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Patients with systemic mastocytosis (SM) are at increased risk of hypersensitivity reactions (HRs). Although Hymenoptera venoms are the predominant triggers, cases of contrast media-induced HR (CMIHR) have also been reported and prophylactic premedication is often performed. However, data from larger series are limited and differences between indolent and advanced SM have not yet been investigated.To determine the incidence and severity of CMIHR in all subtypes of SM.We analyzed 162 adult patients with SM (indolent systemic mastocytosis [ISM], n = 65; advanced systemic mastocytosis [advSM], n = 97). First, the cumulative incidence of CMIHR was retrospectively assessed in the patient's history. Second, at our institution, patients underwent 332 contrast media (CM)-enhanced imaging including 80 computed tomography (CT) scans with iodine-based contrast agent and 252 magnetic resonance imaging (MRI) with a gadolinium-based contrast agent, and tolerance was assessed.Previous CMIHRs to CT (vomiting, n = 1, erythema, n = 1, cardiovascular shock, n = 1), and MRI (dyspnea, n = 1, cardiovascular shock, n = 1) had been reported by 4 out of 162 (2.5%) patients (ISM, n = 3; advSM, n = 1). In contrast, during or after 332 CM-enhanced CT or MRI examinations at our institution, no CMIHRs were reported. Premedication was solely given to 3 patients before CT scans, including 1 with previous CMIHR, who tolerated the imaging well.We conclude that: (1) there is a substantial discrepancy between the perception and prevalence of HRs to CM in SM; (2) reactions are scarce in ISM and even rarer in advSM; and (3) in SM patients without previous history of CM hypersensitivity, prophylactic premedication before CM-enhanced CT or MRI is dispensable.

Circulating tumor mast cells (CTMCs) have been identified in the blood of a small number of patients with advanced systemic mastocytosis (SM). However, data are limited about their frequency and prognostic impact in patients with MC activation syndrome (MCAS), cutaneous mastocytosis (CM) and nonadvanced SM. We investigated the presence of CTMCs and MC-committed CD34+ precursors in the blood of 214 patients with MCAS, CM, or SM using highly sensitive next-generation flow cytometry. CTMCs were detected at progressively lower counts in almost all patients with advanced SM (96%) and smoldering SM (SSM; 100%), nearly half of the patients (45%) with indolent SM (ISM), and a few patients (7%) with bone marrow (BM) mastocytosis but were systematically absent in patients with CM and MCAS (P < .0001). In contrast to CTMC counts, the number of MC-committed CD34+ precursors progressively decreased from MCAS, CM, and BM mastocytosis to ISM, SSM, and advanced SM (P < .0001). Clinically, the presence (and number) of CTMCs in blood of patients with SM in general and nonadvanced SM (ISM and BM mastocytosis) in particular was associated with more adverse features of the disease, poorer-risk prognostic subgroups as defined by the International Prognostic Scoring System for advanced SM (P < .0001) and the Global Prognostic Score for mastocytosis (P < .0001), and a significantly shortened progression-free survival (P < .0001) and overall survival (P = .01). On the basis of our results, CTMCs emerge as a novel candidate biomarker of disseminated disease in SM that is strongly associated with advanced SM and poorer prognosis in patients with ISM.

Einleitung: Die Mastozytose ist eine spontan auftretende Erkrankung, die mit einer klonalen und neoplastischen Proliferation morphologisch und immunphänotypisch veränderter Mastzellen in verschiedenen Organen verbunden ist, wie beispielsweise Haut, Knochenmark und Gastrointestinaltrakt. Die Ausprägung der Symptome, die meist durch die Freisetzung von Mastzellmediatoren ausgelöst werden, kann sich negativ auf die Kontrolle der Erkrankung auswirken. Bisher gibt es kein validiertes Instrument für die Erfassung der Krankheitskontrolle bei Patienten mit Mastozytose. Das Ziel dieser Arbeit besteht daher darin, ein krankheitsspezifisches Instrument für die Erfassung der Krankheitskontrolle bei Patienten mit Mastozytose zu entwickeln und zu validieren. Methoden: Im Rahmen der Itemgenerierung wurden anhand von semi-strukturierten Patienteninterviews, Literaturrecherchen und Expertenmeinungen 6 vorläufige Items abgeleitet. Danach erfolgte nach einer ersten Patientenbefragung mit einer Impactanalyse, einem anschließenden Expertenreview und einer Inhaltskontrolle eine Itemreduzierung. Das vorläufige Instrument wurde durch eine zweite Patientenbefragung anhand von Cognitive Debriefing getestet, um dadurch den Fragebogen zu finalisieren. Der Fragebogen wurde dann auf Validität, Reliabilität und weitere Einflussfaktoren getestet. Ergebnisse: Es nahmen 101 Patienten an der Validierungsstudie teil. Das finale Instrument MCT besteht aus 5 Fragen. Dabei ist es möglich, eine valide Gesamtpunktzahl zu erheben. Der MCT zeigte eine exzellente interne Konsistenz, Test- Retest-Reliabilität, eine Korrelation mit Ankerfragebögen und eine Known-groups Validität. Außerdem wurde eine ROC-Analyse durchgeführt, wonach ein Wert von 13 oder mehr eine gute Kontrolle der Erkrankung widerspiegelt. Zusammenfassung: Der MCT ist das erste deutschsprachige Instrument zur Messung der Krankheitskontrolle bei erwachsenen Patienten mit Mastozytose. Mit diesem kurzen Instrument kann zuverlässig ein wertvoller Beitrag für eine individuelle Patientenversorgung, für die Qualitätssicherung und die Datenerhebung in klinischen Studien geleistet werden., Background: Mastocytosis is a spontaneously occurring heterogeneous disease characterized by a clonal expansion of neoplastic mast cells in various organs as skin, bone marrow and gastrointestinal tract. The vast majority of patients suffer from symptoms caused by mediator release from mast cells, which can have a negative effect on disease control. As of yet, there is no specific and validated instrument available to measure disease control in patients with mastocytosis. Objective: To develop and validate a disease-specific tool to measure and monitor the control of disease in patients with mastocytosis, the Mastocytosis Control Test (MCT). Methods: Six potential MCT items were generated in a combined approach consisting of semi-structured patient interviews, expert input and literature research. Item selection was performed by impact analysis followed by an expert review. In addition, a cognitive debriefing was performed. The resulting MCT was tested for validity, reliability and influence factors. Results: 101 patients took part in the MCT validation study. The final MCT consists of 5 items. The test showed a valid total score and an excellent test-retest reliability. The MCT was further tested for convergent and known groups validity. The tool showed a strong correlation with related anchors. A ROC curve analysis suggested a cutoff value of 13 or more points to identify patients with a good control of disease. Conclusions: The MCT is a disease-specific, valid and reliable patient-reported outcome measure for adult patients with mastocytosis. It may serve as a valuable tool to measure and monitor disease control, both, in clinical trials and in routine care.

BACKGROUND: Organomegaly, including splenomegaly, hepatomegaly, and/or lymphadenopathy, are important diagnostic and prognostic features in patients with cutaneous mastocytosis (CM) or systemic mastocytosis (SM). OBJECTIVES: To investigate the prevalence and prognostic impact of 1 or more organomegalies on clinical course and survival in patients with CM/SM. METHODS: Therefore, 3155 patients with CM (n = 1002 [32%]) or SM (n = 2153 [68%]) enrolled within the registry of the European Competence Network on Mastocytosis were analyzed. RESULTS: Overall survival (OS) was adversely affected by the number of organomegalies (OS: #0 vs #1 hazard ratio [HR], 4.9; 95% CI, 3.4-7.1, P < .001; #1 vs #2 HR, 2.1, 95% CI, 1.4-3.1, P < .001; #2 vs #3 HR, 1.7, 95% CI, 1.2-2.5, P = .004). Lymphadenopathy was frequently detected in patients with smoldering SM (SSM, 18 of 60 [30%]) or advanced SM (AdvSM, 137 of 344 [40%]). Its presence confered an inferior outcome in patients with AdvSM compared with patients with AdvSM without lymphadenopathy (median OS, 3.8 vs 2.6 years; HR, 1.6; 95% CI, 1.2-2.2; P = .003). OS was not different between patients having organomegaly with either ISM or SSM (median, 25.5 years vs not reached; P = .435). At time of disease progression, a new occurrence of any organomegaly was observed in 17 of 40 (43%) patients with ISM, 4 of 10 (40%) patients with SSM, and 33 of 86 (38%) patients with AdvSM, respectively. CONCLUSIONS: Organomegalies including lymphadenopathy are often found in SSM and AdvSM. ISM with organomegaly has a similar course and prognosis compared with SSM. The number of organomegalies is adversely associated with OS. A new occurrence of organomegaly in all variants of SM may indicate disease progression. (c) 2022 American Academy of Allergy, Asthma & Immunology

Background Systemic mastocytosis (SM) is a rare myeloproliferative disease that results from a clonal proliferation of abnormal mast cells in one or more extra-cutaneous organs. Systemic mastocytosis with an associated hematological neoplasm (SM-AHN) is the second most common subgroup and is diagnosed when WHO criteria for both SM and a hematological neoplasm of non-mast cell lineage are met. The SM-AHN category as currently proposed is highly heterogeneous in terms of pathogenesis, clinical presentation, and prognosis. Case presentation We present the first reported case of SM-AHN associated with two hematological malignancies of different lineages, a monocytic myeloid sarcoma and a B-cell chronic lymphatic leukemia. Cytogenetic and molecular analyses revealed a distinct clonal origin of the two associated malignancies. The SM-myeloid sarcoma clone demonstrated an abnormal karyotype, trisomy 8 and del(13)(q12.3q14.3), as well as mutations in KITD816V, DNMT3A and RUNX1. The DNMT3A mutation could be detected years before disease onset, supporting its potential role as early driver of leukemogenesis. No genetic aberrations could be identified in the CLL clone, which is assumed to present coincidentally. Conclusions This report highlights the importance of full diagnostic work-up in SM patients in whom an associated hematological malignancy is suspected. Moreover, the importance of genetic analysis is highlighted, as it provides additional insights in the underlying clonal pathogenesis of different phenotypes, can aid in risk stratification, and may help identify potential therapy targets.

Mast cell leukemia (MCL) is the leukemic form of SM with at least 20% mostly immature mast cells on bone marrow aspirate. MCL may develop de novo, in the absence of a prior SM, or it may represent a progression from a previous SM. MCL may be sub-divided into the more frequent, aggressive acute form with signs of organ damage (C-findings) and the chronic form lacking C-findings and presenting a more stable course, although over time, progression to acute MCL is common. The 2022 WHO subtype of MCL with an associated hematological neoplasm was renamed MCL with an associated myeloid neoplasm in the 2022 International Consensus Classification (ICC). The relevance of the distinction between the leukemic and aleukemic forms based on the percentage of circulating mast cells is a matter of debate. The current knowledge on MCL is restricted mainly to single reports or case series with a limited number of larger studies. Our aim is to provide a comprehensive overview of this rare disease in terms of clinical manifestations, morphology, phenotype, molecular characteristics, differential diagnosis, outcome and treatment. A general overview on mastocytosis is also included.

Mastocytosis is a heterogeneous disease characterized by an abnormal accumulation of mast cells (MCs) in 1 or several organs. Although a somatic KIT D816V mutation is detected in ∼85% of patients, attempts to demonstrate its oncogenic effect alone have repeatedly failed, suggesting that additional pathways are involved in MC transformation. From 3 children presenting with both Greig cephalopolysyndactyly syndrome (GCPS, Mendelian Inheritance in Man [175700]) and congenital mastocytosis, we demonstrated the involvement of the hedgehog (Hh) pathway in mastocytosis. GCPS is an extremely rare syndrome resulting from haploinsufficiency of GLI3, the major repressor of Hh family members. From these familial cases of mastocytosis, we demonstrate that the Hh pathway is barely active in normal primary MCs and is overactive in neoplastic MCs. GLI3 and KIT mutations had a synergistic, tumorigenic effect on the onset of mastocytosis in a GCPS mouse model. Finally, Hh inhibitors suppressed neoplastic MC proliferation in vitro and extend the survival time of mice with aggressive systemic mastocytosis (ASM). This work revealed, for the first time, the involvement of Hh signaling in the pathophysiology of mastocytosis and demonstrated the cooperative effects of the KIT and Hh oncogenic pathways in mice with ASM, leading to the identification of new promising therapeutic targets.

A case of bicavitary effusion affecting a 12-year-old female spayed mixed breed dog that was presented to Tuskegee University College of Veterinary Medicine's Emergency Service for abdominal distension and vomiting. Upon physical exam, the patient exhibited signs of pain and sensitivity to touch and pain on abdominal palpation with a positive fluid wave. The patient also had dull mentation and increased respiratory effort with an abdominal component. On labwork, there was a leukocytosis characterized by a mature neutrophilia, monocytosis, and basophilia. A mild thrombocytopenia with low numbers of poorly granulated mast cells were also noted on peripheral blood smear review. Serum biochemistry revealed a mild azotemia and abnormal SNAP cPL test. The patient received a full abdominal ultrasound, which detected bicavitary effusion, hepatomegaly, and splenomegaly. Cytology of the cavitary effusions was moderately cellular with significant numbers of mast cells. The patient was euthanized following a tentative diagnosis of systemic mastocytosis. The clinical signs, in this case, are consistent with published data for systemic mastocytosis, which include organomegaly, abdominal pain, gastrointestinal signs, and hematologic abnormalities. However, this is the first report of bicavitary effusion due to presumed systemic mastocytosis.

Perioperative management in patients suffering from systemic mastocytosis is challenging. Most recommendations regarding anesthetic management in these patients are based on clinical reports, and there are controversies about the use of rocuronium and sugammadex. We present a case report of a patient with systemic mastocytosis who was given sugammadex for rocuronium reversal. Tryptase levels were monitored during the first postoperative 24 h, without evidence of elevation. We also performed a systematic review to provide an overview of current evidence regarding the safety of using sugammadex in patients suffering from systemic mastocytosis. The search strategy included PubMed and Google Scholar. All studies published up to and including January 2021 concerning anesthetic management in systemic mastocytosis were included. Of the 122 articles located, 9 articles were included: 2 reviews and 7 case reports. Data from reviewed studies confirm that sugammadex can safely be administered in patients suffering from systemic mastocytosis.Die perioperative Behandlung von Patienten mit systemischer Mastozytose ist eine Herausforderung. Die meisten Empfehlungen zur Anästhesiebehandlung von diesen Patienten basieren auf klinischen Berichten und es gibt Kontroversen über die Anwendung von Rocuronium und Sugammadex. Wir präsentieren einen Fallbericht über eine Patientin mit systemischer Mastozytose, der Sugammadex zur Rocuronium-Umkehr verabreicht wurde. Die Tryptasespiegel wurden während der ersten postoperativen 24 h überwacht, wobei keine Erhöhung dieser Tryptasespiegel beobachtet wurde. Es wurde auch ein systematisches Review durchgeführt, um einen Überblick über die aktuelle Evidenz zur Sicherheit der Anwendung von Sugammadex bei diesen Patienten zu geben. Die Suchstrategie umfasste PubMed und Google Scholar. Alle Studien zur Anästhesiebehandlung bei systemischer Mastozytose bis einschließlich Januar 2021 wurden eingeschlossen. Von den 122 gefundenen Artikeln wurden 9 Artikel aufgenommen: 2 Reviews und 7 Fallberichte. Die Daten aus überprüften Studien bestätigen, dass Sugammadex bei Patienten mit systemischer Mastozytose sicher verabreicht werden kann.

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. (C) 2021 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology.

Background : Mastocytosis is a risk factor for hymenoptera venom anaphylaxis (HVA). Current guidelines recommend measuring tryptase in HVA patients and that those with mastocytosis pursue lifelong venom immunotherapy (VIT). Available data on HVA and mastocytosis largely derives from European single-center studies and the prevalence of HVA with and without mastocytosis in the United States (US) is unknown. Objective : We sought to determine the prevalence of HVA and mastocytosis in the US using an insurance claims database and evaluate the impact of mastocytosis on VIT in HVA patients in a US cohort. Methods :The IBM Watson Database, consisting of insurance claims from approximately 27 million US patients in 2018, was queried to identify patients with HVA and/or mastocytosis. Further, a retrospective study of 161 patients undergoing VIT between 2015 – 2018 at the University of Michigan (U-M) was conducted. Results :In the IBM Watson Database, the prevalence of HVA was 167 per 100,000 (0.167%) and the prevalence of mastocytosis 10 per 100,000 (0.010%) overall and 97 per 100,000 (0.097%) among those with HVA. Mastocytosis showed a 9.7-fold increase among HVA patients versus the general population. In the U-M cohort, 2.6% of VIT patients had mastocytosis. Tryptase level did not correlate with venom reaction severity but was higher in patients with systemic VIT reactions. Conclusions :We observed a lower US HVA prevalence than previously reported. Mastocytosis was more common in US HVA patients, though at lower rates than previously reported. In VIT patients there was no correlation between tryptase level and reaction severity. Key words :Tryptasevenom allergyvenom immunotherapyanaphylaxismastocytosismast cell activation syndromemast cell disease Abbreviations Hymenoptera venom allergyHVAUnited StatesUSVenom immunotherapyVITMast Cell DiseaseMCDAmerican Academy of Allergy, Asthma, and Immunology WOS:000717466600002 2-s2.0-85106369702 PMID: 33895259 Science Citation Index Expanded Q1 Article Uluslararası işbirliği ile yapılan - EVET Kasım 2021 YÖK - 2021-22

Mastocytosis is a clonal hematopoietic disorder characterized by proliferation of abnormal mast cells in various organs including the skin, digestive system, lymph nodes, and bone marrow. We report on a 75-year-old woman presenting with abdominal pain, vomiting, diarrhoea, myalgia, and weight loss. Abdominal CT showed hepatosplenomegaly with heterogeneous splenic parenchyma, lymphadenopathy, and osteopenia with areas of osteosclerosis but no primary tumour. AnDie Mastozytose ist eine klonale hämatopoetische Erkrankung, welche durch eine Proliferation von abnormalen Mastzellen in verschiedenen Organen wie Haut, Verdauungstrakt, Lymphknoten und Knochenmark gekennzeichnet ist. Wir berichten über eine 75-jährige Frau mit Bauchschmerzen, Erbrechen, Diarrhö, Myalgie und Gewichtsverlust. Ein CT des Abdomens zeigte eine Hepatosplenomegalie mit heterogenem Milzparenchym, Lymphadenopathie und Osteopenie mit osteosklerotischen Herden, aber keinen Primärtumor. Im PET/CT fand sich eine insgesamt niedrige metabolische Aktivität der Läsionen, mit einer diffusen Knochenmarkbeteiligung die verdächtig auf eine hämatologische Neoplasie war. Eine Untersuchung des Knochenmarks und des peripheren Blutes bestätigte anschließend die Diagnose einer aggressiven systemischen Mastozytose.

Mast cells and eosinophils are commonly found, expectedly or unexpectedly, in human tissue biopsies. Although the clinical significance of their presence, absence, quantity, and quality continues to be investigated in homeostasis and disease, there are currently gaps in knowledge related to what constitutes quantitatively relevant increases in mast cell and eosinophil number in tissue specimens for several clinical conditions. Diagnostically relevant thresholds of mast cell and eosinophil numbers have been proposed and generally accepted by the medical community for a few conditions, such as systemic mastocytosis and eosinophilic esophagitis. However, for other mast cell- and eosinophil-associated disorders, broad discrepancies remain regarding diagnostic thresholds and how samples are processed, routinely and/or specially stained, and interpreted and/or reported by pathologists. These discrepancies can obfuscate or delay a patient's correct diagnosis. Therefore, a work group was assembled to review the literature and develop a standardized consensus for assessing the presence of mast cells and eosinophils for a spectrum of clinical conditions, including systemic mastocytosis and cutaneous mastocytosis, mast cell activation syndrome, eosinophilic esophagitis, eosinophilic gastritis/enteritis, and hypereosinophilia/hypereosinophilic syndrome. The intent of this work group is to build a consensus among pathology, allergy, dermatology, hematology/oncology, and gastroenterology stakeholders for qualitatively and quantitatively assessing mast cells and eosinophils in skin, gastrointestinal, and bone marrow pathologic specimens for the benefit of clinical practice and patients.

[Objective]: Mast cell (MC) activation (MCA) defines the mechanism by which certain patients have symptoms owing to the effect of a wide range of mediators released from MCs upon their activation, when triggered by different stimuli. When these symptoms are severe and recurrent, the diagnosis of MCA syndrome (MCAS) might be considered. Here, we review the relevant aspects related to the pathogenesis of MCAS, with special emphasis on the prevalence and diagnostic relevance of KIT mutations., [Data Sources]: PubMed was searched between 1980 and 2021 using the following terms: mast cell activation syndromes, mast cell activation, anaphylaxis, KIT mutations, KIT D816V, indolent systemic mastocytosis, bone marrow mastocytosis, cutaneous mastocytosis, IgE anaphylaxis, and idiopathic anaphylaxis., [Study Selections]: Only articles published in English were selected based on their relevance to MCAS or severe and recurrent anaphylaxis., [Results]: MCAS can be classified as clonal MCAS and nonclonal MCAS depending on the presence vs absence of an underlying KIT mutation (mostly KIT D816V), respectively. In contrast to clonal MCAS in which MCA is associated with a primary MC disorder (ie, primary MCAS) such as mastocytosis or monoclonal MCAS, nonclonal MCAS can be secondary to known or unidentified triggers (ie, secondary and idiopathic MCAS, respectively)., [Conclusion]: The clinical heterogeneity and complexity of the molecular assays needed for the study of patients with MCAS might lead to misdiagnosis, particularly when patients are evaluated at nonspecialized centers. Thus, referral of patients having clinical manifestations suggestive of MCAS to reference centers on mastocytosis and MC diseases is strongly recommended., This work was supported by grants from the Instituto de Salud Carlos III (Madrid, Spain), Fondos Europeos de Desarrollo Regional (reference numbers: PI19/01166 and Centro de Investigación Biomédica en Red de Cáncer, CB16/12/00400), Fundación Española de Mastocitosis (Madrid, Spain; reference number: FEM2021-SAM), and Asociación Española de Pacientes con Mastocitosis y otras Enfermedades Relacionadas (Madrid, Spain; reference number: AEDM2019-SAM).

