Clonal Mast Cell Research Articles

Clonal mast cell disorders and hereditary α-tryptasemia as risk factors for anaphylaxis.

The association between Hymenoptera venom-triggered anaphylaxis (HVA) and clonal mast cell-related disorders (cMCD) has been known for decades. However, recent breakthroughs in peripheral blood screening for KIT p.D816V missense variant have revealed the true extent of this clinical association whilst adding to our understanding of the underlying aetiology. Thus, recent large studies highlighted the presence of KIT p.D816V among 18.2% and 23% of patients with severe Hymenoptera venom-triggered anaphylaxis. A significant proportion of those patients have normal serum basal tryptase (BST) levels, with no cutaneous findings such as urticaria pigmentosa or other systemic findings such as organomegaly that would have suggested the presence of cMCD. These findings of an increased prevalence suggest that the impact of cMCD on anaphylaxis could be clinically underestimated and that the leading question for clinicians could be changed from 'how many patients with cMCD have anaphylaxis?' to 'how many patients with anaphylaxis have cMCD?'. The discovery of hereditary α-tryptasemia (HαT)-a genetic trait caused by an increased copy number of the Tryptase Alpha/Beta 1 (TPSAB1) gene-, first described in 2016, is now known to underlie the majority of cases of elevated BST outside of cMCD and chronic kidney disease. HαT is the first common heritable genetic modifier of anaphylaxis described, and it is associated with increased risk for severe HVA (relative risk=2.0), idiopathic anaphylaxis, and an increased prevalence of anaphylaxis in patients with cMCD, possibly due to the unique activity profile of α/β -tryptase heterotetramers that may potentiate immediate hypersensitivity reaction severity. Our narrative review aims to highlight recent research to have increased our understanding of cMCD and HαT, through recent lessons learned from studying their association with HVA. Additionally, we examined the studies of mast cell-related disorders in food and drug allergy in an effort to determine whether one should also consider cMCD and/or HαT in cases of severe anaphylaxis triggered by food or drugs.

Patterns of Disease Progression in Patients with Systemic Mastocytosis: A US Population-Level Analysis Using Health Claims-Based Dataset

