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•Serum chemistry profiling is of diagnostic and prognostic relevance based on easily accessible parameters.•Serum chemistry markers help to assess and quantify organ damage.

Physiological levels of basal serum tryptase vary among healthy individuals, depending on the numbers of mast cells, basal secretion rate, copy numbers of the TPSAB1gene encoding alpha tryptase, and renal function. Recently, there has been a growing debate about the normal range of tryptase because individuals with the hereditary alpha tryptasemia (HαT) trait may or may not be symptomatic, and if symptomatic, uncertainty exists as to whether this trait directly causes clinical phenotypes or aggravates certain conditions. In fact, most HαT-positive cases are regarded as asymptomatic concerning mast cell activation. To address this point, experts of the European Competence Network on Mastocytosis (ECNM) and the American Initiative in Mast Cell Diseases met at the 2022 Annual ECNM meeting and discussed the physiological tryptase range. Based on this discussion, our faculty concluded that the normal serum tryptase range should be defined in asymptomatic controls, inclusive of individuals with HαT, and based on 2 SDs covering the 95% confidence interval. By applying this definition in a literature screen, the normal basal tryptase in asymptomatic controls (HαT-positive persons included) ranges between 1 and 15 ng/mL. This definition should avoid overinterpretation, unnecessary referrals, and unnecessary anxiety or anticipatory fear of illness in healthy individuals.

Diagnostic testing of patients who present for evaluation of insect venom allergy can involve many levels of investigation. A detailed initial history is critical for diagnosis and prognosis. The severity of previous sting reactions and the presence or absence of urticaria or hypotension predict severe future sting reactions and underlying mast cell disorders. Venom skin tests and specific IgE measurement can confirm the diagnosis but have limited positive predictive value for the frequency and severity of future sting reactions. Testing for serum IgE to recombinant venom component allergens can distinguish true allergy from cross-reactivity to honey bee and yellowjacket venoms. Basophil activation tests can improve the detection of venom allergy and predict the severity of reactions and the efficacy of venom immunotherapy but are limited in availability. An elevated basal serum tryptase level is an important marker for severe sting anaphylaxis and underlying mast cell disorders (eg, hereditary α-tryptasemia and clonal mast cell disease). When there is high suspicion (eg, using the Red Espanola de Mastocytosis score), bone marrow biopsy is the definitive tool to characterize mast cell disorders that are associated with the most severe outcomes in patients with insect sting allergy.

•Characterizing genetic regulation of tryptase expression redefines clinical laboratory reference ranges based on TPSAB1replication number.•Individualized reference values for serum tryptase change and improve the utility of this biomarker in the diagnosis of myeloid neoplasms.

•The median OS of patients with MCL was 1.6 years; a diagnosis of MCL-AHN and an abnormal karyotype were each associated with inferior outcomes.•Midostaurin was the most commonly used agent in MCL and was associated with improved OS in a multivariate analysis.

Since 2010, patients and physicians have collaborated to understand unmet needs of patients with mast cell diseases, incorporating mastocytosis and mast cell activation disorders, which include mast cell activation syndromes.

Mast cell activation (MCA) is common and occurs in a number of pathologic conditions, including IgE-dependent and independent allergic reactions, atopic disorders, autoimmune processes, and mastocytosis. In a subset of patients, no underlying disease and no known trigger of MCA are found. When the symptoms are severe, systemic, and recurrent, and accompanied by a diagnostic increase in the serum tryptase level or other mast cell mediators, an MCA syndrome (MCAS) may be diagnosed. In these patients, the symptoms typically respond to drugs suppressing MCA, mediator production in mast cells, or mediator effects. In each case, diagnostic consensus criteria must be fulfilled to diagnose MCAS. In other patients, MCA may be local, less severe, or less acute, or may be suspected but not confirmed, so that the diagnostic criteria of MCAS are not fulfilled. In these patients, it may be difficult to prove MCA, for example, by measuring multiple mast cell mediators or basophil activation, the latter as a surrogate of IgE-dependent hypersensitivity. However, validated diagnostic criteria for implicating suspected MCA behind such conditions are lacking, even if some of these conditions have recently been assigned to an International Classification of Diseases-10-Clinical Modificationcode (ICD-10-CM). In this article, we discuss diagnostic features and criteria and propose a ICD-10-CM–adjusted classification for disorders associated with MCA, herein referred to as MCA disorders (MCADs), with special emphasis on the delineation between confirmed MCAS, MCAD not fulfilling MCAS criteria, and suspected MCAD that is not present. In addition, we discuss the discrimination between overt MCAD and predisposing conditions, such as atopic states, mastocytosis, and hereditary alpha tryptasemia.

