Non-Skin-Related Symptoms are Common in Chronic Spontaneous Urticaria and Linked to Active and Uncontrolled Disease: Results from CURE.

BACKGROUND: Chronic spontaneous urticaria (CSU) can present with non-skin-related symptoms (NSRS), including recurrent unexplained fever, joint/bone/muscle pain (JBMP), and malaise, which also occur in other conditions that manifest with wheals (e.g., urticarial vasculitis or autoinflammatory disorders) or without wheals (e.g., infection). OBJECTIVE: We sought to determine the rate of patients with CSU affected by fever, JBMP and malaise, their trigger factors, links with clinical and laboratory characteristics, and their impact on everyday life and treatment responses. METHODS: We analyzed baseline data from the Chronic Urticaria Registry (CURE) of 2,521 patients with CSU who were ≥16 years old. RESULTS: One-third of CSU patients (31.2%, 786/2,521) had ≥1 NSRS, including recurrent fever (5.3%), JBMP (19.1%), and/or malaise (18.6%). In a multivariable analysis, having ≥1 of these NSRS correlated with food and infection as trigger factors of urticaria (adjusted odds ratio [aOR]=1.7 and 1.5), wheals of ≥24 hours duration (aOR=2.5), sleep disturbance (aOR=2.4), anxiety (aOR=2.8), comorbid atopic dermatitis (aOR=2.1), gastrointestinal disease (aOR=1.8), elevated leukocytes (aOR=1.7) and erythrocyte sedimentation rate (aOR=1.5). In a bivariate analysis, these NSRS were additionally associated with higher disease activity (UAS7, median: 21 vs. 14, p=0.009), longer disease duration (years, median: 2 vs. 1, p=0.001), presence of angioedema (74.6% vs. 58.7%, p<0.001), worse quality of life (CU-Q2oL, median: 42 vs. 29, p<0.001) and more frequent poor control of CSU (78% vs. 69%, p<0.001). CONCLUSION: The presence of NSRS in a subpopulation of CSU patients points to a need for better control of the disease, exclusion of comorbid conditions and/or exclusion of urticarial vasculitis and urticarial autoinflammatory diseases.

A systematic review of the clinical evidence for an association between type I hypersensitivity and inner ear disorders.

Inner ear disorders have a variety of causes, and many factors can contribute to the exacerbation of cochlear and vestibular pathology. This systematic review aimed to analyze clinical data on the coexistence and potential causal interaction between allergic diseases and inner ear conditions. A search of PubMed and Web of Science identified 724 articles, of which 21 were selected for full-text analysis based on inclusion and exclusion criteria. The epidemiologic evidence found overwhelmingly supports an association between allergic disease and particular inner ear disorders represented by a high prevalence of allergic reactions in some patients with Ménière's disease (MD), idiopathic sudden sensorineural hearing loss (ISSHL), and acute low-tone hearing loss (ALHL). In addition, patients with MD, ISSHL, and ALHL had higher levels of total serum IgE than healthy subjects. Finally, in some cases, changes in cochlear potential may have been induced by antigen exposure, while desensitization alleviated allergy and inner ear-related symptoms. The exact mechanism of interaction between the auditory/vestibular and immune systems is not fully understood, and further clinical and basic research is needed to understand the relationship between the two systems fully.

Detecting Changes in Mast Cell Numbers Versus Activation in Human Disease: A Roadblock for Current Biomarkers?

The pathophysiology of mast cell (MC)-driven disorders is diverse, ranging from localized reactions to systemic disorders caused by abnormal accumulation and activation in multiorgan systems. Prompt and accurate diagnosis is critically important, both for informing treatment and objective assessment of treatment outcomes. As new therapeutics are being developed to deplete MCs or silence them (eg, by engaging inhibitory receptors that block activation), new biomarkers are needed that can distinguish between MC activation versus burden. Serum tryptase is the gold standard for assessing both MC burden and activation; however, commercial tryptase assays have limitations related to timing of release, lack of discernment between inactive (α) and active (ß) forms of tryptase, and interpatient variability of baseline levels. Alternative approaches to measuring MC activation include urinary MC mediators, flow cytometry-based assays or gene expression profiling. Additional markers of MC activation are needed for use in clinical diagnostics, to help selection of treatment of MC diseases, and for assessing outcomes of therapy. We review the spectrum of disorders with known or suspected MC contribution, describe the utility and limitations of current MC markers and assays, and discuss the need for new markers that can differentiate between MC activation and burden.

Correction: Predatory journals: Perception, impact and use of Beall's list by the scientific community-A bibliometric big data study.

[This corrects the article DOI: 10.1371/journal.pone.0287547.].

[Mastocytosis-a frequently unrecognized disease]. / Mastozytose ­ eine häufig unerkannte Erkrankung.

Mastocytosis is a rare disease characterized by clonal expansion and accumulation of mast cells (MC) in various organs. Mastocytosis results from an activating mutation of the KIT surface receptor leading to an increased proliferation of MC. There are significant differences between children and adult patients with mastocytosis. Children mainly present the cutaneous form, whereas adults more often exhibit the systemic form of mastocytosis. Patients with mastocytosis may be asymptomatic or affected by a variety of symptoms. Treatment is primarily supportive and aims at symptom control. New approved targeted therapies such as midostaurin and avapritinib changed the treatment paradigm in advanced forms of the disease, and next-generation inhibitors currently in clinical trials are expected in the near future.

Mast cell silencing: A novel therapeutic approach for urticaria and other mast cell-mediated diseases.

Chronic urticaria (CU) is a mast cell (MC)-dependent disease with limited therapeutic options. Current management strategies are directed at inhibiting IgE-mediated activation of MCs and antagonizing effects of released mediators. Due to the complexity and heterogeneity of CU and other MC diseases and mechanisms of MC activation-including multiple activating receptors and ligands, diverse signaling pathways, and a menagerie of mediators-strategies of MC depletion or MC silencing (i.e., inhibition of MC activation via binding of inhibitory receptors) have been developed to overcome limitations of singularly targeted agents. MC silencers, such as agonist monoclonal antibodies that engage inhibitory receptors (e.g., sialic acid-binding immunoglobulin-like lectin8 -[Siglec-8] [lirentelimab/AK002], Siglec-6 [AK006], and CD200R [LY3454738]), have reached preclinical and clinical stages of development. In this review, we (1) describe the role of MCs in the pathogenesis of CU, highlighting similarities with other MC diseases in disease mechanisms and response to treatment; (2) explore current therapeutic strategies, categorized by nonspecific immunosuppression, targeted inhibition of MC activation or mediators, and targeted modulation of MC activity; and (3) introduce the concept of MC silencing as an emerging strategy that could selectively block activation of MCs without eliciting or exacerbating on- or off-target, immunosuppressive adverse effects.

The diagnostic workup for systemic mastocytosis differs from consensus recommendations: Results of a worldwide survey.

Objective: Mastocytosis is a complex disorder affecting various organs. The diagnostic workup can be challenging and requires a multidisciplinary approach including the use of uncommon tests. To assess mastocytosis management around the globe, we conducted the first worldwide online survey for physicians. Methods: A 21-item questionnaire was sent out to the members of the World Allergy Organization (WAO), the Global Allergy and Asthma European Network (GA2LEN), the Urticaria (UCARE) and Angioedema (ACARE) Centers of Reference and Excellence, the German Society of Allergology and Clinical Immunology (DGAKI), and the European Mast Cell and Basophil Research Network (EMBRN) in April-June 2021. Results: Across 628 respondents from 79 countries 87.7% and 9.7% of physicians were allergists/clinical immunologists and/or dermatologists. Participating physicians were from all regions of the world (Europe, EU: 41.6%; North America, NA: 24.8%; Latin America, LA: 14.5%; Asia-Pacific, AP: 12.6%; and Africa/Middle East, AME: 6.5%). Only 2.2% of respondents worked at Specialized Mastocytosis Centers (SMCs) in North America or European Union. Physicians reported caring for 4 patients with mastocytosis per year, with higher numbers in European Union and Asia Pacific (5/year) compared to Latin America (2/year). Dermatologists and physicians who work at SMCs reported higher patient numbers (15/year and 80/year, respectively). Suspicion of mastocytosis in the allergology and dermatology community is commonly driven by anaphylaxis (82.9%), mastocytosis skin lesions (82.1%), or elevated tryptase levels (76.6%). Osteoporosis and gastrointestinal symptoms less often prompted suspicion of mastocytosis (21.4% and 49.9%, respectively). World Health Organisation (WHO)-diagnostic criteria and classification, regardless of the region, are only used by about 50% of physicians, with higher rates for SMCs (83.3%). Serum tryptase, bone marrow biopsy, and KIT D816V mutation analysis are included in the diagnostic workup by 90.9%, 61.5%, and 58.4% of physicians, respectively. The biggest challenges for the management of mastocytosis are the lack of more effective treatment options (51.1%), missing multidisciplinary networks (47.1%), and the lack of experience of specialists from other disciplines (39.0%). Conclusions: The diagnostic workup for mastocytosis differs from consensus recommendations and varies between regions. This may be improved by establishing active multidisciplinary networks, increasing access to diagnostic procedures, consistently applying WHO criteria, and developing new Mastocytosis Centers of Reference and Excellence.

Measuring Symptom Severity and Quality of Life in Mastocytosis.

Mastocytosis is a heterogeneous disease with a wide spectrum of signs, symptoms, and concomitant disorders, such as skin lesions, anaphylaxis, osteoporosis, gastrointestinal involvement, and organomegaly. Disease specificity for frequently reported symptoms, such as fatigue, headache, anxiety, and brain fog, is poorly defined and need to be addressed in further studies. Patients with CM and non-AdvSM are mostly affected by mast cell mediator-related symptoms, whereas in AdvSM symptoms also result from organ damage, which makes their assessment challenging. In this paper we discuss approaches currently used to measure symptom burden and QoL impairment in relation to the clinical phenotype.

The Normal Range of Baseline Tryptase Should Be 1 to 15 ng/mL and Covers Healthy Individuals With HαT.

Physiological levels of basal serum tryptase vary among healthy individuals, depending on the numbers of mast cells, basal secretion rate, copy numbers of the TPSAB1 gene 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.

Predatory journals: Perception, impact and use of Beall's list by the scientific community-A bibliometric big data study.

Beall's list is widely used to identify potentially predatory journals. With this study, we aim to investigate the impact of Beall's list on the perception of listed journals as well as on the publication and citation behavior of the scientific community. We performed comprehensive bibliometric analyses of data extracted from the ISSN database, PubMed, PubMed Central (PMC), Crossref, Scopus and Web of Science. Citation analysis was performed by data extracted from the Crossref Cited-by database. At the time of analysis, Beall's list consisted of 1,289 standalone journals and 1,162 publishers, which corresponds to 21,735 individual journals. Of these, 3,206 (38.8%) were located in the United States, 2,484 in India (30.0%), and 585 in United Kingdom (7.1%). The majority of journals were listed in the ISSN database (n = 8,266), Crossref (n = 5,155), PubMed (n = 1,139), Scopus (n = 570), DOAJ (n = 224), PMC (n = 135) or Web of Science (n = 50). The number of articles published by journals on Beall's list as well as on the DOAJ continuously increased from 2011 to 2017. In 2018, the number of articles published by journals on Beall's list decreased. Journals on Beall's list were more often cited when listed in Web of Science (CI 95% 5.5 to 21.5; OR = 10.7) and PMC (CI 95% 6.3 to 14.1; OR = 9.4). It seems that the importance of Beall's list for the scientific community is overestimated. In contrast, journals are more likely to be selected for publication or citation when indexed by commonly used and renowned databases. Thus, the providers of these databases must be aware of their impact and verify that good publication practice standards are being applied by the journals listed.

Positive Basophil Tests Are Linked to High Disease Activity and Other Features of Autoimmune Chronic Spontaneous Urticaria: A Systematic Review.

BACKGROUND: Chronic spontaneous urticaria (CSU) is believed to be Autoimmune (aiCSU) (type IIb CSU) in at least 8% of patients, associated with mast cell-activating IgG autoantibodies. Basophil tests such as the basophil activation test (BAT) and basophil histamine release assay (BHRA) are considered the best single tests for an aiCSU diagnosis. To date, the strength of associations among a positive BAT and/or BHRA (BAT/BHRA+) and CSU features, patient demographics, and response to treatment remains poorly characterized. OBJECTIVE: To evaluate the strength of current evidence on basophil tests as parameters for CSU characteristics. METHODS: We performed a systematic literature search and review to assess the relationship between BAT/BHRA+ and clinical and laboratory parameters of CSU. Of 1,058 records found in the search, 94 studies were reviewed by experts in urticaria and 42 were included in the analysis. RESULTS: In CSU patients, BAT/BHRA+ showed a strong level of evidence for an association with high disease activity and low levels of total IgE. A weak level of evidence was shown for the association of BAT/BHRA+ and the presence of angioedema, and basopenia. CONCLUSIONS: Our results suggest that aiCSU defined by BAT/BHRA+ is more active or severe and is linked to other aiCSU markers such as low total IgE/basopenia. Basophil tests should be standardized and implemented in routine clinical care to improve the diagnosis and treatment of patients with aiCSU.

Safety and efficacy of lirentelimab in patients with refractory indolent systemic mastocytosis: a first-in-human clinical trial.

BACKGROUND: Indolent systemic mastocytosis (ISM) is characterized by excessive mast cell (MC) accumulation and MC-driven signs and symptoms. Currently used therapies are not approved and have limited efficacy. Lirentelimab (AK002) is a monoclonal antibody against sialic acid-binding immunoglobulin-like lectin (Siglec)-8 that inhibits MC activation. OBJECTIVES: To determine the safety, tolerability and efficacy of lirentelimab in reducing the symptoms of ISM. METHODS: At a specialty centre for mastocytosis in Germany, we conducted a phase I first-in-human single-ascending and multidose clinical trial of lirentelimab in patients with ISM. Eligible adults had World Health Organization-confirmed ISM and an unsatisfactory response to available treatment. In part A, patients received a single dose of lirentelimab 0.0003, 0.001, 0.003, 0.01 or 0.03 mg kg-1; in part B, patients received one lirentelimab dose of 0.3 mg kg-1 or 1.0 mg kg-1; and in part C, patients received either 1.0 mg kg-1 lirentelimab every 4 weeks for 6 months or ascending doses of lirentelimab (one dose of 1 mg kg-1 followed by five doses of 3-10 mg kg-1 every 4 weeks). The primary endpoint was safety/tolerability. Secondary endpoints included changes from baseline in Mastocytosis Symptom Questionnaire (MSQ), Mastocytosis Activity Score (MAS) and Mastocytosis Quality of Life Questionnaire (MC-QoL) scores at 2 weeks after the final dose. RESULTS: In 25 patients with ISM (13 in parts A + B and 12 in part C; median age 51 years, 76% female, median 4.6 years from diagnosis), the most common treatment-related adverse events (AEs) were feeling hot (76%) and experiencing a headache (48%). No serious AEs occurred. Median MSQ and MAS symptom severity scores in part C improved (vs. baseline) across all symptoms [MSQ: skin (38-56%), gastrointestinal (49-60%), neurological (47-59%), musculoskeletal (26-27%); MAS: skin (53-59%), gastrointestinal (72-85%), neurological (20-57%), musculoskeletal (25%)]. Median MC-QoL scores improved across all domains: symptoms (39%), social life/functioning (42%), emotions (57%) and skin (44%). CONCLUSIONS: Lirentelimab was generally well tolerated and improved symptoms and quality of life in patients with ISM. The therapeutic potential of lirentelimab should be considered for ISM.

European Competence Network on Mastocytosis (ECNM): 20-Year Jubilee, Updates, and Future Perspectives.

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 (MC) disorders. The ECNM consists of a net of specialized centers, expert physicians, and scientists who dedicate their work to MC 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, and to the classification, prognostication, and treatments of patients with mastocytosis and MC activation disorders. The ECNM also organized annual meetings and several working conferences, thereby supporting the development of the World Health Organization classification between 2002 and 2022. In addition, the ECNM established a robust and rapidly expanding patient registry and supported the development of new prognostic scoring systems and new treatment approaches. In all projects, ECNM representatives collaborated closely with their U.S. colleagues, various patient organizations, and other scientific networks. Finally, ECNM members have started several 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 MC disorders and to improve diagnosis, prognostication, and therapy in patients.

Psychometric evaluation of the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF©) and determination of a threshold score for moderate symptoms.

BACKGROUND: The Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) (©Blueprint Medicines Corporation), a 12-item daily diary that assesses 11 signs and symptoms of indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM), was psychometrically evaluated among patients with ISM. Additionally, thresholds of the ISM-SAF total symptom score (TSS) to distinguish patients with moderate to severe symptoms from those with mild symptoms were evaluated. METHODS: The ISM-SAF was completed daily as an electronic diary in a prospective, observational study utilizing an online survey of patients with ISM in the United States. Descriptive statistics, psychometric analyses, and analyses to estimate ISM-SAF TSS clinical cutoff values were conducted. RESULTS: A total of 103 patients (81.6% female; mean age = 50.2 [± 12.6]) with a self-reported diagnosis of ISM or SSM (58 of whom also had a medically documented diagnosis) contributed to the analyses. Psychometric analysis supported the trustworthiness of the biweekly TSS, which was reliable (α > 0.8, ICC > 0.9), construct-valid, and able to distinguish among clinically distinct groups as specified by the Patient Global Impression of Severity, 12-item Short-Form Health Survey, and Mastocytosis Quality of Life Questionnaire (p < 0.01). A biweekly ISM-SAF TSS from 21 to 28 begins to distinguish the moderately to severely symptomatic ISM/SSM patients from mildly symptomatic patients. CONCLUSION: The biweekly TSS of ISM-SAF was reliable, construct-valid, and able to distinguish among clinically distinct groups. A cut-off value of 28 is a conservative threshold that can be used for screening purposes in future clinical studies to identify patients with at least a moderate severity of ISM symptoms.

Stepping Down Treatment in Chronic Spontaneous Urticaria: What We Know and What We Don't Know.

In chronic spontaneous urticaria (CSU), wheals, angioedema, or both appear spontaneously for > 6 weeks. Current recommended treatment options for urticaria target mast cell mediators such as histamine, or activators, such as autoantibodies. The goal of CSU treatment is to treat the disease until it is gone as effectively and safely as possible. As no cure is available for CSU as of now, the treatment is aimed at continuously suppressing disease activity, with complete control of the disease and a normalization of quality of life. To achieve this, pharmacological treatment should be continued until no longer needed. Treatment of CSU should follow the basic principles of treating as much as needed and as little as possible taking into consideration that the activity of the disease may vary. Since CSU is a disease with spontaneous remission, it is hard to tell, in patients with complete control and no signs or symptoms, when medication is no longer needed. The current international guideline for urticaria suggests that the treatment can be stepped down once a patient is free of signs and symptoms. Other reasons for stepping down the treatment of CSU patients include safety concerns or issues, pregnancy or wanting to become pregnant, and economic factors. As of now, it is unclear over which period, with what intervals and with which dosages CSU treatment should be stepped down. Guidance on this is needed for all recommended therapies: (i) standard-dosed second-generation H1-antihistamine (sgAH), (ii) higher than standard-dosed sgAH, (iii) standard-dosed omalizumab, (iv) higher than standard-dosed omalizumab, and (v) cyclosporine. However, there is a lack of controlled trials on the step down and discontinuation of these treatments. Here, we aim to provide a summary of what is known and what needs to be investigated in further studies, based on our own experience and real-world evidence.

Most Patients With Autoimmune Chronic Spontaneous Urticaria Also Have Autoallergic Urticaria, but Not ViceVersa.

BACKGROUND: Two endotypes of chronic spontaneous urticaria (CSU) associated with mast cell-activating autoantibodies are described, namely autoallergic chronic spontaneous urticaria (aaCSU; with immunoglobulin E [IgE]-anti-autoallergens) and autoimmune chronic spontaneous urticaria (aiCSU; with IgG-anti-high-affinity receptor for the Fc region of immunoglobulin E [FcεRI]/IgE). OBJECTIVE: To investigate the rates of CSU patients with aaCSU and aiCSU. METHODS: We analyzed 111 CSU patients for aaCSU (ie, IgE to thyroid peroxidase, interleukin 24) and for aiCSU (ie, a positive autologous serum skin and Basophil Activation Test plus immunoglobulin G [IgG]-anti-FcεRI/IgE). Clinical and laboratory parameters were compared in patients with aaCSU, aiCSU, and both. RESULTS: Across 111 patients with CSU, 64 (58%) had aaCSU and 9 (8%) had aiCSU. Eight of the 9 aiCSU patients had aaCSU, but only 8 of 64 patients with aaCSU had aiCSU. In total, 7% (8 of 111) of patients had both aiCSU and aaCSU, 41% (46 of 111) had neither, and 16% (18 of 111) tested negative for all markers of aaCSU and aiCSU assessed. Patients with aaCSU or aiCSU are different from those without: patients with stand-alone aaCSU tend to be younger than non-aaCSU patients, aiCSU, and aaCSU/aiCSU overlapping subpopulations. In contrast, patients with aiCSU, with or without aaCSU coexistence, are more often female, have higher levels of thyroid peroxidase autoantibodies (both IgG and IgE), and show more severe quality of life impairment. CONCLUSIONS: Our novel finding that aiCSU coexisting with aaCSU needs to be confirmed in bigger cohorts and multicenter studies. Autoimmunity driven by autoreactive IgE and/or IgG in CSU needs further investigation for better understanding of the pathophysiology.

Virus-infected mast cells activate virus-specific CD8+ T cells.

Efficient anti-viral responses of CD8+ T cells require signals that promote their effector cell differentiation, that are mainly provided by dendritic cells (DCs). Mast cells (MCs) are key drivers of DC maturation, but also influence their migration and antigen presenting properties and therefore indirectly mediate CD8+ T cell activation. MCs initiate innate immune responses at pathogen entry sites, promote the development of adaptive immune responses after infection, and release mediators including chemokines that recruit and activate immune cells including T cells during viral infections. However, whether MCs can directly activate virus-specific CD8+ T cells remains largely unknown. Here, we used an in vitro viral infection model with lymphocytic choriomeningitis virus (LCMV)-infected MCs or DCs co-cultured with either LCMV-specific CD8+ T cells or with WT (unspecific) CD8+ T cells. Similar to LCMV-infected DCs, LCMV-infected MCs clustered with virus-specific CD8+ T cells and induced their activation and production of antiviral cytokines. In addition, the co-stimulatory molecules CD86 and OX40L, but not CD80, were upregulated on MCs and an increased production of IL-6 and type I interferons after LCMV infection was shown. Our findings suggest that MCs can promote CD8+ T cell activation during viral infections. MC-mediated CD8+ T cell activation might be especially important within infected tissues where direct cellular interaction can take place. A better understanding of anti-viral functions of MCs may help developing new strategies to better treat viral infections.

Avapritinib versus Placebo in Indolent Systemic Mastocytosis.

Avapritinib in Indolent Systemic MastocytosisIn a randomized trial, patients with indolent systemic mastocytosis were treated with avapritinib or placebo along with supportive care. The trial primary end point was the change in mean total symptom scores at 24 weeks. Avapritinib-treated patients had a decrease in mean total symptom score of 15.6 points compared with 9.2 points in the placebo group.