Background Systemic mastocytosis (SM) is a rare clonal mast cell neoplasm driven by the KIT D816V mutation in ~95% of patients (pts). SM includes AdvSM (aggressive SM, SM with associated hematological neoplasm, and mast cell leukemia) and non-advanced SM (indolent & smoldering SM), which accounts for ~95% of cases. The uncontrolled proliferation and activation of mast cells can cause severe & unpredictable symptoms resulting in debilitation, reduced QOL, and organ infiltration and damage with reduced survival in AdvSM. While WHO criteria differentiate between subtypes of mastocytosis, there remains a lack of understanding of patterns of disease progression between SM subtypes. In this analysis we developed a novel claims-based algorithm to identify SM cases and assess disease progression. Methods Using a large, nationally representative claims database, we identified a cohort of SM pts with observed claims activity in each of the year 2019-2022. We developed a novel claims-based algorithm based on WHO diagnostic criteria (2016), including codes for laboratory tests, procedures, and treatments typically used for management of SM. Pts were included if they fulfilled 1 of the following criteria: had ≥2 diagnoses with an SM-specific ICD-10 code (D47.02, C96.21, C94.3X) at least 30 days apart in any setting of care; bone marrow biopsy followed by 1 SM diagnosis (dx) claim code in any setting of care; or 1 SM dx code in any setting of care & at least 1 prescription claim for an SM-specific treatment (avapritinib, midostaurin, imatinib, cladribine, interferons, brentuximab, omalizumab, montelukast, or cromolyn sodium). Pts were then categorized as either AdvSM, higher symptom ISM (ISM-higher), or lower symptom ISM (ISM-lower) based on additional disease-specific codes (Table 1) accumulated over the pt's total observable claims history, from 2015 to the date of evaluation. For pts who met these criteria, SM subtyping was evaluated as of Dec 31, 2019, Dec 31, 2020, and Dec 31, 2021. Treatment rates of select SM-directed therapies were also evaluated over the 12- month period from Jan-Dec, 2021. Results Of 10,939 pts with SM, 80% (8,707 pts) with claims in each of the years 2019, 2020, 2021 and 2022 were included. The first analysis looked at pts’ disease category as of Dec 2021 and assessed utilization of several SM-directed Rx therapies. This included 1,587 AdvSM, 2,705 ISM-higher, and 4,415 ISM-lower pts. Among pts across all cohorts, the most frequently observed therapies were anti-mediator therapies (AdvSM 20%, ISM-higher 37%, ISM-lower 20%) and cromolyn sodium (AdvSM 10%, ISM-higher 19%, ISM-lower 12%). When evaluating disease category evolution, 11.3% and 18.8% of pts with ISM-low migrated to ISM-higher or AdvSM over a 12-month (Dec 2020 - Dec 2021), or 24-month (Dec 2019 - Dec 2021) interval respectively. Across all ISM types, 2.2% of pts progressed to AdvSM in a 12-month interval, and 3.9% progressed to AdvSM over a 24-month interval. Among those pts who emerged with AdvSM in a 12-month interval ending Dec 2021 (N=392), 33% progressed from ISM-Lower or ISM-higher while 67% appeared as de novo diagnoses. Conclusions This study used a large claims dataset to identify pts with SM, classified them with a novel algorithm, and describe patterns of disease progression over a 12-month or 24-month interval. Of note, while this algorithm has been developed with expert clinical input, inherent limitations of claims and a single ICD-10 code for SM leave some ambiguity around the true clinical dx of these pts. Despite this, these analyses reflect the accumulation of severe symptoms over time by a meaningful subset of pts. Approximately 35% of pts with an SM dx did not have a SM dx 2 years prior, possibly due in part to the recency of the SM ICD-10 codes and also raising concerns regarding timely dx. Further, not all ISM pts demonstrated truly indolent disease behavior, illustrated by the 30% of ISM pts categorized as ISM-high requiring greater use of symptom-directed and disease-specific therapies. Finally, the proportion of AdvSM pts on FDA-approved TKI-directed therapies remain low, highlighting large unmet treatment need. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

PERSISTENTLY ELEVATED BASELINE TRYPTASE - A CASE OF HEREDITARY ALPHA TRYPTASEMIA

<h3>Introduction</h3> Hereditary Alpha Tryptasemia (HaT) is an autosomal dominant genetic condition resulting from inheriting an extra <i>TPSAB1</i> gene copy, which encodes alpha and beta tryptase. Most cases involve increased copy numbers of alpha tryptase gene, but documented cases of beta tryptase gene duplications exist. HaT typically presents with tryptase levels greater than 8 ng/mL. Phenotypes vary in severity and history may include idiopathic anaphylaxis, vibratory urticaria, musculoskeletal problems, and dysautonomia. HaT can coexist with clonal mast cell diseases, particularly systemic mastocytosis (SM). <h3>Case Description</h3> A 15-year-old female presented for elevated blood tryptase levels. She reported frequent emesis, diarrhea, anorexia and unintentional weight loss. She reported generalized fatigue, anxiety, and musculoskeletal pain with 2-years of frequent flushing and postural orthostatic hypotension. She denied dysphagia, urticaria, and anaphylaxis. Lab evaluation revealed negative <i>c-KIT</i> mutation. Tryptase range was 12.2-14.2 ng/mL. <i>TPSAB1</i> gene analysis was obtained demonstrating two copies of alpha-tryptase and three copies of beta-tryptase. She was diagnosed with HaT based on a duplication at <i>TPSAB1</i> allele. Initiation of cromolyn and high dose cetirizine resulted in suboptimal symptomatic improvement. Management is currently ongoing. <h3>Discussion</h3> When assessing elevated tryptase levels, considering HaT in the differential diagnosis is important, in addition to possible confounding conditions. A diagnosis of HaT also does not preclude concomitant conditions such as SM. This case demonstrates the need for more inclusive nomenclature to account for beta-tryptase duplications sometimes presenting with similar clinical manifestations. We propose HaT be renamed Hereditary Tryptasemia, accounting for cases of additional beta-tryptase copies as demonstrated in this patient.

MAST CELL LEUKEMIA: A CASE REPORT

<h3>Introduction</h3> Systemic mastocytosis (SM) is a rare disorder involving infiltration of clonal mast cells into one or more organ systems, with subsequent episodic mast cell-mediator release and associated inflammatory responses. The most aggressive form of SM is mast cell leukemia (MCL). Diagnosis of MCL requires the presence of >20% atypical mast cells in bone marrow or >10% mast cells in peripheral blood. Prompt recognition and treatment is crucial, as median survival is 2-6 months.^1,2 Here we present a patient with aleukemic MCL. <h3>Case Description</h3> A 65-year-old-male presented with one month of fatigue, anorexia, flushing, diarrhea, and rash to upper extremities. Evaluation revealed pancytopenia, hypogammaglobulinemia, elevated creatinine with proteinuria, elevated alkaline phosphatase. Imaging showed splenomegaly, ascites, and a left humeral lytic focus. Bone marrow biopsy showed 60% blasts/neoplastic mast cells and six percent peripheral blasts; serum tryptase obtained and 1684 ng/ml, with peripheral KIT D816V negative. Pulse dose steroids were initiated. Chemotherapy and midostaurin were discussed with patient, but rapid progression to multi-organ failure occurred, resulting in death 11 days after diagnosis. <h3>Discussion</h3> This patient met multiple criteria considered to be high risk under various SM scoring systems, including age>60, pancytopenia, and elevated alkaline phosphatase and tryptase.^3,4,5,6 Studies on midostaurin indicate post-diagnosis median survival increased to 9-18 months,^7,8 with similar or better survival seen in initial studies of avapritinib.⁹ Early recognition and intervention is key for this most rare form of a rare disorder, and knowing the diagnostic criteria and available treatment options is critical in caring for these patients.

Disease correlates and clinical relevance of hereditary α-tryptasemia in patients with systemic mastocytosis

Systemic mastocytosis (SM) encompasses a heterogeneous group of clonal disorders characterized by abnormal expansion of mast cells (MCs). Beyond KIT and other genes recurrently mutated in myeloid neoplasms, several genetic variants have been described as predisposing to the development of the disease and influencing its clinical phenotype. Increased copy number variants of the TPSAB1 gene were identified as a cause of nonclonal elevated tryptasemia and defined as hereditary α-tryptasemia (HαT). Moreover, HαT is enriched in patients with SM, where it can affect the incidence of mediator-related symptoms. In a multicenter data set of 444 patients with MC disorders, we aimed to investigate the clinical correlates of germline TPSAB1 copy number gains. Droplet digital PCR was performed in all cases to ascertain the presence of HαT. Clinical history along with blood values and bone marrow examination were analyzed. We confirmed a higher incidence of HαT+ cases (n= 59, 13.3%) in patients diagnosed with mastocytosis with respect to the general population (approximately 5%). HαT+ patients were characterized by a lower MC-associated disease burden and higher levels of tryptase. Several disease variables were coherent with this pattern, from bone marrow MC infiltration to MC-related histopathologic traits, which also accounted for a significantly higher incidence of clonal MC activation syndrome in HαT+ (10.2%) compared to HαT- (3.4%, P= .029) patients. We also confirmed that HαT+ carriers had a significantly higher frequency of anaphylaxis, without relevant differences for other clinical manifestations. These findings on a large patient series support and extend previous data, and suggest that knowledge of HαT status may be useful for personalized management of patients with SM.

New Insights into the Pathogenesis of Mastocytosis: Emerging Concepts in Diagnosis and Therapy.

Mastocytosis is a heterogeneous group of neoplasms defined by a numerical increase and accumulation of clonal mast cells (MCs) in various organ systems. The disease may present as cutaneous mastocytosis or systemic mastocytosis (SM). On the basis of histopathological and molecular features, clinical variables, and organ involvement, SM is divided into indolent SM, smoldering SM, SM with an associated hematologic neoplasm, aggressive SM, and MC leukemia. Each variant is defined by unique diagnostic criteria and a unique spectrum of clinical presentations. A key driver of MC expansion and disease evolution is the oncogenic machinery triggered by mutant forms of KIT. The genetic background, additional somatic mutations, and comorbidities also contribute to the course and prognosis. Patients with SM may also suffer from mediator-related symptoms or even an MC activation syndrome. This article provides an update of concepts on the genetics, etiology, and pathology of mastocytosis, with emphasis on diagnostic criteria and new treatment concepts.

