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Haematologica Jan 2020
Topics: Humans; Interleukin-6; Mast Cells; Mastocytosis; Mastocytosis, Systemic; Oncogenes
PubMed: 31894094
DOI: 10.3324/haematol.2019.234864 -
Hematology. American Society of... Dec 2022The historically poor prognosis of patients with advanced systemic mastocytosis (AdvSM) and primary eosinophilic neoplasms has shifted to increasingly favorable outcomes... (Review)
Review
The historically poor prognosis of patients with advanced systemic mastocytosis (AdvSM) and primary eosinophilic neoplasms has shifted to increasingly favorable outcomes with the discovery of druggable targets. The multikinase/KIT inhibitor midostaurin and the highly selective KIT D816V inhibitor avapritinib can elicit marked improvements in measures of mast cell (MC) burden as well as reversion of MC-mediated organ damage (C-findings) and disease symptoms. With avapritinib, the achievement of molecular remission of KIT D816V and improved survival compared with historical therapy suggests a potential to affect disease natural history. BLU-263 and bezuclastinib are KIT D816V inhibitors currently being tested in trials of AdvSM. In the new World Health Organization and International Consensus Classifications, the category of "myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase (TK) gene fusions" is inclusive of rearrangements involving PDGFRA, PDGFRB, FGFR1, JAK2, FLT3, and ETV6::ABL1. While the successful outcomes with imatinib in FIP1L1::PDGFRA-positive cases and PDGFRB-rearranged neoplasms have become the "poster children" of these disorders, the responses of the other TK-driven neoplasms to small-molecule inhibitors are more variable. The selective FGFR inhibitor pemigatinib, approved in August 2022, is a promising therapy in aggressive FGFR1-driven diseases and highlights the role of such agents in bridging patients to allogeneic transplantation. This review summarizes the data for these approved and investigational agents and discusses open questions and future priorities regarding the management of these rare diseases.
Topics: Child; Humans; Mastocytosis, Systemic; Protein Kinase Inhibitors; Myeloproliferative Disorders; Imatinib Mesylate; Eosinophilia; Proto-Oncogene Proteins c-kit; Mastocytosis
PubMed: 36485158
DOI: 10.1182/hematology.2022000368 -
International Journal of Molecular... Jun 2023Mastocytosis is a heterogeneous group of diseases associated with excessive proliferation and accumulation of mast cells in different organs. Recent studies have... (Review)
Review
Mastocytosis is a heterogeneous group of diseases associated with excessive proliferation and accumulation of mast cells in different organs. Recent studies have demonstrated that patients suffering from mastocytosis face an increased risk of melanoma and non-melanoma skin cancer. The cause of this has not yet been clearly identified. In the literature, the potential influence of several factors has been suggested, including genetic background, the role of cytokines produced by mast cells, iatrogenic and hormonal factors. The article summarizes the current state of knowledge regarding the epidemiology, pathogenesis, diagnosis, and management of skin neoplasia in mastocytosis patients.
Topics: Humans; Mastocytosis; Mast Cells; Skin Neoplasms; Cytokines; Melanoma; Skin
PubMed: 37372988
DOI: 10.3390/ijms24129840 -
The Journal of Allergy and Clinical... May 2023Mastocytosis encompasses a heterogeneous group of diseases characterized by tissue accumulation of clonal mast cells, which frequently includes bone involvement. Several...
BACKGROUND
Mastocytosis encompasses a heterogeneous group of diseases characterized by tissue accumulation of clonal mast cells, which frequently includes bone involvement. Several cytokines have been shown to play a role in the pathogenesis of bone mass loss in systemic mastocytosis (SM), but their role in SM-associated osteosclerosis remains unknown.
OBJECTIVE
To investigate the potential association between cytokine and bone remodeling markers with bone disease in SM, aiming at identifying biomarker profiles associated with bone loss and/or osteosclerosis.
METHODS
A total of 120 adult patients with SM, divided into 3 age and sex-matched groups according to their bone status were studied: (1) healthy bone (n = 46), (2) significant bone loss (n = 47), and (3) diffuse bone sclerosis (n = 27). Plasma levels of cytokines and serum baseline tryptase and bone turnover marker levels were measured at diagnosis.
RESULTS
Bone loss was associated with significantly higher levels of serum baseline tryptase (P = .01), IFN-γ (P = .05), IL-1β (P = .05), and IL-6 (P = .05) versus those found in patients with healthy bone. In contrast, patients with diffuse bone sclerosis showed significantly higher levels of serum baseline tryptase (P < .001), C-terminal telopeptide (P < .001), amino-terminal propeptide of type I procollagen (P < .001), osteocalcin (P < .001), bone alkaline phosphatase (P < .001), osteopontin (P < .01), and the C-C Motif Chemokine Ligand 5/RANTES chemokine (P = .01), together with lower IFN-γ (P = .03) and RANK-ligand (P = .04) plasma levels versus healthy bone cases.
CONCLUSIONS
SM with bone mass loss is associated with a proinflammatory cytokine profile in plasma, whereas diffuse bone sclerosis shows increased serum/plasma levels of biomarkers related to bone formation and turnover, in association with an immunosuppressive cytokine secretion profile.
Topics: Cytokines; Mastocytosis, Systemic; Bone Remodeling; Bone Resorption; Osteosclerosis; Biomarkers; Humans; Male; Female; Adolescent; Young Adult; Adult; Middle Aged; Aged
PubMed: 36801493
DOI: 10.1016/j.jaip.2023.02.007 -
Actas Dermo-sifiliograficas Jul 2021
Topics: Humans; Mast Cells; Mastocytosis, Cutaneous
PubMed: 33901482
DOI: 10.1016/j.ad.2021.01.004 -
Clinical Pharmacology : Advances and... 2019Mastocytosis is a myeloproliferative neoplasm characterized by expansion of abnormal mast cells (MCs) in various tissues, including skin, bone marrow, gastrointestinal... (Review)
Review
Mastocytosis is a myeloproliferative neoplasm characterized by expansion of abnormal mast cells (MCs) in various tissues, including skin, bone marrow, gastrointestinal tract, liver, spleen, or lymph nodes. Subtypes include indolent systemic mastocytosis, smoldering systemic mastocytosis and advanced systemic mastocytosis (AdvSM), a term collectively used for the three most aggressive forms of the disease: aggressive systemic mastocytosis, mast cell leukemia, and systemic mastocytosis with an associated clonal hematological non-mast cell disease (SM-AHNMD). MC activation and proliferation is physiologically controlled in part through stem cell factor (SCF) binding to its cognate receptor, KIT. Gain-of-function KIT mutations that lead to ligand-independent kinase activation are found in most SM subtypes, and the overwhelming majority of AdvSM patients harbor the KIT mutation. Several approved tyrosine kinase inhibitors (TKIs), such as imatinib and nilotinib, have activity against wild-type KIT but lack activity against KIT. Midostaurin, a broad spectrum TKI with activity against KIT, has a 60% clinical response rate, and is currently the only drug specifically approved for AdvSM. While this agent improves the prognosis of AdvSM patients and provides proof of principle for targeting KIT as a driver mutation, most responses are partial and/or not sustained, indicating that more potent and/or specific inhibitors are required. Avapritinib, a KIT and PDGFRα inhibitor, was specifically designed to inhibit KIT. Early results from a Phase 1 trial suggest that avapritinib has potent antineoplastic activity in AdvSM, extending to patients who failed midostaurin. Patients exhibited a rapid reduction in both symptoms as well as reductions of bone marrow MCs, serum tryptase, and KIT mutant allele burden. Adverse effects include expected toxicities such as myelosuppression and periorbital edema, but also cognitive impairment in some patients. Although considerable excitement about avapritinib exists, more data are needed to assess long-term responses and adverse effects of this novel TKI.
PubMed: 31372066
DOI: 10.2147/CPAA.S206615 -
Immunology and Allergy Clinics of North... Nov 2023A KIT activating mutation (usually KIT D816V) is detected in neoplastic cells in greater than 90% of indolent patients with systemic mastocytosis (SM). In more advanced... (Review)
Review
A KIT activating mutation (usually KIT D816V) is detected in neoplastic cells in greater than 90% of indolent patients with systemic mastocytosis (SM). In more advanced variants of SM, additional genetic defects can be found in several myeloid malignancy-related genes, which can be detected by applying next-generation sequencing. Currently, the techniques recommended to detect the KIT D816V mutation and quantify the mutational burden in peripheral blood, bone marrow, or other organs/tissues are allele specific-quantitative PCR or droplet digital PCR. These techniques are useful for diagnosis, prognostication, follow-up and monitoring of therapeutic efficacy of cytoreductive agents in patients with SM.
Topics: Humans; Proto-Oncogene Proteins c-kit; Mastocytosis; Mutation; Mastocytosis, Systemic; Bone Marrow; Mast Cells
PubMed: 37758404
DOI: 10.1016/j.iac.2023.04.008 -
Deutsches Arzteblatt International Apr 2024Hereditary alpha-tryptasemia (HAT) is a genetic predisposition of autosomal dominant inheritance that leads to a high normal (≥ 8-11.4 μg/L) or pathologically... (Review)
Review
BACKGROUND
Hereditary alpha-tryptasemia (HAT) is a genetic predisposition of autosomal dominant inheritance that leads to a high normal (≥ 8-11.4 μg/L) or pathologically elevated (>11.4 μg/L) basal serum tryptase (BST) concentration. