (23/29, 12/15 from central PB testing and 11/14 from local follow-up assessment) with confirmed cMCD (including SM) in PROSPECTOR had BST <20 ng/mL, suggesting that restricting screening for cMCD to cases with BST >20 ng/mL may lead to delayed diagnosis. BST of >11.4 ng/mL in the absence of HaT should be considered for evaluation of cMCD.

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2025
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