Publications by authors named "Michel Arock"

110 Publications

Eosinophils and eosinophil-associated disorders: immunological, clinical, and molecular complexity.

Semin Immunopathol 2021 May 30. Epub 2021 May 30.

Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Eosinophils and their mediators play a crucial role in various reactive states such as bacterial and viral infections, chronic inflammatory disorders, and certain hematologic malignancies. Depending on the underlying pathology, molecular defect(s), and the cytokine- and mediator-cascades involved, peripheral blood and tissue hypereosinophilia (HE) may develop and may lead to organ dysfunction or even organ damage which usually leads to the diagnosis of a HE syndrome (HES). In some of these patients, the etiology and impact of HE remain unclear. These patients are diagnosed with idiopathic HE. In other patients, HES is diagnosed but the etiology remains unknown - these patients are classified as idiopathic HES. For patients with HES, early therapeutic application of agents reducing eosinophil counts is usually effective in avoiding irreversible organ damage. Therefore, it is important to systematically explore various diagnostic markers and to correctly identify the disease elicitors and etiology. Depending on the presence and type of underlying disease, HES are classified into primary (clonal) HES, reactive HES, and idiopathic HES. In most of these patients, effective therapies can be administered. The current article provides an overview of the pathogenesis of eosinophil-associated disorders, with special emphasis on the molecular, immunological, and clinical complexity of HE and HES. In addition, diagnostic criteria and the classification of eosinophil disorders are reviewed in light of new developments in the field.
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http://dx.doi.org/10.1007/s00281-021-00863-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164832PMC
May 2021

[The basophil: from control of immunity to control of leukemias].

Authors:
Michel Arock

Ann Pharm Fr 2021 May 26. Epub 2021 May 26.

Unité Fonctionnelle des Urgences Biologiques, Service de Biochimie Métabolique, Groupe Hospitalier Pitié-Salpêtrière Charles-Foix, AP-HP.Sorbonne Université - 47/83 Bd de l'Hôpital, 75013 PARIS, France. Electronic address:

The basophils, first described by Paul Ehlrich in 1879, are rare circulating cells, representing approximately 0.01 to 0.3 % of the blood leukocytes. Until recently, these cells have been neglected because of their minority status among immune cells and because they show some similarities to mast cells residing in tissues. However, basophils and mast cells are now recognized as distinct cell lines and it appears that basophils have important and non-redundant functions, distinct from those of mast cells. On the one hand, basophils have beneficial contribution to protective immunity, in particular against parasitic infections. On the other hand, basophils are involved in the development of various benign and malignant pathologies, ranging from allergy to certain leukemias. Basophils interact with other immune cells or neoplastic cells through direct contacts or soluble mediators, such as cytokines and proteases, thus contributing to the regulation of the immune system but also to allergic responses, and probably to the process of neoplastic transformation. In this review, we will develop recent knowledge on the involvement of basophils in the modulation of innate and adaptive immunity. We will then describe the benign or malignant circumstances in which an elevation of circulating basophils can be observed. Finally, we will discuss the role played by these cells in the pathophysiology of certain leukemias, particularly during chronic myeloid leukemia.
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http://dx.doi.org/10.1016/j.pharma.2021.05.005DOI Listing
May 2021

Mast cells drive pathologic vascular lesions in Takayasu arteritis.

J Allergy Clin Immunol 2021 May 13. Epub 2021 May 13.

Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR S 959, Immunology-Immunopathology- Immunotherapy (I3); F-75005, Paris, France;; Biotherapy (CIC-BTi), Hôpital Pitié-Salpêtrière, AP-HP, F-75651, Paris, France;; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology,F-75013, Paris, France. Electronic address:

Background: Takayasu arteritis (TAK) is a large vessel vasculitis (LVV) resulting in artery wall remodeling with segmental stenosis and/or aneurysm formation. Mast cells (MC) are instrumental in bridging cell injury and inflammatory response.

Objective: To investigate the contribution of MC on vessel permeability, angiogenesis and fibrosis in TAK patients.

Methods: MC activation and their tissue expression were assessed in sera and in aorta from patients with Takayasu arteritis (TAK) and from healthy donors (HD). In vivo permeability was assessed using a modified Miles assay. Subconfluent cultured HUVECs and fibroblasts were used in vitro to investigate the effects of MC mediators on angiogenesis and fibrogenesis.

Results: We found increased levels of mast cell activation markers (histamine and Indoleamine 2,3-Dioxygenase (IDO)) in sera of TAK patients as compared to sera of HD. Marked expression of MC was shown in aortic lesions of TAK patients compared to non-inflammatory aorta controls. Using Miles assay, we showed that sera of TAK patients significantly increased vascular permeability in vivo as compared to HD. Vessel permeability was abrogated in MC deficient mice. Mast cells stimulated by sera of TAK patients supported neoangiogenesis (increased HUVEC proliferation and branches) and fibrosis by inducing increased production of fibronectin, type 1 collagen and α-smooth muscle actin by fibroblasts as compared to MC stimulated by sera of HD.

Conclusion: MC is a key regulator of vascular lesions in TAK patients and may represent a new therapeutic target in LVV.
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http://dx.doi.org/10.1016/j.jaci.2021.05.003DOI Listing
May 2021

COVID-19 Vaccination in Mastocytosis: Recommendations of the European Competence Network on Mastocytosis (ECNM) and American Initiative in Mast Cell Diseases (AIM).

J Allergy Clin Immunol Pract 2021 Jun 5;9(6):2139-2144. Epub 2021 Apr 5.

Department of Hematological Biology, Pitié-Salpêtrière Hospital, Paris Sorbonne University, Paris, France.

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.
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http://dx.doi.org/10.1016/j.jaip.2021.03.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019658PMC
June 2021

Epigenetic Changes in Neoplastic Mast Cells and Potential Impact in Mastocytosis.

Int J Mol Sci 2021 Mar 15;22(6). Epub 2021 Mar 15.