Indolent systemic mastocytosis (ISM) has a favorable prognosis and normal life expectancy. However, many patients suffer from mast cell (MC) mediator-related symptoms, which significantly affect quality of life (QoL). Cutaneous, gastrointestinal, and neurological complaints, musculoskeletal pain, and the presence of skin lesions, anaphylaxis, and osteoporosis are the main symptoms and signs in ISM and must be assessed in all patients before and during treatment. Validated mastocytosis-specific patient-reported outcome measures (PROMs) should be used for this purpose. Serum tryptase and KITD816V allele burden are recommended as secondary outcome parameters, noting that they do not reflect the severity of signs, symptoms, and related QoL impairment, but indirectly express MC burden. Changes from baseline of 90%, 60%, and 30% indicate complete response >90%, major response 60% to 90%, partial response 30% to 60%, and no response <30% to treatment. To conclude, we recommend the use of PROMs as primary outcome parameters to define treatment response in patients with ISM in clinical trials and in everyday clinical practice.

In the current classification of the World Health Organization (WHO), bone marrow mastocytosis (BMM) is a provisional variant of indolent systemic mastocytosis (ISM) defined by bone marrow involvement and absence of skin lesions. However, no additional diagnostic criteria for BMM have been proposed. Within the registry dataset of the European Competence Network on Mastocytosis, we compared characteristics and outcomes of 390 patients with BMM and 1175 patients with typical ISM. BMM patients were significantly older, predominantly male, had lower tryptase and lower burden of neoplastic mast cells, and displayed a higher frequency of allergic reactions, mainly triggered by Hymenoptera, than patients with typical ISM. The estimated 10-year progression-free survival of BMM and typical ISM was 95.9% and 92.6%, respectively. In BMM patients defined by WHO-based criteria, the presence of one B-Finding and tryptase level ≥125 ng/mL were identified as risk factors for progression in multivariate analyses. BMM patients without any of these risk factors were found to have better progression-free survival (p< 0.05) and better overall survival (p< 0.05) than other ISM patients. These data support the proposal to define BMM as a separate SM variant characterized by SM criteria, absence of skin lesions, absence of B-Findings, and tryptase levels <125 ng/mL.

In recent years, knowledge about mechanisms underlying mast cell activation (MCA) and accumulation in various pathologic conditions increased substantially. In addition, criteria and a classification of MCA syndromes (MCASs) have been set forth. MCAS is defined by typical clinical symptoms, a substantial increase in serum tryptase level during an attack over the patient's baseline tryptase, and a response of the symptoms to drugs targeting mast cells, mediator production, and/or mediator effects. Alternative diagnostic criteria of MCAS have also been suggested, but these alternative criteria often lack specificity and validation. In this report, we critically review the contemporary literature relating to MCAS and compare the specificity, sensitivity, and strength of MCAS-related parameters within proposals to diagnose and classify MCAS and its variants. Furthermore, we highlight the need to apply specific consensus criteria in the evaluation and classification of MCAS in individual patients. This is an urgent and important medical necessity because as an increasing number of patients are being given a misdiagnosis of MCAS based on nonspecific criteria, which contributes to confusion and frustration by patients and caregivers and sometimes may delay recognition and treatment of correct medical conditions that often turn out to be unrelated to MCA.

Mastocytosis is a neoplasm characterized by an accumulation of mast cells in various organs and increased risk for severe anaphylaxis in patients with concomitant allergies. Coronavirus disease 2019 (COVID-19) is a pandemic that is associated with a relatively high rate of severe lung disease and mortality. The mortality is particularly high in those with certain comorbidities and increases with age. Recently, several companies have developed an effective vaccination against COVID-19. Although the reported frequency of severe side effects is low, there is an emerging discussion about the safety of COVID-19 vaccination in patients with severe allergies and mastocytosis. However, even in these patients, severe adverse reactions are rare. We therefore recommend the broad use of COVID-19 vaccination in patients with mastocytosis on a global basis. The only well-established exception is a known or suspected allergy against a constituent of the vaccine. Safety measures, including premedication and postvaccination observation, should be considered in all patients with mastocytosis, depending on the individual personal risk and overall situation in each case. The current article provides a summary of published data, observations, and expert opinion that form the basis of these recommendations.

Several risk stratification models have been proposed in recent years for systemic mastocytosis but have not been directly compared. Here we designed and validated a risk stratification model for progression-free survival (PFS) and overall survival (OS) in systemic mastocytosis on the basis of all currently available prognostic factors, and compared its predictive capacity for patient outcome with that of other risk scores.

Systemic mastocytosis (SM) is frequently associated with eosinophilia. To examine its prevalence and clinical impact in all WHO classification-based subcategories, we analyzed eosinophil counts in 2350 mastocytosis patients using the dataset of the European Competence Network on Mastocytosis. Ninety percent of patients had normal eosinophil counts, 6.8% mild eosinophilia (0.5–1.5 × 109/l), and 3.1% hypereosinophilia (HE; >1.5 × 109/l). Eosinophilia/HE were mainly present in patients with advanced SM (17%/19%), and only rarely recorded in patients with indolent and smoldering SM (5%/1%), and some patients with cutaneous mastocytosis. The eosinophil count correlated with organomegaly, dysmyelopoiesis, and the WHO classification, but not with mediator-related symptoms or allergy. Eosinophilia at diagnosis had a strong prognostic impact (p< 0.0001) on overall survival (OS) and progression-free survival (PFS), with a 10-year OS of 19% for patients with HE, 70% for those with mild eosinophilia, and 88% for patients with normal eosinophil counts. In 89% of patients with follow-up data (n= 1430, censored at start of cytoreductive therapy), eosinophils remained stable. In those with changing eosinophil counts (increase/decrease or mixed pattern), OS and PFS were inferior compared with patients with stable eosinophil counts. In conclusion, eosinophilia and HE are more prevalent in advanced SM and are predictors of a worse outcome.

The WHO classification separates mastocytosis into distinct variants, but prognostication remains a clinical challenge. The aim of this study was to improve prognostication for patients with mastocytosis.

Mastocytosis is a clonal myeloid disorder defined by an increase and accumulation of mast cells (MCs) in one or multiple organ systems. The complex pathology of mastocytosis results in variable clinical presentations, courses, and outcomes. The World Health Organization (WHO) divides the disease into cutaneous mastocytosis (CM), several forms of systemic mastocytosis (SM), and MC sarcoma. In most patients with SM, a somatic KITmutation, usually D816V, is identified. Patients diagnosed with CM or nonadvanced SM, including indolent SM, have a near-normal life expectancy, whereas those with advanced SM, including aggressive SM and MC leukemia, have limited life expectancy. Since 2001, a multidisciplinary consensus group consisting of experts from the European Competence Network on Mastocytosis and the American Initiative in Mast Cell Diseases has supported the field by developing diagnostic criteria for mastocytosis. These criteria served as the basis for the WHO classification of mastocytosis over 2 decades. More recently, an International Consensus Classification group proposed slightly modified diagnostic criteria and a slightly revised classification. In this article, these changes are discussed. Furthermore, we propose harmonization among the proposals of the American Initiative in Mast Cell Diseases/European Competence Network on Mastocytosis consensus group, WHO, and the International Consensus Classification Group. Such harmonization will facilitate comparisons of retrospective study results and the conduct of prospective trials.

Understanding the risk factors leading to severe systemic sting reactions (SSRs) is crucial for initiating venom immunotherapy (VIT) and for educating affected individuals and their families. Some of these risk factors are well established, some are no longer considered risk factors, and some remain controversial. Well-established risk factors for severe SSRs include clonal mast cell disease, high baseline serum tryptase, and advanced age. The absence of skin symptoms and the rapid onset of symptoms are indicators of severe SSRs. Recent publications indicate that antihypertensive treatment and stings in the head and neck area are not risk factors for severe SSRs. VIT is the only available treatment that can potentially prevent further anaphylactic reactions. Although rare and generally manageable, individuals undergoing VIT may experience systemic adverse events (sAEs). More sAEs are expected in patients undergoing bee VIT compared with vespid VIT. The role of elevated baseline serum tryptase as a risk factor for sAEs remains debated, but if it is a factor, the risk is increased by only about 1.5-fold. Rapid updosing protocols, depending on the specific regimen, can also be associated with more sAEs. Severe initial SSRs, antihypertensive medication, high skin test reactivity, and high specific IgE levels are not risk factors for sAEs.

Immediate hypersensitivity reactions (HSRs) to taxanes have been increasing in recent years, but the importance of skin tests in allergological workup has not been established.

Mastocytosis is a unique hematologic neoplasm with complex biology and pathology and a variable clinical course. The disease can essentially be divided into cutaneous mastocytosis (CM) and systemic mastocytosis (SM). In adults, SM is diagnosed in most cases and manifests as either indolent or advanced disease. Patients with advanced SM have an unfavorable prognosis with reduced survival. However, so far, little is known about the prevalence of various categories of SM and about prognostic factors. In an attempt to learn more about the behavior and evolution of various forms of CM and SM, the European Competence Network on Mastocytosis (ECNM) initiated a mastocytosis registry in 2012. In this article, the set up and start phase of this registry are described. Until 2018, more than 3000 patients from 12 countries and 25 centers have been enrolled. In a majority of all patients, robust follow-up data and relevant clinical end points are available. Using this data set, a series of registry projects have been launched, with the aim to validate previously identified diagnostic and prognostic variables and to identify new disease-related and patient-related parameters in various forms of mastocytosis. Moreover, the core data set of the registry will be useful to establish multiparametric scoring systems through which prognostication and individualized management of patients with mastocytosis should improve in the foreseeable future.

Up to 7% of adult patients with Hymenoptera venom allergy may suffer from a clonal mast cell disease. Patients with clonal mast cell disease and Hymenoptera venom anaphylaxis are commonly males, without skin lesions, and anaphylaxis is characterized by hypotension and syncope in the absence of urticaria and angioedema. A normal value of tryptase does not exclude a mastocytosis. The diagnosis of a mast cell disease leads to several therapeutic consequences concerning the treatment of Hymenoptera venom allergy as matter of fact these patients have to undergo long-life venom immunotherapy, to prevent further, potentially fatal severe reactions.

Up to 75% of patients with severe anaphylactic reactions after Hymenoptera sting are at risk of further severe reactions if re-stung. Venom immunotherapy (VIT) is highly effective in protecting individuals with ascertained Hymenoptera venom allergy (HVA) and previous severe reactions. After a 3- to 5-year VIT course, most patients remain protected after VIT discontinuation. Otherwise, a lifelong treatment should be considered in high-risk patients (eg, in mastocytosis). Several case reports evidenced that patients with mastocytosis and HVA, although protected during VIT, can re-experience severe and sometimes fatal reactions after VIT discontinuation.