MDS-094 Characteristics and Management of Medicare Beneficiaries With Advanced Systemic Mastocytosis

Advanced systemic mastocytosis (AdvSM) (subtypes: aggressive SM, SM with associated hematological neoplasm, mast cell leukemia) is a rare clonal mast cell neoplasm driven by the KIT D816V mutation. Uncontrolled proliferation, accumulation, and activation of mast cells result in severe symptoms in various organ systems, making SM difficult to diagnose. Clinical guidelines recommend comprehensive testing and specialist care management. To describe AdvSM patient characteristics and use of healthcare services before AdvSM diagnosis in the US Medicare population. Design, Patients, and Outcomes: Medical and pharmacy encounter data for the full US Medicare Fee-for-Service population and a claims-based algorithm were used to identify patients with newly diagnosed AdvSM (≥2 medical claims for AdvSM-related diagnoses [ICD-10 C94.3, D47.02, C96.21] or other qualifying mast cell neoplasm codes by subtype) between January 1, 2017, and December 31, 2019. Continuous enrollment in Medicare for 12 months pre- and post-AdvSM diagnosis was required. Demographics, comorbidity profile, and pre-diagnosis healthcare resource utilization were analyzed. A total of 468 patients with AdvSM met the criteria for analysis; most received their index diagnosis from a hematologist/oncologist. The mean (SD) age was 66.8 (13.6) years, 62% were female, 91% were Caucasian, 30% were dually eligible for Medicare/Medicaid (indicating lower socioeconomic status), and 31% qualified for Medicare due to non-age-related factors (e.g., disability). The mean (SD) Charlson Comorbidity Index score was 4.1 (3.2). Comorbidities included hypertension, 65%; malignancies (including mast cell neoplasms, solid tumors, and hematologic cancers), 62%; pulmonary disease, 43%; depression, 32%; anxiety, 29%; diabetes, 29%; asthma, 26%; and osteoporosis, 22%. In the year before AdvSM diagnosis, patients had a mean (SD) of 4.6 (5.1) primary care visits and 19.6 (18.5) physician specialist visits; 22% underwent bone marrow biopsy, 5% KIT D816V mutation testing, and 48% serum tryptase testing. The majority of patients were prescribed anti-mediator drug therapy (67% corticosteroids, 41% proton pump inhibitors, 29% antileukotrienes, 28% montelukast); 20% were prescribed epinephrine injectors for treatment or prevention of anaphylaxis. Medicare patients newly diagnosed with AdvSM had evidence of high rates of comorbid disease, specialist visits, and symptom management regimens prior to confirmed diagnosis. Care should be closely coordinated by specialists to optimize timely AdvSM diagnosis and management.

Hereditary alpha-tryptasemia: Brief overview of current knowledge and proposal of indications

Human tryptases are serine proteases, which are synthesized nearly exclusively by mast cells (MCs). Immature pro-tryptases, under the form of α- and β-monomers are constantly released by MCs, can be measured in the serum of normal individuals and constitute the basal serum tryptase (bST) level, usually below 6μg/L. By contrast, tetramers of tryptases, which are the mature forms of the enzyme, are normally retained in the secretory granules of MCs. These mature (α- and β-tetramers of tryptase) are only released when MC are activated by different stimuli, leading to a transient increase in serum tryptase level. Such event occurs for instance after IgE-mediated MC degranulation (immediate hypersensitivity reaction). The mature tryptases, through their various biological activities, account for the pathophysiology of immediate hypersensitivity. Of note, recent studies have reported that around 5% of the general population present with increased bST levels related to a genetic trait called hereditary α-tryptasemia (HαT). While there is still a debate on the fact that HαT+ patients may present more frequently various clinical phenotypes, it is now clearly established that the clinical phenotype of patients with primary (clonal) MC disorders, including mastocytosis, is modified by the presence of the HαT trait. In addition, HαT penetrance seems clearly increased in such patients (up to 18% of the cases), leading to the conclusion that HαT is a disease penetrance and phenotype modifier. In the present manuscript, we will describe briefly the genetic patterns of HαT and the clinical phenotypes encountered in HαT+ patients harboring or not a clonal MC disorder. Finally, we will describe the situations when the search for HαT in human can be considered and the preferred method to be used for such investigation.

Detection of clonal mast cell disease in wasp venom allergic patients with normal tryptase.

BackgroundClonal mast cell disease (CMD) is an underlying aggravating condition in wasp venom allergy (WVA) which requires a different treatment strategy. CMD is increasingly recognized in patients with normal basal serum tryptase (bsT). However, methods to identify at risk patients have not yet been assessed in large cohorts of WVA patients with normal bsT.MethodsThis retrospective study evaluated the reliability of the REMA score in detecting CMD in a cohort of grade IV WVA patients with normal bsT and assessed the added value of other clinical parameters, KIT D816V mutation analysis in peripheral blood (PB) and the diagnosis of hereditary alpha tryptasemia (HAT). All patients had a conclusive bone marrow evaluation that demonstrated or excluded underlying CMD.ResultsIn total 35 CMD and 96 non‐CMD patients were included. REMA score had a sensitivity of 72% (95% CI 56%–88%) and specificity of 79% (95% CI 70%–87%) in this cohort. Loss of consciousness during systemic reaction and bsT between 6.3 and 11.4 ng/ml were additional parameters independently associated with CMD. Sensitivity of KIT in PB was relatively low, 56% (95% CI 36%–75%), but had added value as screening method in patients with a low REMA score due to 100% specificity.ConclusionThe REMA score is a relatively reliable method to detect patients at risk of CMD among WVA patients with normal bsT. KIT mutation analysis in PB could serve as additional screening method in patients with low REMA scores.

Dermoscopic Features of Different Forms of Cutaneous Mastocytosis: A Systematic Review.

The term mastocytosis refers to a heterogeneous group of disorders characterised by accumulation of clonal mast cells in different organs, most commonly in the skin. Little is known about the role of dermoscopy in the diagnostics of mastocytosis. To date, no systematic review on the dermoscopic features of cutaneous mastocytosis has been performed. The aim of this study was to summarise the current knowledge in the field as well as to identify the knowledge gaps to show possible directions for further studies, based on a systematic search of PubMed, Scopus, and Web of Science databases and related references published before 3 January 2022. Dermoscopic features, type of dermoscope, polarisation mode, magnification, and number of cases were analysed. In total, 16 articles were included in this review (3 case series and 13 case reports), analysing 148 patients with different variants of cutaneous mastocytosis; all of the studies analysed had a low level of evidence (V). The main dermoscopic features of urticaria pigmentosa included brown structureless areas, brown lines arranged in a network, and linear vessels distributed in a reticular pattern, with this last finding also being typical of telangiectasia macularis eruptiva perstans. The presence of either circumscribed yellow structureless areas or diffuse yellowish background was a constant pattern of mastocytoma, while nodular, pseudoangiomatous xanthelasmoid, and plaque-type mastocytosis were typified by light-brown structureless areas and/or pigment network, though the first two variants also showed yellow/yellow-orange structureless areas. Finally, pigmented streaks of radial distribution surrounding hair follicles were described to be a pathognomonic dermoscopic feature of pseudoxanthomatous mastocytosis. Although this review shows that the various clinical forms of cutaneous mastocytosis may feature diagnostic dermoscopic clues, it also underlines the need for further investigation as several relevant data are missing, including evaluation of dermoscopic pattern according to anatomical locations or “lesion age”, studies on rare mastocytosis variants, evaluation of the prognostic role of dermoscopy in the context of systemic involvement, and comparative analyses with common clinical mimickers.

Incorporating Tryptase Genotyping Into the Workup and Diagnosis of Mast Cell Diseases and Reactions

The measurement of mast cell tryptase levels in serum has found utility in the diagnosis and management of both clonal mast cell disorders and severe mast cell-dependent systemic reactions in the form of anaphylaxis. A more recent discovery is that a majority of individuals with elevated basal serum tryptase levels have increased germline TPSAB1 gene copy number encoding α-tryptase. This genetic trait is referred to as hereditary α-tryptasemia (HαT) and affects nearly 6% of the general population. In clinical practice, the presence or absence of HαT should thus now be determined when defining what constitutes an abnormal serum tryptase level in the diagnosis of mastocytosis. Further, as rises in serum tryptase levels are used to support the diagnosis of systemic anaphylaxis, variability in baseline serum tryptase levels should be factored into how significant a rise in serum tryptase is required to confirm the diagnosis of a systemic allergic reaction. In practicality, this dictates that symptomatic individuals undergoing evaluation for a mast cell-associated disorder or reaction with a baseline serum tryptase level exceeding 6.5 ng/mL should be considered for tryptase genotyping in order to screen for HαT. This review provides detailed information on how to use the results of such testing in the diagnosis and management of both mastocytosis and anaphylaxis.

COVID-19 Vaccination Is Safe among Mast Cell Disorder Patients, under Adequate Premedication.

Reported cases of anaphylaxis following COVID-19 vaccination raised concerns about the safety of these vaccines, namely in patients suffering from clonal mast cell (MC) disorders—a heterogenous group of disorders in which patients may be prone to anaphylaxis caused by vaccination. This study aimed to assess the safety of COVID-19 vaccines in patients with clonal MC disorders. We performed an ambidirectional cohort study with 30 clonal MC disorder patients (n = 26 in the prospective arm and n = 4 in the retrospective arm), that were submitted to COVID-19 vaccination. Among these, 11 (37%) were males, and median age at vaccination date was 41 years (range: 5y to 76y). One patient had prior history of anaphylaxis following vaccination. Those in the prospective arm received a premedication protocol including H1- and H2-antihistamines and montelukast, while those in the retrospective arm did not premedicate. Overall, patients received a total of 81 doses, 73 under premedication and 8 without premedication. No MC activation symptoms were reported. COVID-19 vaccination seems to be safe in patients with clonal mast cell disorders, including those with prior anaphylaxis following vaccination. Robust premedication protocols may allow for vaccination in ambulatory settings.

Advances in mast cell biology

Mast cells (MCs) contribute prominently to all allergic diseases, yet are still poorly understood owing to their exclusive residence in tissues. Recently, the use of RNA-sequencing, proteomics, and other technological advances have accelerated the acquisition of new knowledge. This includes an expanded definition of MC heterogeneity and developmental origins, previously unrecognized functions for MCs, discoveries of genetic causes of MC-related disorders, the introduction of new therapies for clonal MC disease, and the identification of new potential target for treatments. This issue of Advances addresses key studies from 2020 to 2021.

Idiopathic mast cell activation syndrome is more often suspected than diagnosed-A prospective real-life study.

Idiopathic mast cell activation syndrome (MCAS) is characterized by three diagnostic criteria: (1) episodic mast cell (MC)-driven signs/symptoms of at least two organ systems in the absence of clonal MC expansion and definite triggers, (2) episodic increase in tryptase, and (3) response to MC-targeted treatment. Many patients believe they have MCAS, but how often this is the case remains unknown. We prospectively investigated patients with suspected MCAS (n=100) for the diagnostic criteria including baseline tryptase, KIT D816V mutation, and patient-reported outcome measures (PROMs) over the course of 12weeks. Comorbid depression and anxiety were explored with the Hospital Anxiety and Depression Scale (HADS). In 53% of our patients (80% females), suspicion of MCAS was based on self-evaluation. In total, patients reported 87 different symptoms, mostly fatigue (n=57), musculoskeletal pain/weakness (n=49), and abdominal pain (n=43), with overall high disease activity and impact. Two of 79 patients had increased tryptase (by >20% +2ng/ml) following an episode. Only 5%, with any of the PROMs used, showed complete response to MC-targeted treatment. Depression and anxiety disorders were frequent comorbidities (n=23 each), and 65 patients had pathological HADS values, which were linked to high disease impact and poor symptom control. Mast cell activation syndrome was confirmed in only 2% of patients, which implies that it is not MC activation that drives signs and symptoms in most patients with suspected MCAS. There is a high need for comprehensive research efforts aimed at the identification of the true underlying pathomechanism(s) in patients with suspected MCAS.

Personalized Management Strategies in Mast Cell Disorders: ECNM-AIM User’s Guide for Daily Clinical Practice

Mastocytosis is a myeloid neoplasm defined by expansion and focal accumulation of clonal mast cells (MCs) 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 KIT are detected. Patients with indolent SM have a normal to near-normal life expectancy, whereas 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, an MC activation syndrome may be diagnosed. In these patients, relevant comorbidities include IgE-dependent and IgE-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 MC activation syndrome, 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.

Remission of indolent systemic mastocytosis in the absence of targeted therapy

Systemic mastocytosis (SM) is a heterogeneous group of disorders characterized by clonal mast cell expansion within the hematopoietic compartment and other tissues. Patients present with manifestations ranging from cutaneous to systemic symptoms relating to mast cell mediator release and/or tissue infiltration. SM is currently classified into one of several variants: indolent SM (ISM), smoldering SM, SM with associated hematological neoplasm, aggressive SM, and mast cell leukemia, with important implications relating to prognosis and management.

Overexpression of FcεRI on Bone Marrow Mast Cells, but Not MRGPRX2, in Clonal Mast Cell Disorders With Wasp Venom Anaphylaxis.

BackgroundUncertainties remain about the molecular mechanisms governing clonal mast cell disorders (CMCD) and anaphylaxis.ObjectiveThis study aims at comparing the burden, phenotype and behavior of mast cells (MCs) and basophils in patients with CMCD with wasp venom anaphylaxis (CMCD/WVA+), CMCD patients without anaphylaxis (CMCD/ANA-), patients with an elevated baseline serum tryptase (EBST), patients with wasp venom anaphylaxis without CMCD (WVA+) and patients with a non-mast cell haematological pathology (NMHP).MethodsThis study included 20 patients with CMCD/WVA+, 24 with CMCD/ANA-, 19 with WVA+, 6 with EBST and 5 with NMHP. We immunophenotyped MCs and basophils and compared baseline serum tryptase (bST) and both total and venom specific IgE in the different groups. For basophil studies, 13 healthy controls were also included.ResultsHigher levels of bST were found in CMCD patients with wasp venom anaphylaxis, CMCD patients without anaphylaxis and EBST patients. Total IgE levels were highest in patients with wasp venom anaphylaxis with and without CMCD. Bone marrow MCs of patients with CMCD showed lower CD117 expression and higher expression of CD45, CD203c, CD63, CD300a and FcεRI. Within the CMCD population, patients with wasp venom anaphylaxis showed a higher expression of FcεRI as compared to patients without anaphylaxis. Expression of MRGPRX2 on MCs did not differ between the study populations. Basophils are phenotypically and functionally comparable between the different patient populations.ConclusionPatients with CMCD show an elevated burden of aberrant activated MCs with a significant overexpression of FcεRI in patients with a wasp venom anaphylaxis.

COVID-19 vaccination in the setting of mastocytosis—Pfizer-BioNTech mRNA vaccine is safe and well tolerated

COVID-19 vaccination in the setting of mastocytosis—Pfizer-BioNTech mRNA vaccine is safe and well tolerated

Safety of COVID-19 vaccination in patients with clonal mast cell disorders

Safety of COVID-19 vaccination in patients with clonal mast cell disorders

A Phase 2/3 Study of BLU-263 in Patients with Indolent Systemic Mastocytosis or Monoclonal Mast Cell Activation Syndrome

Systemic mastocytosis (SM) is a rare, clonal mast cell neoplasm driven by the KIT D816V mutation in ∼95% of cases. Indolent SM (ISM) is characterized by mast cell aggregates in skin, bone marrow, and multiple internal organs, and is often associated with chronic, debilitating, and potentially life-threatening symptoms. Monoclonal mast cell activation syndrome (mMCAS) is a clonal mast cell expansion, defined by the presence of 1 or 2 minor World Health Organization SM criteria, including D816V KIT mutation.