Systemic mastocytosis (SM) is a protean hematologic disorder characterized by uncontrolled expansion and accumulation of tissue mast cells (MC) in various organs, including skin, bone marrow, spleen, and gastrointestinal tract. In most cases, neoplastic cells exhibit the transforming KIT mutation D816V. Clinical symptoms arise from organ infiltration by neoplastic MC and/or pro-inflammatory mediators and cytokines released by these cells. Indeed, in a majority of the patients, acute or chronic mediator-induced symptoms are recorded, and in some instances, symptoms are severe and drug-resistant or even manifest as life-threatening anaphylaxis. In this article, we review the role of MC and basophils in anaphylactic reactions in patients with SM and the impact of genetic variables, co-morbidities, specific IgE, and factors counteracting MC activation. Whereas avoidance of all known and potential triggers of MC activation is crucial in the management of anaphylaxis in SM patients, specific therapy is also standard, including histamine receptor blockers, other anti-mediator-type drugs and drugs suppressing MC activation and/or expansion. Novel KIT D816V-targeting drugs can potentially decrease the anaphylaxis risk by reducing the MC burden and by targeting KIT-dependent and IgE-receptor-dependent signaling processes in neoplastic MC. Application of such drugs often leads to sustained responses and an increase in the quality of life in these patients.

This study evaluated the measurement properties and ability to detect clinically meaningful change of the Mastocytosis Symptom Severity Daily Diary (MS2D2), a patient-reported outcome instrument designed to measure symptom severity in adults with nonadvanced systemic mastocytosis (NonAdvSM). Psychometric evaluation of the MS2D2 used blinded data from 230 adults with NonAdvSM enrolled in the Summit Phase 2 study (NCT05186753). The study comprised two parts: Part 1 (n = 54) for dose-finding and initial domain structure development, and Part 2 (n = 179) for efficacy evaluation, validation and longitudinal assessment. Analyses included item-level statistics, confirmatory factor analysis (CFA), internal consistency (Cronbach’s α), test–retest reliability (ICC), convergent and known-groups validity, responsiveness, and anchor-based estimation of meaningful change thresholds. Structural validity supported a four-domain, 11-item Total Symptom Score (TSS) framework. Internal consistency and test–retest reliability were excellent (α = 0.79–0.95; ICC = 0.95–0.98). Convergent validity was supported through strong correlations with disease-specific symptom and health-related quality of life (HRQoL) measures (r = 0.85 and r = 0.59). Known-groups validation revealed domain scores differing by 2–5 points between anchor severity strata and TSS by 2.8 points (all p < 0.05). Scores were sensitive to change, correlating (r = 0.39–0.74) with changes in patient status. TSS within-patient meaningful improvement thresholds were 1.6–2.2 points (0–10 scale) and 17.2–24.7 points (0–110 sum), with domains showing similar ranges. Percent change thresholds indicated meaningful improvement at approximately 30–40

BACKGROUND:Indolent systemic mastocytosis (ISM), a clonal mast cell disease primarily driven by the KIT D816V mutation, can cause long-term debilitating symptoms and poor quality of life. Most patients rely on symptom-directed best supportive care (BSC) medications, which do not treat the underlying driver of ISM. Avapritinib, an oral, potent, selective KIT D816V inhibitor, is approved in adults with ISM. OBJECTIVE:We sought to understand the long-term efficacy and safety of avapritinib in ISM. METHODS:The PIONEER trial (NCT03731260) enrolled adults with moderate to severe ISM symptoms. Patients initiated avapritinib 25 mg once daily (QD; recommended dose) plus BSC in part 1, 2, or 3; open-label part 3 is ongoing with up to 5 years of follow-up. As per investigator discretion and disease burden, a dose increase up to avapritinib 50 mg QD was permitted in part 3. RESULTS:As of February 21, 2025, 226 patients initiated avapritinib at 25 mg QD. The median (range) treatment duration was 40.0 (0.7-67.2) months. Patients receiving avapritinib experienced durable and clinically meaningful symptom improvement (mean change, -19.39 [n = 127] in the Indolent Systemic Mastocytosis Symptom Assessment Form total symptom score) through approximately 3 years. Avapritinib continued to be well tolerated for a longer term with a safety profile comparable with the previously reported placebo-controlled portion. Most treatment-related adverse events (TRAEs) were grades 1 to 2, with limited grade 3 or higher reported. Edema events were the most frequent TRAEs (mostly grade 1). Serious TRAEs occurred in 3 patients (1%), and 7 patients (3%) discontinued treatment because of TRAEs. CONCLUSIONS:Long-term follow-up (median, ∼3 years) demonstrates that avapritinib is effective and well tolerated. Avapritinib shows a favorable benefit-risk profile as a chronic ISM treatment.