Organomegaly, including splenomegaly, hepatomegaly, and/or lymphadenopathy, are important diagnostic and prognostic features in patients with cutaneous mastocytosis (CM) or systemic mastocytosis (SM).

In 2002, the European Competence Network on Mastocytosis (ECNM) was launched as a multidisciplinary collaborative initiative to increase the awareness and to improve diagnosis and management of patients with mast cell disorders. The ECNM consists of a net of specialized centers, expert physicians and scientists who dedicate their work to mast cell diseases. One essential aim of the ECNM is to timely distribute all available information about the disease to patients, doctors, and scientists. In the past 20 years, the ECNM has expanded substantially and contributed successfully to the development of new diagnostic concepts, the classification, prognostication, and treatments of patients with mastocytosis and mast cell activation disorders. The ECNM also organized Annual Meetings and several Working Conferences supporting the development of the WHO classification between 2002 and 2022. In addition, the ECNM has established a robust and rapidly expanding patient registry and has supported the development of new prognostic scoring systems and new treatment approaches. In all projects, ECNM representatives collaborated closely with their US colleagues, various patient organizations, and with other scientific networks. Finally, ECNM members have started several fruitful collaborations with industrial partners, leading to the preclinical development and clinical testing of KIT-targeting drugs in systemic mastocytosis, and some of these drugs received licensing approval in recent years. All these networking activities and collaborations have strengthened the ECNM and supported our efforts to increase awareness of mast cell disorders and to improve diagnosis, prognostication and therapy in patients.

Pathology plays a central role in the diagnosis of systemic mastocytosis (SM), its delineation from other neoplasms and reactive conditions, and in monitoring of SM under therapy. The morphologic hallmark of SM is the accumulation of spindle-shaped, hypogranulated mast cells (MCs) in bone marrow (BM) and other extracutaneous tissues. Four of the 5 World Health Organization–defined diagnostic criteria (ie, compact MC aggregates [=major criterion]; atypical MC morphology; activating KITpoint mutations; aberrant expression of CD25 and/or CD2 and/or CD30 in MCs [=minor criteria]) can be addressed by the pathologist. The final classification of SM variants as either BM mastocytosis, indolent SM, smoldering SM, aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), or MC leukemia (MCL) has important prognostic significance and requires the integration of certain morphological, clinical, radiological, and biochemical data, referred to as B- and C-findings. Substantial diagnostic challenges may be posed to the pathologist and clinician especially in the so-called advanced SM variants, that is, ASM, MCL, and SM-AHN. In this article, updated recommendations of the EU-US Cooperative Group regarding standards of pathology in the diagnosis of SM, presented during the year 2020 Working Conference held in September in Vienna, are reported.

A preferential association between systemic mastocytosis (SM) and hymenoptera allergy (HVA) has been observed. Patients with both diseases are at risk for more severe reactions, and venom immunotherapy (VIT) may represent a life-saving treatment, but the use of VIT in such patients raised concerns about its safety.

Standard venom immunotherapy involves the administration of the maintenance dose every 4 to 6 weeks. This regimen may have adherence problems, especially in the long term; thus, extended intervals have been proposed.

Mastocytosis in adults is associated with a history of anaphylaxis in 22–49. In addition, monoclonal mast cell activation syndrome has been described presenting with anaphylaxis, especially in patients with hymenoptera venom anaphylaxis. Data on patients with drug hypersensitivity and mast cell diseases are scarce.

To analyse the association of systemic allergic hymenoptera sting reactions with mastocytosis and elevated baseline serum tryptase and to discuss diagnosis and treatment in patients with both diseases.

Large local reactions (LLRs) caused by insect stings have attracted the interest of clinicians for decades, especially because of their possible role as risk factor for subsequent more severe reaction. Nonetheless, the literature on epidemiological and clinical aspects of LLR is fragmentary. Therefore, we aimed at reviewing the data available so far on the argument and the clinical implications.

Mastocytosis is a myeloid neoplasm defined by expansion and focal accumulation of clonal mast cells (MC) in one or more organs. The disease exhibits a complex pathology and may be complicated by MC activation, bone abnormalities, neurological problems, gastrointestinal symptoms, and/or hematologic progression. The World Health Organization divides mastocytosis into cutaneous forms, systemic mastocytosis (SM) and MC sarcoma. In most patients with SM, somatic mutations in KITare detected. Whereas patients with indolent SM have a normal to near-normal life expectancy, patients with advanced SM, including aggressive SM and MC leukemia, have a poor prognosis. In those with advanced SM, multiple somatic mutations and an associated hematologic neoplasm may be detected. Mediator-related symptoms can occur in any type of mastocytosis. Symptoms may be mild, severe, or even life-threatening. In patients with severe acute symptoms, a MC activation syndrome (MCAS) may be diagnosed. In these patients, relevant co-morbidities include IgE-dependent and independent allergies. Management of patients with SM is an emerging challenge in daily practice and requires in-depth knowledge and a multidisciplinary and personalized approach with selection of appropriate procedures and interventions. In this article, we review the current knowledge on SM and MCAS, with emphasis on multidisciplinary aspects in diagnosis and patient-specific management. In addition, we provide a user´s guide for application of markers, algorithms, prognostic scores, and treatments for use in daily practice.