Department of Allergology, Medical University of Gdansk, 80-211 Gdansk, Poland.

Systemic mastocytosis (SM) is a hematologic neoplasm with abnormal accumulation of mast cells in various organ systems such as the bone marrow, other visceral organs and skin. So far, only little is known about epigenetic changes contributing to the pathogenesis of SM. In the current article, we provide an overview of epigenetic changes that may occur and be relevant to mastocytosis, including mutations in genes involved in epigenetic processes, such as , and , and global and gene-specific methylation patterns in neoplastic cells. Moreover, we discuss methylation-specific pathways and other epigenetic events that may trigger disease progression in mast cell neoplasms. Finally, we discuss epigenetic targets and the effects of epigenetic drugs, such as demethylating agents and BET-targeting drugs, on growth and viability of neoplastic mast cells. The definitive impact of these targets and the efficacy of epigenetic therapies in advanced SM need to be explored in future preclinical studies and clinical trials.
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http://dx.doi.org/10.3390/ijms22062964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999363PMC
March 2021

Proceedings from the Inaugural American Initiative in Mast Cell Diseases (AIM) Investigator Conference.

J Allergy Clin Immunol 2021 Jun 11;147(6):2043-2052. Epub 2021 Mar 11.

Division of Allergy and Immunology, University of Michigan, Ann Arbor, Mich.

The American Initiative in Mast Cell Diseases (AIM) held its inaugural investigator conference at Stanford University School of Medicine in May 2019. The overarching goal of this meeting was to establish a Pan-American organization of physicians and scientists with multidisciplinary expertise in mast cell disease. To serve this unmet need, AIM envisions a network where basic, translational, and clinical researchers could establish collaborations with both academia and biopharma to support the development of new diagnostic methods, enhanced understanding of the biology of mast cells in human health and disease, and the testing of novel therapies. In these AIM proceedings, we highlight selected topics relevant to mast cell biology and provide updates regarding the recently described hereditary alpha-tryptasemia. In addition, we discuss the evaluation and treatment of mast cell activation (syndromes), allergy and anaphylaxis in mast cell disorders, and the clinical and biologic heterogeneity of the more indolent forms of mastocytosis. Because mast cell disorders are relatively rare, AIM hopes to achieve a coordination of scientific efforts not only in the Americas but also in Europe by collaborating with the well-established European Competence Network on Mastocytosis.
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http://dx.doi.org/10.1016/j.jaci.2021.03.008DOI Listing
June 2021

Genetic Regulation of Tryptase Production and Clinical Impact: Hereditary Alpha Tryptasemia, Mastocytosis and Beyond.

Int J Mol Sci 2021 Feb 28;22(5). Epub 2021 Feb 28.

Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria.

Tryptase is a serine protease that is predominantly produced by tissue mast cells (MCs) and stored in secretory granules together with other pre-formed mediators. MC activation, degranulation and mediator release contribute to various immunological processes, but also to several specific diseases, such as IgE-dependent allergies and clonal MC disorders. Biologically active tryptase tetramers primarily derive from the two genes (encoding β-tryptase) and (encoding either α- or β-tryptase). Based on the most common gene copy numbers, three genotypes, 0α:4β, 1α:3β and 2α:2β, were defined as "canonical". About 4-6% of the general population carry germline -α copy number gains (2α:3β, 3α:2β or more α-extra-copies), resulting in elevated basal serum tryptase levels. This condition has recently been termed hereditary alpha tryptasemia (HαT). Although many carriers of HαT appear to be asymptomatic, a number of more or less specific symptoms have been associated with HαT. Recent studies have revealed a significantly higher HαT prevalence in patients with systemic mastocytosis (SM) and an association with concomitant severe Hymenoptera venom-induced anaphylaxis. Moreover, HαT seems to be more common in idiopathic anaphylaxis and MC activation syndromes (MCAS). Therefore, genotyping should be included in the diagnostic algorithm in patients with symptomatic SM, severe anaphylaxis or MCAS.
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http://dx.doi.org/10.3390/ijms22052458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957558PMC
February 2021

A Challenge for Allergologist: Application of Allergy Diagnostic Methods in Mast Cell Disorders.

Int J Mol Sci 2021 Feb 1;22(3). Epub 2021 Feb 1.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria.

Primary and secondary mast cell activation syndromes (MCAS) can occur in patients with mastocytosis. During the past few years our knowledge about the pathogenesis and disease-triggering mechanisms in MCAS and mastocytosis have increased substantially. Whereas mastocytosis is characterized by an accumulation of neoplastic (clonal) mast cells (MC) in various organ systems, MCAS is defined by a massive and systemic activation of these cells. Mast cells are crucial effector cells in allergic diseases, thus their elevated number and activation can cause severe anaphylactic reactions and MCAS in patients with mastocytosis. However, these cells may also degranulate spontaneously or degranulate in response to non-allergic triggers leading to clinical symptoms. In mastocytosis patients, such symptoms may lead to the diagnosis of a primary MCAS. The diagnosis of a concomitant allergy in mastocytosis patients is challenging. In these patients, a mixed form (primary and secondary) of MCAS may be diagnosed. These patients may also suffer from life-threatening anaphylactic reactions when exposed to allergens. In these cases, the possibility of severe side effects of in vivo provocations can sometimes also limit diagnostic evaluations. In the current article, we discuss the diagnosis and management of patients suffering from mastocytosis and concomitant MCAS, with special emphasis on novel diagnostic tests and management, including allergen microarrays, recombinant allergen analysis, basophil activation tests, optimal prophylaxis, and specific therapies.
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http://dx.doi.org/10.3390/ijms22031454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867197PMC
February 2021

Clinical Impact of Inherited and Acquired Genetic Variants in Mastocytosis.

Int J Mol Sci 2021 Jan 2;22(1). Epub 2021 Jan 2.

Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria.

Mastocytosis is a rare and complex disease characterized by expansion of clonal mast cells (MC) in skin and/or various internal organ systems. Involvement of internal organs leads to the diagnosis of systemic mastocytosis (SM). The WHO classification divides SM into indolent SM, smoldering SM and advanced SM variants, including SM with an associated hematologic neoplasm, aggressive SM, and MC leukemia. Historically, genetic analysis of individuals with pure cutaneous mastocytosis (CM) and SM have focused primarily on cohort studies of inherited single nucleotide variants and acquired pathogenic variants. The most prevalent pathogenic variant (mutation) in patients with SM is p.D816V, which is detectable in most adult patients. Other somatic mutations have also been identified-especially in advanced SM-in , , , , and , and shown to impact clinical and cellular phenotypes. Although only small patient cohorts have been analyzed, disease associations have also been identified in several germline variants within genes encoding certain cytokines or their receptors (, , , , ) and toll-like receptors. More recently, an increased prevalence of hereditary alpha-tryptasemia (HαT) caused by increased copy number encoding alpha-tryptase has been described in patients with SM. Whereas HαT is found in 3-6% of general Western populations, it is identified in up to 17% of patients with SM. In the current manuscript we review the prevalence, functional role and clinical impact of various germline and somatic genetic variants in patients with mastocytosis.
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http://dx.doi.org/10.3390/ijms22010411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795405PMC
January 2021

Cytogenetic and molecular aberrations and worse outcome for male patients in systemic mastocytosis.

Theranostics 2021 1;11(1):292-303. Epub 2021 Jan 1.

Department of Dermatology and Venereology, Allergy Centrr, Kepler University Hospital, Linz, Austria.

In systemic mastocytosis (SM), the clinical features and survival vary greatly. Patient-related factors determining the outcome in SM are largely unknown. We examined the impact of sex on the clinical features, progression-free survival (PFS), and overall survival (OS) in 3403 patients with mastocytosis collected in the registry of the European Competence Network on Mastocytosis (ECNM). The impact of cytogenetic and molecular genetic aberrations on sex differences was analyzed in a subset of patients. Of all patients enrolled, 55.3% were females. However, a male predominance was found in a subset of advanced SM (AdvSM) patients, namely SM with an associated hematologic neoplasm (SM-AHN, 70%; 0.001). Correspondingly, organomegaly (male: 23% female: 13%, 0.007) was more, whereas skin involvement (male: 71% female: 86%, 0.001) was less frequent in males. In all patients together, OS ( 0.0001) was significantly inferior in males, and also within the WHO sub-categories indolent SM, aggressive SM (ASM) and SM-AHN. PFS was significantly ( 0.0002) worse in males when all patients were grouped together; due to low numbers of events, this significance persisted only in the subcategory smoldering SM. Finally, prognostically relevant cytogenetic abnormalities (10% 5%, 0.006) or molecular aberrations (// profile; 63% 40%, 0.003) were more frequently present in males. Male sex has a major impact on clinical features, disease progression, and survival in mastocytosis. Male patients have an inferior survival, which seems related to the fact that they more frequently develop a multi-mutated AdvSM associated with a high-risk molecular background.
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http://dx.doi.org/10.7150/thno.51872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681091PMC
January 2021

Scoring the Risk of Having Systemic Mastocytosis in Adult Patients with Mastocytosis in the Skin.

J Allergy Clin Immunol Pract 2021 04 23;9(4):1705-1712.e4. Epub 2020 Dec 23.

Division of Allergy and Clinical Immunology, Department of Medicine, University of Salerno, Salerno, Italy.

Background: 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 develop a risk score to predict SM in adults with MIS.

Methods: We examined 1145 patients with MIS from the European Competence Network on Mastocytosis Registry who underwent a bone marrow biopsy. A total of 944 patients had SM and 201 patients had cutaneous mastocytosis; 63.7% were female, and 36.3% were male. Median age was 44 ± 13.3 years. The median serum tryptase level amounted to 29.3 ± 81.9 ng/mL. We established a multivariate regression model using the whole population of patients as a training and validation set (bootstrapping). A risk score was developed and validated with receiver-operating curves.

Results: In the multivariate model, the tryptase level (P < .001), constitutional/cardiovascular symptoms (P = .014), and bone symptoms/osteoporosis (P < .001) were independent predictors of SM (P < .001; sensitivity, 90.7%; specificity, 69.1%). A 6-point risk score was established (risk, 10.7%-98.0%) and validated.

Conclusions: Using a large data set of the European Competence Network on Mastocytosis Registry, we created a risk score to predict the presence of SM in patients with MIS. Although the score will need further validation in independent cohorts, our score seems to discriminate safely between patients with SM and with pure cutaneous mastocytosis.
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http://dx.doi.org/10.1016/j.jaip.2020.12.022DOI Listing
April 2021

Th1-Polarized, Dengue Virus-Activated Human Mast Cells Induce Endothelial Transcriptional Activation and Permeability.

Viruses 2020 12 2;12(12). Epub 2020 Dec 2.

Program in Emerging Infectious Diseases, Duke-National University of Singapore, Singapore 169857, Singapore.

Dengue virus (DENV), an arbovirus, strongly activates mast cells (MCs), which are key immune cells for pathogen immune surveillance. In animal models, MCs promote clearance of local peripheral DENV infections but, conversely, also promote pathological vascular leakage when widely activated during systemic DENV infection. Since DENV is a human pathogen, we sought to ascertain whether a similar phenomenon could occur in humans by characterizing the products released by human MCs (huMCs) upon direct (antibody-independent) DENV exposure, using the phenotypically mature huMC line, ROSA. DENV did not productively infect huMCs but prompted huMC release of proteases and eicosanoids and induced a Th1-polarized transcriptional profile. In co-culture and trans-well systems, huMC products activated human microvascular endothelial cells, involving transcription of vasoactive mediators and increased monolayer permeability. This permeability was blocked by MC-stabilizing drugs, or limited by drugs targeting certain MC products. Thus, MC stabilizers are a viable strategy to limit MC-promoted vascular leakage during DENV infection in humans.
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http://dx.doi.org/10.3390/v12121379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761533PMC
December 2020

Diagnosis, Classification and Management of Mast Cell Activation Syndromes (MCAS) in the Era of Personalized Medicine.

Int J Mol Sci 2020 Nov 27;21(23). Epub 2020 Nov 27.

Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD 20852, USA.

Mast cell activation (MCA) is seen in a variety of clinical contexts and pathologies, including IgE-dependent allergic inflammation, other immunologic and inflammatory reactions, primary mast cell (MC) disorders, and hereditary alpha tryptasemia (HAT). MCA-related symptoms range from mild to severe to life-threatening. The severity of MCA-related symptoms depends on a number of factors, including genetic predisposition, the number and releasability of MCs, organs affected, and the type and consequences of comorbid conditions. In severe systemic reactions, MCA is demonstrable by a substantial increase of basal serum tryptase levels above the individual's baseline. When, in addition, the symptoms are recurrent, involve more than one organ system, and are responsive to therapy with MC-stabilizing or mediator-targeting drugs, the consensus criteria for the diagnosis of MCA syndrome (MCAS) are met. Based on the etiology of MCA, patients can further be classified as having i) primary MCAS where -mutated, clonal, MCs are detected; ii) secondary MCAS where an underlying IgE-dependent allergy or other reactive MCA-triggering pathology is found; or iii) idiopathic MCAS, where neither a triggering reactive state nor -mutated MCs are identified. Most severe MCA events occur in combined forms of MCAS, where -mutated MCs, IgE-dependent allergies and sometimes HAT are detected. These patients may suffer from life-threatening anaphylaxis and are candidates for combined treatment with various types of drugs, including IgE-blocking antibodies, anti-mediator-type drugs and MC-targeting therapy. In conclusion, detailed knowledge about the etiology, underlying pathologies and co-morbidities is important to establish the diagnosis and develop an optimal management plan for MCAS, following the principles of personalized medicine.
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http://dx.doi.org/10.3390/ijms21239030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731385PMC
November 2020

Mast cells as a unique hematopoietic lineage and cell system: From Paul Ehrlich's visions to precision medicine concepts.

Theranostics 2020 29;10(23):10743-10768. Epub 2020 Aug 29.

Departments of Pathology and of Microbiology and Immunology, and the Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, USA.

The origin and functions of mast cells (MCs) have been debated since their description by Paul Ehrlich in 1879. MCs have long been considered 'reactive bystanders' and 'amplifiers' in inflammatory processes, allergic reactions, and host responses to infectious diseases. However, knowledge about the origin, phenotypes and functions of MCs has increased substantially over the past 50 years. MCs are now known to be derived from multipotent hematopoietic progenitors, which, through a process of differentiation and maturation, form a unique hematopoietic lineage residing in multiple organs. In particular, MCs are distinguishable from basophils and other hematopoietic cells by their unique phenotype, origin(s), and spectrum of functions, both in innate and adaptive immune responses and in other settings. The concept of a unique MC lineage is further supported by the development of a distinct group of neoplasms, collectively referred to as mastocytosis, in which MC precursors expand as clonal cells. The clinical consequences of the expansion and/or activation of MCs are best established in mastocytosis and in allergic inflammation. However, MCs have also been implicated as important participants in a number of additional pathologic conditions and physiological processes. In this article, we review concepts regarding MC development, factors controlling MC expansion and activation, and some of the fundamental roles MCs may play in both health and disease. We also discuss new concepts for suppressing MC expansion and/or activation using molecularly-targeted drugs.
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http://dx.doi.org/10.7150/thno.46719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482799PMC
May 2021

Impact of Point-of-care Testing on Length of Stay of Patients in the Emergency Department: A Cluster-randomized Controlled Study.

Acad Emerg Med 2020 10 27;27(10):974-983. Epub 2020 Jul 27.

and the, Biochemisty and Emergency Biology Department, Hôpital Pitié-Salpêtrière, APHP, Paris, France.

Objectives: Crowding is a frequent concern in the emergency department (ED). Laboratory point-of-care testing (POCT) has been proposed to decrease patients' length of stay (LOS). Our objective was to determine whether an extended panel of POCT solutions could reduce LOS.

Methods: This was a single-center, prospective, open-label, controlled cluster-randomized study. Blood test processing was randomized into 1-week inclusion periods: interventional arm (laboratory analyses performed on POCT analyzers implemented in the ED) or control arm (central laboratory). The primary endpoint was LOS of patients in the ED. Secondary endpoints were time to result (TTR), ED crowding surrogates, and average total cost of an ED visit in each arm.

Results: A total of 23,231 patients were included and 20,923 were analyzed for the main outcome measure. Mean ± SD age was 46 ± 20 years, and 7,905 (36%) underwent blood sampling. Mean ± SD LOSs were 203 ± 161 and 210 ± 168 minutes in the POCT and control arms, respectively. LOS reduction for the entire ED population was -9 minutes (95% confidence interval [CI] = -22 to 5, p = 0.22) compared to the control arm and -17 minutes (95% CI = -34.0 to 0.6, p = 0.06) for patients undergoing blood sampling. The mean ± SD TTRs were 28 ± 31 and 79 ± 34 minutes in the POCT and control arms, respectively (TTR reduction = -51 minutes, 95% CI = -54 to -48 minutes, p < 0.001).

Conclusions: The implementation of an extended panel of POCT solutions in an ED did not significantly reduce the LOS, but reduced the TTR.
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http://dx.doi.org/10.1111/acem.14072DOI Listing
October 2020

Risk and management of patients with mastocytosis and MCAS in the SARS-CoV-2 (COVID-19) pandemic: Expert opinions.

J Allergy Clin Immunol 2020 08 17;146(2):300-306. Epub 2020 Jun 17.

Division of Allergy, Department of Dermatology, and Department of Biomedicine, University of Basel, Basel, Switzerland.

The coronavirus disease 2019 (COVID-19) (caused by severe acute respiratory syndrome coronavirus 2) pandemic has massively distorted our health care systems and caused catastrophic consequences in our affected communities. The number of victims continues to increase, and patients at risk can only be protected to a degree, because the virulent state may be asymptomatic. Risk factors concerning COVID-19-induced morbidity and mortality include advanced age, an impaired immune system, cardiovascular or pulmonary diseases, obesity, diabetes mellitus, and cancer treated with chemotherapy. Here, we discuss the risk and impact of COVID-19 in patients with mastocytosis and mast cell activation syndromes. Because no published data are yet available, expert opinions are, by necessity, based on case experience and reports from patients. Although the overall risk to acquire the severe acute respiratory syndrome coronavirus 2 may not be elevated in mast cell disease, certain conditions may increase the risk of infected patients to develop severe COVID-19. These factors include certain comorbidities, mast cell activation-related events affecting the cardiovascular or bronchopulmonary system, and chemotherapy or immunosuppressive drugs. Therefore, such treatments should be carefully evaluated on a case-by-case basis during a COVID-19 infection. In contrast, other therapies, such as anti-mediator-type drugs, venom immunotherapy, or vitamin D, should be continued. Overall, patients with mast cell disorders should follow the general and local guidelines in the COVID-19 pandemic and advice from their medical provider.
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http://dx.doi.org/10.1016/j.jaci.2020.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297685PMC
August 2020

Immunomodulatory role of Interleukin-33 in large vessel vasculitis.

Sci Rep 2020 04 14;10(1):6405. Epub 2020 Apr 14.

Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR S 959, Immunology-Immunopathology- Immunotherapy (I3), F-75005, Paris, France.

The mechanisms regulating inflammation in large vessels vasculitis (LVV) are poorly understood. Interleukin 33 (IL-33) has been shown to license innate and adaptive immunity by enhancing Th2 cytokines production. We aimed to examine the role of IL-33 in the immunomodulation of T cell activation in LVV. T cell homeostasis and cytokines production were determined in peripheral blood from 52 patients with giant cell arteritis (GCA) and 50 healthy donors (HD), using Luminex assay, flow cytometry, quantitative RT-PCR and by immunofluorescence analysis in inflammatory aorta lesions. We found increased level of IL-33 and its receptor ST2/IL-1R4 in the serum of patient with LVV. Endothelial cells were the main source of IL-33, whereas Th2 cells, Tregs and mast cells (MC) express ST2 in LVV vessels. IL-33 had a direct immunomodulatory impact by increasing Th2 and Tregs. IL-33 and MC further enhanced Th2 and regulatory responses by inducing a 6.1 fold increased proportion of Tregs (p = 0.008). Stimulation of MC by IL-33 increased indoleamine 2 3-dioxygenase (IDO) activity and IL-2 secretion. IL-33 mRNA expression was significantly correlated with the expression of IL-10 and TGF-β within aorta inflammatory lesions. To conclude, our findings suggest that IL-33 may exert a critical immunoregulatory role in promoting Tregs and Th2 cells in LVV.
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http://dx.doi.org/10.1038/s41598-020-63042-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156501PMC
April 2020

Clinical features and survival of patients with indolent systemic mastocytosis defined by the updated WHO classification.

Allergy 2020 08 16;75(8):1927-1938. Epub 2020 Mar 16.

Departement of Hematology, Centre National de Référence des Mastocytoses, Imagine Institute, INSERM U1123, Université Paris Descartes, Sorbonne, Paris Cité, Hôpital Necker, Assistance Publique des Hôpitaux de Paris (APHP), Paris, France.

Background: In indolent systemic mastocytosis (ISM), several risk factors of disease progression have been identified. Previous studies, performed with limited patient numbers, have also shown that the clinical course in ISM is stable and comparable to that of cutaneous mastocytosis (CM). The aim of this project was to compare the prognosis of patients with ISM with that of patients with CM.

Methods: We employed a dataset of 1993 patients from the registry of the European Competence Network on Mastocytosis (ECNM) to compare outcomes of ISM and CM.

Results: We found that overall survival (OS) is worse in ISM compared to CM. Moreover, in patients with typical ISM, bone marrow mastocytosis (BMM), and smoldering SM (SSM), 4.1% of disease progressions have been observed (4.9% of progressions in typical ISM group, 1.7% in BMM, and 9.4% in SSM). Progressions to advanced SM were observed in 2.9% of these patients. In contrast, six patients with CM (1.7%) converted to ISM and no definitive progression to advanced SM was found. No significant differences in OS and event-free survival (EFS) were found when comparing ISM, BMM, and SSM. Higher risk of both progression and death was significantly associated with male gender, worse performance status, and organomegaly.

Conclusion: Our data confirm the clinical impact of the WHO classification that separates ISM from CM and from other SM variants.
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http://dx.doi.org/10.1111/all.14248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115854PMC
August 2020

Activation of Siglec-7 results in inhibition of in vitro and in vivo growth of human mast cell leukemia cells.

Pharmacol Res 2020 08 5;158:104682. Epub 2020 Feb 5.

Pharmacology & Experimental Therapeutics Unit, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel. Electronic address:

Advanced systemic mastocytosis is a rare and still untreatable disease. Blocking antibodies against inhibitory receptors, also known as "immune checkpoints", have revolutionized anti-cancer treatment. Inhibitory receptors are expressed not only on normal immune cells, including mast cells but also on neoplastic cells. Whether activation of inhibitory receptors through monoclonal antibodies can lead to tumor growth inhibition remains mostly unknown. Here we show that the inhibitory receptor Siglec-7 is expressed by primary neoplastic mast cells in patients with systemic mastocytosis and by mast cell leukemia cell lines. Activation of Siglec-7 by anti-Siglec-7 monoclonal antibody caused phosphorylation of Src homology region 2 domain-containing phosphatase-1 (SHP-1), reduced phosphorylation of KIT and induced growth inhibition in mast cell lines. In SCID-beige mice injected with either the human mast cell line HMC-1.1 and HMC-1.2 or with Siglec-7 transduced B cell lymphoma cells, anti-Siglec-7 monoclonal antibody reduced tumor growth by a mechanism involving Siglec-7 cytoplasmic domains in "preventive" and "treatment" settings. These data demonstrate that activation of Siglec-7 on mast cell lines can inhibit their growth in vitro and in vivo. This might pave the way to additional treatment strategies for mastocytosis.
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http://dx.doi.org/10.1016/j.phrs.2020.104682DOI Listing
August 2020

New developments in the field of mastocytosis and mast cell activation syndromes: a summary of the Annual Meeting of the European Competence Network on Mastocytosis (ECNM) 2019.

Leuk Lymphoma 2020 05 26;61(5):1075-1083. Epub 2019 Dec 26.

Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria.

Mastocytosis are a group of hematologic neoplasms characterized by an accumulation of atypical mast cells in one or several organs/tissues, often accompanied by mast cell activation. Whereas in children the disease manifestations are mostly limited to the skin, in adults the disease is usually systemic (systemic mastocytosis; SM) and involves the bone marrow and/or other internal organs. Several variants of SM have been defined. Whereas most patients have indolent SM, some patients have advanced SM, which underlines the complexity of SM. In 2002, a European consortium of clinicians and scientists initiated a multidisciplinary, multi-national cooperative network, termed the 'European Competence Network on Mastocytosis' (ECNM), with the aim to improve diagnosis and therapy of patients with mastocytosis and other mast cell activation disorders. Since then, members of the ECNM have organized Annual Meetings in several European countries. The present article provides a summary of advances in the field presented during the 17th Annual ECNM meeting held in Salzburg in October 2019.
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http://dx.doi.org/10.1080/10428194.2019.1703974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115828PMC
May 2020

Prognostic impact of eosinophils in mastocytosis: analysis of 2350 patients collected in the ECNM Registry.

Leukemia 2020 04 18;34(4):1090-1101. Epub 2019 Nov 18.

Department Immunol, Genetics and Pathology (MM) and Dept Hematol (MM, HH), Uppsala University Hospital, Uppsala University, Uppsala, Sweden.

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 × 10/l), and 3.1% hypereosinophilia (HE; >1.5 × 10/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.
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http://dx.doi.org/10.1038/s41375-019-0632-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115841PMC
April 2020

International prognostic scoring system for mastocytosis (IPSM): a retrospective cohort study.

Lancet Haematol 2019 Dec 31;6(12):e638-e649. Epub 2019 Oct 31.

Department of Oncology, Haematology, Haemostaseology and Stem Cell Transplantation, University Hospital RWTH Aachen, Aachen, Germany.

Background: 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.

Methods: We analysed data of the registry of the European Competence Network on Mastocytosis including 1639 patients (age 17-90 years) diagnosed with mastocytosis according to WHO criteria between Jan 12, 1978, and March 16, 2017. Univariate and multivariate analyses with Cox regression were applied to identify prognostic variables predicting survival outcomes and to establish a prognostic score. We validated this International Prognostic Scoring System in Mastocytosis (IPSM) with data of 462 patients (age 17-79 years) from the Spanish network Red Española de Mastocitosis diagnosed between Jan 22, 1998, and Nov 2, 2017.

Findings: The prognostic value of the WHO classification was confirmed in our study (p<0·0001). For patients with non-advanced mastocytosis (n=1380), we identified age 60 years or older (HR 10·75, 95% CI 5·68-20·32) and a concentration of alkaline phosphatase 100 U/L or higher (2·91, 1·60-5·30) as additional independent prognostic variables for overall survival. The resulting scoring system divided patients with non-advanced mastocytosis into three groups: low (no risk factors), intermediate 1 (one risk factor), and intermediate 2 (two risk factors). Overall survival and progression-free survival differed significantly among these groups (p<0·0001). In patients with advanced mastocytosis (n=259), age 60 years or older (HR 2·14, 95% CI 1·42-3·22), a concentration of tryptase 125 ng/mL or higher (1·81, 1·20-2·75), a leukocyte count of 16 × 10 per L or higher (1·88, 1·27-2·79), haemoglobin of 11 g/dL or lower (1·71, 1·13-2·57), a platelet count of 100 × 10 per L or lower (1·63, 1·13-2·34), and skin involvement (0·46, 0·30-0·69) were prognostic variables. Based on these variables, a separate score for advanced mastocytosis with four risk categories was established, with significantly different outcomes for overall survival and progression-free survival (p<0·0001). The prognostic value of both scores was confirmed in 413 patients with non-advanced disease and 49 with advanced mastocytosis from the validation cohort.

Interpretation: The IPSM scores for patients with non-advanced and advanced mastocytosis can be used to predict survival outcomes and guide treatment decisions. However, the predictive value of the IPSM needs to be confirmed in forthcoming trials.

Funding: Austrian Science Fund, Deutsche Forschungsgemeinschaft, Koeln Fortune Program, Charles and Ann Johnson Foundation, Instituto de Salud Carlos III, Fondos FEDER, Research-Foundation Flanders/Fonds Wetenschappelijk Onderzoek, Clinical Research-Fund of the University Hospitals Leuven, and Research-Foundation Flanders/Fonds Wetenschappelijk Onderzoek.
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http://dx.doi.org/10.1016/S2352-3026(19)30166-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115823PMC
December 2019

Divergent Effects of Acute and Prolonged Interleukin 33 Exposure on Mast Cell IgE-Mediated Functions.

Front Immunol 2019 19;10:1361. Epub 2019 Jun 19.

Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Solna, Sweden.

Epithelial cytokines, including IL-33 and Thymic stromal lymphopoietin (TSLP), have attracted interest because of their roles in chronic allergic inflammation-related conditions such as asthma. Mast cells are one of the major targets of IL-33, to which they respond by secreting cytokines. Most studies performed thus far have investigated the acute effects of IL-33 on mast cells. In the current study, we investigated how acute vs. prolonged exposure of mast cells to IL-33 and TSLP affects mediator synthesis and IgE-mediated activation. Human lung mast cells (HLMCs), cord blood-derived mast cells (CBMCs), and the ROSA mast cell line were used for this study. Receptor expression and the levels of mediators were measured after treatment with IL-33 and/or TSLP. IL-33 induced the release of cytokines. Prolonged exposure to IL-33 increased while TSLP reduced intracellular levels of tryptase. Acute IL-33 treatment strongly potentiated IgE-mediated activation. In contrast, 4 days of exposure to IL-33 decreased IgE-mediated activation, an effect that was accompanied by a reduction in FcεRI expression. We show that IL-33 plays dual roles in mast cells, in which its acute effects include cytokine release and the potentiation of IgE-mediated degranulation, whereas prolonged exposure to IL-33 reduces IgE-mediated activation. We conclude that mast cells act quickly in response to the alarmin IL-33 to initiate an acute inflammatory response, whereas extended exposure to IL-33 during prolonged inflammation reduces IgE-mediated responses. This negative feedback effect suggests the presence of a novel regulatory pathway that modulates IgE-mediated human mast cell responses.
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http://dx.doi.org/10.3389/fimmu.2019.01361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593472PMC
September 2020

Why the 20% + 2 Tryptase Formula Is a Diagnostic Gold Standard for Severe Systemic Mast Cell Activation and Mast Cell Activation Syndrome.

Int Arch Allergy Immunol 2019 28;180(1):44-51. Epub 2019 Jun 28.

Division of Allergy and Clinical Immunology, University of Michigan, Ann Arbor, Michigan, USA.

Mast cell activation syndrome (MCAS) is a condition characterized by recurrent episodes of clinically relevant, systemic, severe reactions to mast cell (MC)-derived mediators released in the context of anaphylaxis or another acute MC-related event. It is important to document MC involvement in these reactions in order to establish the diagnosis MCAS. The most specific and reliable marker of systemic MC activation is an acute and substantial event-related (transient) increase in the serum tryptase level over the individual's baseline value. However, the baseline level of tryptase varies depending on the underlying disease and the genetic background. For example, an estimated 3-5% of healthy individuals exhibit duplications or multiple copies of the TPSAB1 gene encoding for alpha-tryptase, and over 30% of all patients with myeloid neoplasms, including mastocytosis, have elevated basal tryptase levels. Therefore, it is of utmost importance to adjust the event-related diagnostic (MCAS-confirming) increase in tryptase over the individual baseline in a robust approach. To address this challenge, the 20% + 2 formula was proposed by the consensus group in 2012. Since then, this approach has been validated in clinical practice by independent groups and found to be sound. In the current article, we discuss the emerging importance and value of the 20% + 2 formula in clinical practice and its role as a criterion of severe systemic MC activation and MCAS.
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http://dx.doi.org/10.1159/000501079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115850PMC
September 2019

Multidisciplinary Challenges in Mastocytosis and How to Address with Personalized Medicine Approaches.

Int J Mol Sci 2019 Jun 18;20(12). Epub 2019 Jun 18.

Division of Allergy and Clinical Immunology, University of Salerno, 84131 Salerno, Italy.

Mastocytosis is a hematopoietic neoplasm defined by abnormal expansion and focal accumulation of clonal tissue mast cells in various organ-systems. The disease exhibits a complex pathology and an equally complex clinical behavior. The classification of the World Health Organization (WHO) divides mastocytosis into cutaneous forms, systemic variants, and localized mast cell tumors. In >80% of patients with systemic mastocytosis (SM), a somatic point mutation in at codon 816 is found. Whereas patients with indolent forms of the disease have a normal or near-normal life expectancy, patients with advanced mast cell neoplasms, including aggressive SM and mast cell leukemia, have a poor prognosis with short survival times. In a majority of these patients, multiple somatic mutations and/or an associated hematologic neoplasm, such as a myeloid leukemia, may be detected. Independent of the category of mastocytosis and the serum tryptase level, patients may suffer from mediator-related symptoms and/or osteopathy. Depending on the presence of co-morbidities, the symptomatology in such patients may be mild, severe or even life-threatening. Most relevant co-morbidities in such patients are IgE-dependent allergies, psychiatric, psychological or mental problems, and vitamin D deficiency. The diagnosis and management of mastocytosis is an emerging challenge in clinical practice and requires vast knowledge, a multidisciplinary approach, and personalized medicine procedures. In this article, the current knowledge about mastocytosis is reviewed with special emphasis on the multidisciplinary aspects of the disease and related challenges in daily practice.
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http://dx.doi.org/10.3390/ijms20122976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627900PMC
June 2019

Single-cell analysis reveals the KIT D816V mutation in haematopoietic stem and progenitor cells in systemic mastocytosis.

EBioMedicine 2019 May 8;43:150-158. Epub 2019 Apr 8.

Department of Medicine Solna, Karolinska Institutet, and Karolinska University Hospital, Stockholm 17164, Sweden. Electronic address:

Background: Systemic mastocytosis (SM) is a haematological disease characterised by organ infiltration by neoplastic mast cells. Almost all SM patients have a mutation in the gene encoding the tyrosine kinase receptor KIT causing a D816V substitution and autoactivation of the receptor. Mast cells and CD34 haematopoietic progenitors can carry the mutation; however, in which progenitor cell subset the mutation arises is unknown. We aimed to investigate the distribution of the D816V mutation in single mast cells and single haematopoietic stem and progenitor cells.

Methods: Fluorescence-activated single-cell index sorting and KIT D816V mutation assessment were applied to analyse mast cells and >10,000 CD34 bone marrow progenitors across 10 haematopoietic progenitor subsets. In vitro assays verified cell-forming potential.

Findings: We found that in SM 60-99% of the mast cells harboured the KIT D816V mutation. Despite increased frequencies of mast cells in SM patients compared with control subjects, the haematopoietic progenitor subset frequencies were comparable. Nevertheless, the mutation could be detected throughout the haematopoietic landscape of SM patients, from haematopoietic stem cells to more lineage-primed progenitors. In addition, we demonstrate that FcεRI bone marrow progenitors exhibit mast cell-forming potential, and we describe aberrant CD45RA expression on SM mast cells for the first time.

Interpretation: The KIT D816V mutation arises in early haematopoietic stem and progenitor cells and the mutation frequency is approaching 100% in mature mast cells, which express the aberrant marker CD45RA.
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http://dx.doi.org/10.1016/j.ebiom.2019.03.089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557764PMC
May 2019

Omalizumab Therapy for Mast Cell-Mediator Symptoms in Patients with ISM, CM, MMAS, and MCAS.

J Allergy Clin Immunol Pract 2019 Sep - Oct;7(7):2387-2395.e3. Epub 2019 Apr 5.

Imagine Institute, INSERM U1163 and CNRS ERL 8654, Paris Descartes University, Sorbonne Paris Cité, Paris, France; Department of Hematology, Necker Children's Hospital, APHP, Paris, France; French Reference Center for Mastocytosis (CEREMAST), Necker Children's Hospital, APHP, Paris, France.

Background: Patients with mast cell diseases may suffer from various distressing symptoms, which can be insufficiently controlled with available therapies, severely affecting their quality of life. There is a need for new and safe treatment options for these patients.

Objectives: We aimed to evaluate safety and efficacy of omalizumab administration in patients with a symptomatic mast cell disorder.

Methods: We included 55 patients with a mast cell disorder associated with debilitating symptoms who received omalizumab treatment between January 2015 and December 2017, after a multidisciplinary team meeting at the French National Reference Center for Mastocytosis.

Results: A complete response was achieved for 1 patient (1.8%), a major response for 30 patients (54.5%), and a partial response for 12 patients (21.8%), resulting in an overall best response rate of 78.2% (43 of 55 patients). The response was persistent at least 3 months in 33 of 43 responding patients (76.7%). At the last follow-up, the final overall response rate was 58.2% (32 of 55 patients). Median time to first response was 2 months and median time to best response was 6 months. Omalizumab was dramatically effective on all superficial and general vasomotor symptoms and on most gastrointestinal or urinary symptoms, and partially effective on most neuropsychiatric symptoms. Safety profile was acceptable, except for one severe adverse event (edema of the larynx and dyspnea after the first injection of omalizumab). Side effects were reported in 16 patients (29%), mainly of low to mild intensity, yet causing interruption of treatment in 5 patients (9%).

Conclusion: Omalizumab seems to be a useful therapeutic option to control mast cell-mediator symptoms and displays a favorable safety profile.
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http://dx.doi.org/10.1016/j.jaip.2019.03.039DOI Listing
October 2020

Identification of a leukemia-initiating stem cell in human mast cell leukemia.

Leukemia 2019 11 5;33(11):2673-2684. Epub 2019 Apr 5.

Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090, Vienna, Austria.

Mast cell leukemia (MCL) is a highly fatal malignancy characterized by devastating expansion of immature mast cells in various organs. Although considered a stem cell disease, little is known about MCL-propagating neoplastic stem cells. We here describe that leukemic stem cells (LSCs) in MCL reside within a CD34/CD38 fraction of the clone. Whereas highly purified CD34/CD38 cells engrafted NSG mice with fully manifesting MCL, no MCL was produced by CD34/CD38 progenitors or the bulk of KIT/CD34 mast cells. CD34/CD38 MCL cells invariably expressed CD13 and CD133, and often also IL-1RAP, but did not express CD25, CD26 or CLL-1. CD34/CD38 MCL cells also displayed several surface targets, including CD33, which was homogenously expressed on MCL LSCs in all cases, and the D816V mutant form of KIT. Although CD34/CD38 cells were resistant against single drugs, exposure to combinations of CD33-targeting and KIT-targeting drugs resulted in LSC-depletion and markedly reduced engraftment in NSG mice. Together, MCL LSCs are CD34/CD38 cells that express distinct profiles of markers and target antigens. Characterization of MCL LSCs should facilitate their purification and should support the development of LSC-eradicating curative treatment approaches in this fatal type of leukemia.
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http://dx.doi.org/10.1038/s41375-019-0460-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839966PMC
November 2019

In vitro and in vivo efficacy of an anti-CD203c conjugated antibody (AGS-16C3F) in mouse models of advanced systemic mastocytosis.

Blood Adv 2019 02;3(4):633-643

INSERM, Unité Mixte de Recherche (UMR) 1170, Villejuif, France.

Antibody-drug conjugates (ADCs) are a new class of therapeutics that use antibodies to deliver potent cytotoxic drugs selectively to cancer cells. CD203c, an ecto-nucleotide pyrophosphatase-phosphodiesterase 3, is overexpressed on neoplastic mast cells (MCs) in systemic mastocytosis (SM), thus representing a promising target for antibody-mediated therapy. In this study, we have found that human neoplastic MC lines (ROSA and ROSA), which express high levels of CD203c, are highly and specifically sensitive to the antiproliferative effects of an ADC against CD203c (AGS-16C3F). In these cell lines, AGS-16C3F induced cell apoptosis at very low concentrations. To characterize the effects of AGS-16C3F on leukemia progression in vivo, ROSA NOD-SCID γ mouse models of advanced SM (AdvSM) were treated with AGS-16C3F or an ADC control for 2 weeks. Whereas AGS-16C3F had no apparent toxicity in xenotransplanted mice, in vivo neoplastic MC burden significantly decreased in both hematopoietic and nonhematopoietic organs. Furthermore, animals treated with AGS-16C3F had prolonged survival compared with the animals treated with control ADC, and AGS-16C3F efficiently prevented disease relapse. In conclusion, these preclinical studies identified CD203c as a novel therapeutic target on neoplastic MCs, and AGS-16C3F as a promising ADC for the treatment of patients with AdvSM.
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http://dx.doi.org/10.1182/bloodadvances.2018026179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391676PMC
February 2019