BACKGROUND:Indolent systemic mastocytosis (ISM), a clonal mast cell disease driven by the KIT D816V mutation, can often cause debilitating dermatologic symptoms. OBJECTIVE:Assess improvement of ISM-related skin manifestations after treatment with avapritinib, a highly selective KIT D816V inhibitor, vs placebo in Part 2 of the PIONEER study (NCT03731260). METHODS:Patients with moderate to severe ISM received avapritinib 25 mg once daily (n = 141) or placebo (n = 71). Endpoints included skin lesion area and pigmentation at week 24, skin mast cell burden, and change in symptoms. RESULTS:Mean percent reduction in lesional surface area was -36.6% with avapritinib vs -1.8% with placebo in the most affected area; 86% vs 0% had improved skin lesion color. Mean percent change in skin mast cell burden decreased with avapritinib (-22.1%) vs placebo (10.1%). Avapritinib vs placebo significantly improved skin symptom domain score (mean change -7.2 vs -2.8; P < .0001), including the individual skin symptoms itching, flushing, and spots. Avapritinib was well tolerated. LIMITATIONS:Photography was optional, so analysis population for lesion area and color were smaller (n = 111) than the overall study population (n = 212). CONCLUSION:Avapritinib treatment improved dermatologic symptoms, decreased skin lesion size, normalized skin lesion color, and reduced skin mast cell burden in patients with ISM.

Background Patients with indolent systemic mastocytosis (ISM), a clonal mast cell disease primarily driven by the KIT D816V mutation, often have lifelong debilitating symptoms. Anaphylaxis is a common feature of the disease seen in up to half of patients. The effects of KIT D816V-targeted therapy on the incidence of anaphylaxis are unknown. Methods We describe anaphylaxis events occurring in the study population of PIONEER (NCT03731260) during the 12-week screening and/or 24-week treatment period. This study had previously demonstrated the efficacy and safety of the oral, highly selective, KIT D816V inhibitor avapritinib compared with placebo in patients with moderate-to-severe ISM. Results In total, 13/212 (6.1%) patients in PIONEER experienced anaphylaxis during screening or treatment (6 during screening, 5 during treatment, and 2 during both screening and treatment). Baseline demographics, clinical characteristics, and known triggers varied. During the randomized, placebo-controlled treatment period, 4/141 (2.8%) avapritinib-treated patients and 3/71 (4.2%) placebo-treated patients experienced anaphylaxis. Conclusions Larger studies with longer-term follow-up are required to further confirm the effects of avapritinib on anaphylaxis in patients with SM.

Background: Systemic mastocytosis (SM) is characterized by neoplastic mast cell (MC) infiltration of tissues. Nonadvanced SM (NonAdvSM) is the most prevalent form, associated with debilitating symptoms which significantly impair quality of life. Bezuclastinib is an oral, potent, selective type 1 tyrosine kinase inhibitor with activity against KIT D816V, the mutation found in ~95% of SM patients. Study (NCT05186753) Part 1 informed the recommended dose for Part 2. Here we report primary results from SUMMIT Part 2. Objectives: Explain the therapeutic hypothesis of bezuclastinib, an oral, potent, and selective type 1 tyrosine kinase inhibitor, in nonadvanced systemic mastocytosis. April 2026 | Vol. 2, Suppl 1 | 2026 NCODA International Spring Forum 28 NCODA.org NOHMA | Partner Abstracts A21-A33 Evaluate the efficacy and safety data of bezuclastinib from the pivotal SUMMIT trial in patients with nonadvanced systemic mastocytosis and recognize how therapeutic targeting of the underlying disease mechanism may improve patient outcomes. Understand the relevance of correlating subjective and objective measures of disease burden with emerging targeted therapies such as bezuclastinib. Methods: SUMMIT Part 2 is a pivotal trial of bezuclastinib in NonAdvSM patients with inadequate symptom control despite best supportive care (BSC) medications. Patients were randomized 2:1 to 100mg every day (QD) bezuclastinib+ BSC or placebo+BSC. Primary endpoint was 24-week mean change from baseline in Mastocytosis Symptom Severity Daily Diary (MS2D2) total symptom score (TSS) (range 0–110), a fit-for-purpose patient-reported outcome measure of NonAdvSM symptom severity. Key secondary endpoints included the proportion of patients with ≥50% reduction in serum tryptase (ST), KIT p.D816V variant allele frequency (VAF), bone marrow (BM) MC burden, MS2D2 TSS, and ≥30% TSS reduction. Results: 179 patients enrolled in Part 2: n=119 bezuclastinib, n=60 placebo; median age (range) 51 (23-78) years; 65.9% female; mean (SD) baseline MS2D2 TSS 55.6 (19.8). At baseline, median (range) blood KIT p.D816V VAF, BM MC burden, and ST were 0.25% (0-34%), 10% (1-75%), and 40 (6-692) ng/mL, respectively. At Week 24, bezuclastinib significantly improved symptoms versus (vs) placebo (least squares (LS) mean placebo-adjusted difference in MS2D2 TSS: –8.9 points; P=0.0002). Significantly more patients receiving bezuclastinib vs placebo achieved ≥50% reductions in KIT D816V VAF (P<0.0001), ST (P<0.0001), BM MCs (P<0.0001), TSS (P=0.01), and ≥30% reduction in TSS (P=0.0004). Most treatment-emergent adverse events (TEAEs) were low grade (70% grade 1) and reversible. The most common TEAEs (≥10%) in any treatment group and occurring more with bezuclastinib were hair color changes (69.5% vs 5.0%), altered taste (23.7% vs 0%), nausea (22.0% vs 13.3%), increased alanine aminotransferase (ALT)/aspartate aminotransferase (AST) (22.0% vs 6.6%), headache (17.8% vs 11.7%), alopecia (11.9% vs 3.3%), and increased alkaline phosphatase (ALP) (10.2% vs 3.3%). All discontinuations (5.9%) due to treatment-related AEs were due to transaminase elevations; all fully resolved. Conclusions: At 24 weeks, bezuclastinib demonstrated statistically significant superiority to placebo on all primary and key secondary endpoints, showing clinically meaningful improvements in symptoms and disease biomarkers in patients with NonAdvSM; treatment was generally well-tolerated. Results support use of bezuclastinib to reduce SM burden and symptoms in NonAdvSM, and a potentially disease- modifying impact. Funding: Cogent Biosciences. Prior Presentations: Presented at the American Society of Hematology (ASH) Annual Meeting 2025, December 6-9, Orlando, FL.

Background The KIT D816V mutation is a hallmark of clonal mast cell disease (cMCD) including systemic mastocytosis. cMCD diagnosis is frequently delayed because of variable symptoms until confirmatory bone marrow biopsy is performed. Screening techniques for KIT D816V variant in peripheral blood (PB) may facilitate diagnosis. Prevalence of KIT D816V in patients with anaphylaxis or mast cell activation (MCA) symptoms is unknown. Objective We sought to determine the prevalence of KIT D816V in PB of patients with anaphylaxis or systemic MCA symptoms. Methods The PROSPECTOR trial (NCT04811365) included patients with anaphylaxis or systemic MCA symptoms who had (1) moderate to severe anaphylaxis to Hymenoptera sting, (2) 20% + 2 ng/mL increase in tryptase level over the baseline level during moderate to severe anaphylaxis with cardiovascular involvement, and/or (3) involvement of both the cardiovascular system and 1 or more other organ systems with basal serum tryptase (BST) levels greater than or equal to 8 ng/mL. KIT D816V in PB, hereditary α-tryptasemia (HaT), and BST levels were centrally evaluated. Results Of the 381 enrolled patients, 179, 76, and 203 were in groups 1, 2, and/or 3, respectively. Fifteen patients (4%) had detectable KIT D816V in PB; 12 of 15 (80%) had BST levels less than 20 ng/mL. Most patients with KIT D816V (11 of 15 [73%]) had Ring-Messmer grade III/IV anaphylaxis. Fourteen additional patients with BST levels greater than 11.4 ng/mL, no HaT, and local follow-up were diagnosed with cMCD, totaling 29 of 381 patients (8%) with cMCD in the PROSPECTOR trial. The overall prevalence of HaT was 36% (138 of 381). Conclusions The PROSPECTOR trial demonstrated a meaningful KIT D816V prevalence in patients with anaphylaxis or systemic MCA symptoms; more frequent and sensitive screening for KIT D816V is needed in this patient population.

Idiopathic anaphylaxis (IA) refers to recurrent, life-threatening hypersensitivity reactions without identifiable triggers, representing a diagnostic and therapeutic challenge. We describe a 17-year-old girl presenting with recurrent episodes of flushing, pruritus, and respiratory symptoms, without consistent allergen exposure or cofactor involvement. Evaluation revealed elevated acute tryptase levels with a normal baseline, negative skin testing results, and negative galactose-α-1,3-galactose (α-gal) and KIT mutation analysis. The patient improved on daily cetirizine with no further reactions. IA remains a diagnosis of exclusion, requiring careful consideration of IgE-mediated allergies, cofactor-dependent anaphylaxis, clonal mast cell disorders, and systemic mimics such as neuroendocrine tumors or vasovagal syncope. We summarize current evidence on IA pathogenesis, epidemiology, differential diagnosis, and management. Although antihistamines and corticosteroids are commonly used prophylactically, emerging data suggest that anti-IgE therapy with omalizumab may offer benefit in refractory cases. Diagnostic workup should include serum tryptase measurement, trigger identification, and consideration of underlying mast cell disorders. Future research is needed to clarify the natural history, standardize diagnostic pathways, and evaluate long-term treatment strategies for this heterogeneous condition.

Mastocytosis is a spectrum of clonal myeloid disorders defined by abnormal growth and accumulation of mast cells in various organ systems. The disease is divided into cutaneous mastocytosis, systemic mastocytosis (SM) and mast cell sarcoma. SM is further categorized into several non-advanced and advanced forms. The prognosis of cutaneous mastocytosis and non-advanced SM is mostly favourable, whereas prognosis and survival in advanced SM and mast cell sarcoma are poor. During the past 15 years, major advances have been made in the diagnosis, prognosis and management of patients with mast cell neoplasms. Management of mastocytosis consists of symptomatic therapy, including anti-mast cell mediator drugs, and cytoreductive agents for patients with advanced disease and selected individuals with non-advanced disease, as well as recognition and prevention of comorbidities such as osteoporosis and anaphylaxis. The preclinical and clinical development of KIT-D816V-targeting drugs, such as midostaurin or avapritinib, mark a milestone in improving management, the quality of life and survival in patients with SM. These agents induce major responses or even remission in people with advanced SM and lead to rapid improvement of mediator-related symptoms and quality of life in symptomatic patients. Mastocytosis is characterized by focal accumulations of clonal mast cells in the skin and/or in internal organs such as bone marrow, spleen, lymph nodes or the gastrointestinal tract. In this Primer, Akin et al. discuss the epidemiology, pathophysiology, diagnosis and current management of mastocytosis, and future research areas.