Advanced systemic mastocytosis (AdvSM) is characterized by the presence of KITD816V and other somatic mutations (eg, in SRSF2, ASXL1, and RUNX1) in 95% and 60% to 70% of patients, respectively. The biological and clinical consequences of AdvSM include multilineage involvement (eg, associated hematologic neoplasm) in 60% to 80% of patients, variable infiltration and damage (C-findings) of predominantly bone marrow and visceral organs through affected mast cell (MC) and non-MC (associated hematologic neoplasm) lineages, and elevated levels of serum tryptase. Recently, the treatment landscape has substantially changed with the introduction of the multikinase/KITinhibitor midostaurin and the specific KITD816V inhibitor avapritinib. In this review, we discuss the evolution of AdvSM response criteria that have been developed to capture clinical benefit better (eg, improved responses and progression-free and overall survival). We propose refined response criteria from European Competence Network on Mastocytosis and American Initiative in Mast Cell Diseases investigators that use a tiered approach to segregate the effects of histopathologic (eg, bone marrow MC burden, tryptase), molecular (eg, KITD816V variant allele frequency), clinical (eg, C-findings), and symptom response on long-term outcomes. These response criteria require evaluation in future prospective clinical trials of selective KITinhibitors and other novel agents.

Mastocytosis comprises rare heterogeneous diseases characterized by an increased accumulation of abnormal mast cells in various organs/tissues. The pathogenesis of mastocytosis is strongly linked to the presence of KITactivating mutations. In systemic mastocytosis (SM) the most frequent mutation encountered is KITp.D816V, whose presence constitutes one of the minor diagnostic criteria. Different techniques are used to search and quantify the KITp.D816V mutant, however allele-specific quantitative PCR and droplet digital PCR are today the most sensitive. The analysis of the KITp.D816V allele burden has undeniable interest for diagnostic, prognostic and therapeutic monitoring. The analysis of non-mast cell hematological compartments in SM is similarly important since KITp.D816V multilineage involvement is associated with a worse prognosis. In addition, in advanced forms of SM, mutations in genes other than KITare frequently identified and affect negatively disease outcome and response to therapy. Thus, combined quantitative and sensitive analysis of KITmutations and next generation sequencing of other recurrently involved myeloid genes make it possible to better characterize the extent of the affected cellular compartments and additional molecular aberrations, providing a more detailed overview of the complex mutational landscape of SM, in relation with the clinical heterogeneity of the disease. In this manuscript, we report the latest recommendations of the EU-US cooperative group presented in September 2020 in Vienna during an international Working Conference, on the techniques we consider standard to detect and quantify KITp.D816V mutant in SM and additional myeloid mutations found in SM subtypes.

Introduction:Systemic mastocytosis (SM) is a rare clonal mast cell (MC) neoplasm characterized by MC accumulation and is primarily driven by the KITD816V mutation. The D816V mutation is located in the activation loop of the KIT receptor tyrosine kinase resulting in constitutive activation of the receptor, causing aberrant MC proliferation and hyperactivation. MC mediator release can lead to severe clinical manifestations including skin, gastrointestinal, neurocognitive, skeletal, and systemic symptoms. Indolent SM is the most common subtype of SM; abnormal activation of mast cells leads to debilitating symptoms, poor quality of life, and has life-threatening consequences such as anaphylaxis. Although symptomatic treatments are used to control symptom severity (eg, cromolyn sodium, antihistamines, leukotriene inhibitors, omalizumab), there are no approved disease-modifying therapies to reduce MC burden and activation. Avapritinib is a potent, selective tyrosine kinase inhibitor that targets the KIT D816V mutant. Avapritinib has shown good tolerability in toxicology and safety pharmacology studies when assessed at active doses.

Cold-induced rhinitis (CIR) is common among skiers and is perceived as a troublesome disease. We studied the clinical characteristics of CIR in a population of skiers and we evaluated the effectiveness of ipratropium bromide nasal spray (IBNS) in relieving symptoms in a double-blind placebo-controlled fashion. By means of specific questionnaires, we evaluated 144 subjects (69% men; mean age, 42.2 years). The prevalence of CIR was 48.6% and the distinctive symptom was rhinorrhea (96%), often severe. The prevalence of atopy was higher in the CIR patients (χ2; p = 0.004). Twenty-eight CIR subjects participated in a double-blind placebo-controlled cross-over trial for evaluating the effectiveness of IBNS (80 μg twice per day [b.i.d.]). The severity of symptoms was assessed by a visual analog scale, and the number of cleaning tissues used also was evaluated. The actively treated group showed a significant improvement of rhinorrhea (p = 0.0007) and a reduction in the number of cleaning tissues used (p = 0.0023). Only four mild local side effects were reported. We conclude that IBNS could be regarded as an optimal therapeutic option for treating CIR symptoms in skiers.

Mastocytosis in adults often presents with skin lesions. A bone marrow biopsy is necessary to confirm or exclude the presence of systemic mastocytosis (SM) in these cases. When a bone marrow biopsy is not performed, the provisional diagnosis is mastocytosis in the skin (MIS). No generally accepted scoring system has been established to estimate the risk of SM in these patients.

Objective To describe our current understanding of hereditary α-tryptasemia (HαT), how HαT fits into the evolutionary context of tryptases and contemporary framework of mast cellassociated disorders, and to discuss the future clinical and therapeutic landscape for symptomatic individuals with HαT.

Mastocytosis is a rare neoplasm characterized by expansion and accumulation of mast cells in various organ systems. Systemic mastocytosis (SM) may or may not presents with cutaneous lesions. To examine the frequency and clinical impact of cutaneous involvement, 1510 mastocytosis patients collected in the registry of the European Competence Network on Mastocytosis were analyzed. Cutaneous involvement was found in 1195/1510 (79.1%) patients. Of these, 286 had cutaneous mastocytosis (CM) and 721 had SM with skin involvement (SM+). Adult patients with skin involvement who did not have a bone marrow examination (n=188) were defined as mastocytosis in the skin (MIS). In 315 patients with SM, no skin involvement was found (SM-). The percentage of cases with cutaneous involvement was higher in indolent SM (100%) and smoldering SM (87.9%) compared to aggressive SM (46.8%) or mast cell leukemia (38.5%). After a median follow-up of 5.6 years no patient with CM had died, but 2.6% of the patients with MIS, 5.7% with SM+ and 28.95% with SM- had died. Overall survival was longer in patients with skin involvement (CM/MIS/SM+) compared to SM- patients (p<0.0001). These data argue for a thorough examination of both the skin and bone marrow in adult patients with mastocytosis.

Stings by Polistesspecies frequently cause allergic reactions. However, standard allergy diagnostics are often unable to differentiate between primary sensitization and cross-reactivity in case of Vespula/Polistesdouble-sensitization because antigen 5 is the only Polistesvenom molecule currently available in diagnostics (Pol d 5).

Akin: University of Michigan: Employment; Michigan Allergy and Asthma Society: Membership on an entity's Board of Directors or advisory committees; ECNM: Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy, Research Funding; Up to Date: Patents & Royalties; LAD2 cell line: Patents & Royalties; Novartis: Consultancy; NIH: Patents & Royalties. Gotlib:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Promedior: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Allakos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Deceiphera: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding. Deininger:Blueprint: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Ascentage Pharma: Consultancy, Honoraria; Novartis: Honoraria; Sangamo: Consultancy; Humana: Honoraria; Incyte: Honoraria; TRM: Consultancy; Sangoma: Consultancy; Fusion Pharma: Consultancy; Adelphi: Consultancy; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Heaney:Partner Therapeutics: Consultancy; Deciphera: Research Funding; Incyte: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Blueprint: Research Funding; Celgene: Research Funding; CTI: Research Funding; BMS: Research Funding; Constellation: Research Funding; Novartis: Consultancy; AbbVie: Consultancy. van Daele:Erasmus MC, Rotterdam: Employment; Novartis: Speakers Bureau. Radia:Blueprint Medicines: Consultancy; Novartis: Consultancy, Speakers Bureau. Triggiani:Novartis: Membership on an entity's Board of Directors or advisory committees; Deciphera: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees. DeAngelo:Amgen, Autolus, Celgene, Forty-seven, Incyte, Jazzs, Pfizer, Shire, Takeda: Consultancy; Blueprint: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Research Funding; Glycomimetics: Research Funding. George:Blueprint Medicines: Consultancy; Deciphera: Consultancy; Novartis: Honoraria; Allakos: Consultancy. Hartmann:ALK-Abello: Consultancy; Bluepriont: Consultancy; Deciphera: Consultancy; Novartis: Consultancy; Euroimmun: Research Funding. Frank:Blueprint: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Allakos: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Reiter:Novartis: Consultancy, Honoraria, Other: Travel reimbursement, Research Funding; Blueprint: Consultancy, Honoraria, Other: Travel reimbursement; Deciphera: Consultancy, Honoraria, Other: Travel reimbursement. 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Lin:Blueprint Medicines: Employment. Morrison:Blueprint Medicines: Employment. Mar:Blueprint Medicines: Employment. Maurer:Blueprint: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Allakos: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background:

Mast cell activation (MCA) accompanies diverse physiologic and pathologic processes and is one of the more frequently encountered conditions in medicine. MCA-related symptoms are usually mild and often transient. In such cases, histamine receptor blockers and other mediator-targeting drugs can usually control MCA. In severe cases, an MCA syndrome (MCAS) may be diagnosed. However, overt MCAS is an unusual condition, and many patients referred because of suspected MCAS are diagnosed with other diseases (autoimmune, neoplastic, or infectious) unrelated to MCA or suffer from MCA-related (eg, allergic) disorders and/or comorbidities without fulfilling criteria of an overt MCAS. These considerations are important as more and more patients are informed that they may have MCA or even MCAS without completing a thorough medical evaluation. In fact, in several instances, symptoms are misinterpreted as MCA/MCAS, and other clinically relevant conditions are not thoroughly pursued. The number of such referrals is increasing. To avoid such unnecessary referrals and to prevent misdiagnoses, we here propose a diagnostic algorithm through which a clinically relevant (systemic) MCA can be suspected and MCAS can subsequently be documented or excluded. In addition, the algorithm proposed should help guide the investigating care providers to consider the 2 principal diagnoses that may underlie MCAS, namely, severe allergy and systemic mastocytosis accompanied by severe MCA. Although validation is required, we anticipate that this algorithm will facilitate the management of patients with suspected MCAS.

Background.Bone marrow mastocytosis (BMM) is characterized by accumulation of neoplastic mast cells (MC) in the bone marrow (BM), absence of skin lesions and lack of overt infiltration of other extra-cutaneous organs by neoplastic MC. Although clinically relevant due to its association with life-threatening anaphylaxis, BMM is considered a provisional sub-entity of indolent systemic mastocytosis (ISM) in the 2016 WHO classification.

Sperr: Amgen: Honoraria, Research Funding; Novartis: Honoraria. Gotlib:Incyte Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Valent:Amgen: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Deciphera Pharmaceuticals: Research Funding; Ariad: Honoraria, Research Funding.

Mastocytosis is a hematopoietic disorder characterized by abnormal growth and accumulation of neoplastic mast cells (MC) in various organ systems. Using updated WHO criteria and the proposal of the consensus group, the disease can be divided into cutaneous mastocytosis (CM), indolent systemic mastocytosis (ISM), smouldering SM (SSM), SM with an associated hematologic neoplasm (SM-AHN), aggressive SM (ASM), and mast cell leukemia (MCL). In adult patients with skin involvement but unknown/unavailable bone marrow (BM) studies, the provisional diagnosis ´mastocytosis in the skin (MIS)´ is appropriate. Although this classification has been validated repeatedly and is of prognostic significance, additional prognostic parameters have been identified in recent years (yrs). We have established a patient-registry in the ECNM where over 1,000 cases with confirmed mastocytosis are included. The aim of this study was to identify and validate new prognostic variables predicting survival in patients with mastocytosis and to prepare a simple prognostic scoring system applicable in daily practice. Using the data set of the ECNM registry we analyzed overall survival (OS) and event-free survival (EFS; i.e. until death or progression) in 1,088 patients with mastocytosis (median age: 45.7 yrs; range: 0.1-83.3 yrs, f:m ratio, 1:0.79), including CM (n=152), MIS (n=126), ISM (n=650), SSM (n=26), SM-AHN (n=89), ASM (n=35), and MCL (n=10). The median observation period was 3.5 yrs (75-25% percentile: 1.5-6.9 yrs, maximum 34.1 yrs). In the entire cohort, the median OS was not reached. The probability to be alive after 5, 10, and 20 yrs was 89%, 83%, and 70%, respectively. As expected, the WHO classification turned out to be of utmost predictive significance (Figure 1A; p<0.005). In patients with non-advanced disease, namely CM, MIS, ISM, and SSM, the median survival was not reached, and the survival at 5 yrs was 100%, 97%, 98%, and 85%, respectively, whereas in advanced SM, namely SM-AHN, ASM, and MCL, the median survival was 2.8, 4.1, and 0.8 yrs, respectively. Patients with advanced SM were found to be older, to have higher serum tryptase- and alkaline phosphatase (aPhos) levels, higher white blood counts (WBC), lower hemoglobin (Hb) and platelet (PLT) counts, and more frequently presented with organomegaly (hepatomegaly, splenomegaly, or lymphadenopathy). Moreover, the male/female ratio was higher in advanced mastocytosis. To define the relative impact of the identified risk factors we randomly divided the total cohort (50:50) into a learning set and a validation set, performed uni- and multivariate analyses, and subsequently calculated cut off values for optimal prognostication. In these studies, the poor prognosis of patients with advanced SM was confirmed. In patients with non-advanced disease, all variables tested were significant concerning OS in univariate analyses. However, WBC, Hb, and lactate dehydrogenase had to be excluded due to variance inflation. In multivariate analyses, age >70 yrs, PLT <80 G/L (not related to SM), and aPhos ≥240 U/L were significant predictors concerning OS. Based on these parameters, we established a simple prognostic scoring system. In this score, patients with non-advanced disease (CM, MIS, ISM, SSM) without additional risk factors comprised the low risk group, those with non-advanced disease and presence of one or more risk factors (age >70 yrs, PLT <80 G/L, aPhos ≥240 U/L) the intermediate risk group, and those with advanced disease (with or without additional risk factors) the high risk group. The median OS in the low risk group was not reached, in the intermediate risk group it was 13.5 yrs, and in the high risk group 3.5 yrs (p<0.005; Figure 1B). Significant differences were also observed regarding EFS (p<0.005, Figure 1C). In conclusion, the WHO classification remains the gold-standard of prognostication in patients with mastocytosis, but additional factors, namely age, PLT, and aPhos, are powerful additional variables predicting OS in these patients. Based on in-depth analyses of the ECNM registry data-set, a simple prognostic scoring system for mastocytosis was established and is recommended to define the probability of OS and EFS in patients with mastocytosis in daily practice.

Cavo: Celgene: Consultancy, Honoraria, Speakers Bureau. Martinelli:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; ARIAD: Consultancy.

Martinelli: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; ARIAD: Consultancy.

Systemic mastocytosis (SM) is a rare myeloproliferative neoplasm characterized by proliferation and hyperactivation of clonal mast cells. Clinical manifestations are heterogeneous and encompass cutaneous lesions, gastrointestinal alterations, osteoporosis, anaphylaxis and involvement of bone marrow and other organs due to neoplastic mast cells (MC) infiltration. As consequence, diagnosis may be difficult and patients (pts) are often evaluated by different specialists before the disease is recognized. To date, only few studies (Lim 2009, Escribano 2009, Cohen 2014) described relatively large series of pts with SM. We performed a multicentre retrospective study to evaluate clinical and biological features and therapeutic management in a large series of pts from 10 Italian centres experienced in management of SM and organized in multidisciplinary groups of specialists. We collected 455 pts diagnosed with SM according to WHO criteria. Additionally 26 pts with mastocytosis in the skin (MIS) evaluated with BM examination did not fulfil criteria for SM, leading to diagnosis of Cutaneous Mastocytosis (CM); however 2/26 pts with CM had both cKITD816V mutation and CD2/CD25 expression on MC in BM, additional 3 showed either cKITD816V or CD2/CD25. Moreover, we found 22 pts without MIS but with features of monoclonal mast cell activation syndrome. Of the 455 pts with WHO-SM (male 56%), 252 (55%) had MIS: median age at MIS diagnosis (dg) was 37 years (y) (range 0-79), while at SM dg it was 46.5 (range 18-82). Time from onset of MIS to dg of SM was 9 y (range 0-43). In 18/252 pts (7%) MIS occurred before age of 18 y (median 9, range 0-17) and persisted over childhood. Median age at dg of SM without MIS (203/455 pts, 45%) was older: 54 y, range 19-79 (p<0.0001). First manifestations of SM were MIS in 46.5% of pts, anaphylaxis in 47.8%, mediator related symptoms in 6.4%, osteoporosis/bone lesions in 5.2%, organomegaly in 3.4%, hematologic alterations in 0.4%. Anaphylaxis was observed in 76/252 (30.1%) pts with MIS, of which 23 had tryptase <20 mcg/L. BM multifocal infiltrates of MC were present in 61.6% of pts, while in 38.4% dg was performed only by using minor criteria. cKIT D816V mutation was detected in BM of 394/432 analysed pts (91.2%). Three D816V-negative pts had different cKIT mutations: M541L, D816H and K546K. In peripheral blood cKIT D816V was evaluated in 165 pts and found in 49.7%. CD2 and/or CD25 expressing MC were found in 99% of pts of the 426 evaluated. Mean tryptase value at dg was 75.9±263 mcg/L. SM subtypes were indolent SM (ISM) 402/455 (88.4%), of which 140 isolated bone marrow mastocytosis (BMM) (34.5% of ISM) and 34 smoldering SM (SSM) (8.4% of ISM), aggressive SM (ASM) 32/455 (7%), SM associated with hematological non mast cell disorders (SM-AHNMD) 20/455 (4.4%), mast cell leukemia (MCL) 1/455 (0.2%). In SM-AHNMD the associated hematologic disease was chronic myelomonocytic leukemia (6/20, 30%), non-Hodgkin lymphoma and refractory anemia with ring sideroblasts and thrombocytosis (3/20 each, 15%), essential thrombocythemia and not otherwise characterized myeloproliferative neoplasm (2/20 each, 10%), myelodysplastic syndrome, myelofibrosis, multiple myeloma and acute myeloid leukemia (AML) (1/20 each, 5%). Median follow up was 23 months (mo), range 2-289. At last follow up, 27/455 pts died (5.9%). 52% of pts had ASM, 18.5% SM-AHNMD, 14.7% SSM, 7.4% ISM and 3.7% each MCL and BMM. Causes of death were disease progression in 21/27 pts (77.8%), other solid neoplasms in 3/27 (11.1%), arterial thrombosis in 2/27 (9.5%), cerebral haemorrhage in 1/27 (3.7%). Disease progression consisted in evolution to AML in 6 pts with ASM, 1 pts with SSM and 1 pts with SM-AHNMD; median time to progression to AML was 30 mo (range 13-149); 2 pts developed other AHNMD: chronic myeloid leukemia and myelofibrosis. 178/455 pts (39%) were treated with anti MC mediators therapies. Of the 60/455 (13%) treated with cytostatic therapy 47% had ASM, 12% SM-AHNMD, 2% MCL, 35% ISM of which 38% were SSM. The ISM cohort was treated mainly due to severe osteoporosis with vertebral fractures not C-findings or disease evolution. First line therapy was interferon (28.3%), hydroxyurea (20%), midostaurine (18.3%), imatinib (13.3%), cladribin (8.3%), dasatinib (6.7%) and masitinib (5%). This is one of the largest series reporting pts with SM that may provide useful information for clinical management of pts with this probably underestimated “rare” disease.