Background Advanced systemic mastocytosis (AdvSM), indolent systemic mastocytosis (ISM), and smoldering systemic mastocytosis (SSM) are rare diseases characterized by neoplastic mast cell infiltration of more than one organ. A content-valid patient-reported outcome (PRO) questionnaire that assesses relevant signs and symptoms that are important and understandable to individuals with a condition is critical for assessing new treatment benefit as well as supporting product labeling claims. Notably, no such PRO questionnaire has been developed in accordance with regulatory and scientific guidelines for use in AdvSM, ISM, and SSM patient populations. To fill that gap, this study documents the development and content validity of instruments evaluating signs and symptoms of systemic mastocytosis. Methods A review of peer-reviewed literature, advice meetings with clinical therapeutic area experts, patient concept elicitation interviews, concept selection and questionnaire construction meetings, and patient cognitive debriefing interviews were conducted, and regulatory feedback was incorporated. Results For AdvSM, 26 sign- and symptom-level concepts were identified in literature, 39 by clinicians, and 33 by patients. For ISM/SSM, 38 sign- and symptom-level concepts were identified in the literature, 39 by clinicians, and 57 by patients. Two patient-reported instruments, the Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF) and Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF)(©Blueprint Medicines Corporation), were developed based on consolidated findings. Cognitive debriefing interviews with AdvSM and ISM patients showed the AdvSM-SAF and ISM-SAF were understood and interpreted as intended by the majority of patients. Conclusion The AdvSM-SAF and ISM-SAF are content-valid tools measuring symptoms from AdvSM and ISM patients’ perspective.

Background Indolent systemic mastocytosis (ISM) is a rare, clonal mast cell neoplasm characterized by severe, unpredictable symptoms. The Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) items compose a Total Symptom Score (TSS), Gastrointestinal Symptom Score (GSS), and Skin Symptom Score (SSS) to assess symptom severity. This study evaluated the psychometric performance of ISM-SAF among ISM patients. Methods In PIONEER, a Phase 2 trial evaluating safety and efficacy of selective kinase inhibitor avapritinib in patients with ISM, the 12-item ISM-SAF was administered daily. Psychometric evaluation of score reliability, validity, and clinical interpretation was conducted using the trial data. Results Thirty-eight patients contributed to analyses (78.9% female; mean age = 49). Baseline internal consistency reliability (α) for bi-weekly TSS, GSS, and SSS was 0.86, 0.83, and 0.82, respectively. Test–retest reliability among patients exhibiting no change in Patient Global Impression of Symptom Severity (PGIS) between Baseline and Day 15 exceeded 0.74 universally. Construct validity and known-groups analysis showed moderate to strong ISM-SAF score correlation (r = 0.382–0.881) to supportive patient-reported questionnaires (e.g., PGIS and Mastocytosis Quality of Life Questionnaire) symptom and skin scores, and ability to distinguish among clinically unique groups. Correlations of ISM-SAF and other assessment change scores reflect evidence of score sensitivity. Clinically important difference and response estimates were 7–10 and 19, respectively. Discussion ISM-SAF produced reliable, construct-valid, sensitive scores when administered in PIONEER to patients in the target population. Results of this study support the use of the ISM-SAF as a reliable and valid measure to evaluate disease symptomology in ISM patients. Trial registration ClinicalTrials.gov, NCT03731260. Registered 10 October 2018, https://clinicaltrials.gov/ct2/show/study/NCT03731260.