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.

These updated EAACI guidelines aim to standardize skin testing methodologies for both immediate and non-immediate drug hypersensitivity reactions. For immediate reactions, the optimal testing window is 4-6 weeks post-reaction; whereas beyond 6 months, false-negative results increase. For chemotherapy-related reactions, earlier testing (within 2 weeks) remains necessary due to treatment urgency. The previously published multicenter ENDA study established the international reference method for positive immediate intradermal test reading: injection of exactly 0.02 mL with a wheal at 20 min measuring ≥ initial wheal +3 mm, representing a major standardization achievement. For patch testing, exact active ingredient concentrations must be systematically documented. When tablets are crushed and diluted at 30% in petrolatum, significant variability in final concentrations has been observed. The guidelines present validated nonirritant concentrations for major drug classes including antibiotics, contrast media, anesthetics, proton pump inhibitors, chemotherapies, and biologicals. Specific recommendations are based on negative controls demonstrating specificity, while conditional recommendations are provided when few or no negative controls are available. Risk stratification algorithms now allow direct drug provocation testing for mild maculopapular exanthema, bypassing preliminary skin tests. However, more severe reactions such as anaphylaxis require skin testing before considering drug provocation tests. For DRESS/AGEP/SJS/TEN, skin tests are useful and safe for identifying culprit drugs. These harmonized methods enable safe drug allergy delabeling while preserving diagnostic accuracy and patient safety. Strict adherence to these standardized protocols is essential to ensure reproducible results and safe clinical practice in drug hypersensitivity evaluation.

Summary Specificity of sIgE was lower than previously reported; the sIgE‐to‐tIgE ratio performs better and offers excellent specificity. The sIgE‐to‐tIgE ratio can be used as an alternative diagnostic if BAT is unavailable.

Systemic mastocytosis (SM) is a rarely occurring clonal mast-cell disorder defined by aberrant mast-cell accumulation and episodic or chronic mediator release, giving rise to a broad range of manifestations from pruritus and flushing to gastrointestinal symptoms and anaphylaxis. In non-advanced SM, mediator-related symptoms are the major source of morbidity and substantially impair quality of life. Traditional symptom-directed therapies-including antihistamines, leukotriene modifiers, and mast-cell stabilizers-remain the foundation of care, but a subset of patients experience persistent, refractory symptoms. Advances in mast-cell biology have expanded therapeutic options for these patients, including selective KIT inhibitors, mast-cell--modulating small molecules, inhibitory-receptor agonists, epithelial-derived cytokine blockade, and agents targeting IgE-dependent and IgE-independent activation pathways. Key gaps remain, including the absence of validated biomarkers that distinguish activation from mast-cell burden, limited long-term safety data, and uncertainty around optimal dosing strategies. This review summarizes current understanding of mediator-driven disease in non-advanced SM and highlights targeted, mechanism-based therapies for refractory symptoms.

In the era of precision medicine, biologicals demonstrate how therapies can be personalized and directed against new targets. This type of therapy includes different molecules such as growth factors, immune modulators, vaccines, and monoclonal antibodies (mAbs). In recent years, biologicals have been increasingly developed and authorized, although their use in children is limited compared to that in adults, due to the complexity of the pharmacokinetics and pharmacodynamics of the involved proteins, as well as other factors, such as regulations governing clinical trials. Regardless, biologicals are used with efficacy in children to treat various diseases, including oncological, hematological, atopic, and rheumatological diseases. In parallel with the increased use of biologicals, there has been an increase in the unwanted effects of these agents. This paper aims to provide physicians with a practical approach to differentiate between the types of reactions to biologicals in children, especially mAbs, based on the frequency of use, for a comprehensive allergy workup. Starting from a clinical case (i.e., phenotype), specific biomarkers of the involved molecular mechanism (i.e., endotype) are described, providing the reader with currently known instruments to guide the diagnosis. Finally, practical limitations, preventive measures, and unmet needs were discussed by a panel of experts.

Mast cell disorders (MCD), including mastocytosis and mast cell (MC) activation syndrome (MCAS), encompass a heterogeneous spectrum of diseases often presenting with debilitating manifestations. Variable clinical manifestations, ranging from otherwise asymptomatic cutaneous forms to recurrent anaphylaxis, pose significant challenges for timely diagnosis and effective management. Despite increasing recognition of MCD in Europe, diagnosis is frequently delayed, and therapeutic approaches remain inconsistent, potentially due to gaps and disparities in training. An European Academy of Allergy and Clinical Immunology (EAACI) Task Force (TF) was created to address this need. Through iterative consensus, the TF members formulated ten expert-based recommendations outlining the minimum competencies that allergology and clinical immunology trainees should acquire regarding MCD. These include fundamental knowledge of MC biology, pathogenesis of clonality, recognition of systemic manifestations, diagnostic methodologies, pharmacological and preventive strategies, management of comorbid Hymenoptera venom allergy, pediatric aspects, communication skills, and how to acquire and consolidate expertise. This position paper underscores the need for harmonized competency-based training competencies on MCD for Allergists and Clinical Immunologists across Europe. We advocate for the incorporation of these recommendations into national postgraduate curricula, aiming to foster earlier recognition, improve management, and ultimately enhance long-term outcomes for MCD patients.

Flow cytometric analysis of activated basophils, known as the basophil activation test (BAT), is a tool available for the diagnosis of IgE-mediated allergic reactions. Despite its reported clinical utility, around 10%-20% of tested subjects fall into the category of basophil non-releasers, meaning that their basophils fail to degranulate upon IgE-mediated stimulation in vitro. Several factors causing this non-releaser status have been identified, but we currently lack a unified nomenclature to define such inconclusive BAT results and the practical steps to minimize such outcomes. In accordance with the STAndards for the Reporting of Diagnostic accuracy studies (STARD) statement, non-releasers must be reported and considered in the calculation of clinical BAT performance metrics, as failure to do so significantly limits the broader implementation of BAT in routine practice. This review provides an overview of intrinsic and extrinsic factors responsible for the basophil non-releaser phenotype in BAT. Furthermore, it proposes a standardized nomenclature for consistently reporting and integrating inconclusive BAT results in the diagnostic performance metrics and suggests diagnostic algorithms to facilitate their interpretation in clinical practice.

Cryopyrin-associated periodic syndromes (CAPS) are autoinflammatory disorders caused by gain-of-function NLRP3 variants. Although NLRP3 inflammasomes mediate IL-1β secretion through Gasdermin D (GSDMD), we show that GSDMD deletion did not prevent autoinflammation in mice ubiquitously expressing the Nlrp3A350V variant. Inflamed skin of Nlrp3A350V-expressing GSDMD-deficient mice displayed citrullinated histone 3-containing neutrophil extracellular traps (CitH3-NETs). CitH3-NETs induced IL-1β secretion from murine Nlrp3A350V-expressing GSDMD-deficient macrophages as well as from human CAPS patient monocytes and macrophages. Blocking protein arginine deiminase-4 (PAD4) prevented CitH3 release and disabled the IL-1β-inducing NET effects, identifying CitH3 as crucial trigger. Mechanistically, CitH3-NETs activated GSDME in GSDMD-deficient Nlrp3A350V macrophages, and GSDME deletion prevented pathology in Nlrp3A350V-expressing GSDMD-deficient mice. In addition to this GSDME-dependent autoinflammation axis, PAD4 deletion also prevented autoinflammation in mice with neutrophil-specific Nlrp3A350V expression that develop CAPS in a GSDMD-dependent manner. These observations support a CAPS model in which PAD4-mediated CitH3-NET release can trigger both GSDMD-dependent and GSDME-dependent autoinflammation.

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.

Abstract Advanced systemic mastocytosis (AdvSM), comprising aggressive systemic mastocytosis, mast cell leukemia, and systemic mastocytosis with an associated hematological neoplasm, is a heterogeneous myeloid neoplasm with poor prognosis. Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only potentially curative treatment, yet its benefit across AdvSM subtypes in the era of KIT-targeted tyrosine kinase inhibitors (TKIs) such as midostaurin and avapritinib remains unclear. To identify patient subgroups benefiting from allo-HCT and to define prognostic factors for post-transplant survival, we analyzed 631 AdvSM patients from the European Competence Network on Mastocytosis registry, including 69 who underwent allo-HCT. Treatment effects were assessed using time-dependent Cox regression in a transplant-eligible complete-case cohort ( n = 419). In this cohort, allo-HCT showed no overall survival (OS) benefit (hazard ratio [HR] 1.21, 95% CI 0.80–1.84; p = 0.37), whereas TKI response emerged as a strong independent predictor of survival (HR 0.42; p <0.001). Subtype-stratified analysis revealed an allo-HCT benefit exclusively in patients with systemic mastocytosis associated with acute myeloid leukemia ( n = 30; HR 0.20; p = 0.020). Among the 69 transplanted patients, median OS was 49.6 months with 2-year and 5-year survival of 63% and 46%, respectively. The International Prognostic Scoring System for Mastocytosis (IPSM) at transplantation independently predicted both OS (HR per category 1.68; p = 0.026) and progression-free survival (HR 1.99; p = 0.003), whereas the Mutation-Adjusted Risk Score and diagnostic subtype did not reach statistical significance. Competing risk analysis demonstrated that higher IPSM captured both relapse-related and transplant-related mortality. These findings suggest that the survival benefit of allo-HCT in AdvSM is driven primarily by control of the associated myeloid neoplasm. Accordingly, allo-HCT should be prioritized in patients with SM-AML, whereas TKI-directed strategies may be preferred in other subtypes, with IPSM at transplantation potentially guiding transplant selection and timing.

Over the past several decades, there have been significant advances in our understanding of both immunological and pharmacological mechanisms of adverse drug reactions (ADRs). Immune-mediated drug reactions (IMDRs) represent a small proportion of ADRs and are caused by a pathological activation of the immune system or inflammatory pathways. Drugs can act as an antigen or may directly interact with the immune system or inflammatory pathways, making immune-mediated drug reactions observed in contemporary practice not sufficiently explained by the Gell and Coombs (G&C) framework. Moreover, the phenotype alone is neither pathognomonic nor sufficient to infer the endotype. The proposed nomenclature integrates chrono-morphological phenotypes, mechanistic endotypes and characteristics of the involved drug. In this nomenclature, IMDRs are classified, according to the nature of interaction with the immune system, in: (i) drug allergy that encompasses antigen-driven reactions-diagnosed by tests detecting sensitisation-and (ii) drug hypersensitivity that includes the heterogeneous broad group of drug-directly-driven reactions. This framework supports precision medicine, aligns terminology with mechanisms, and provides a common language for interdisciplinary communication, pharmacovigilance, and drug development. It accommodates emerging therapeutic classes and remains adaptable to future discoveries in immunopathogenesis and biomarker development.

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: 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.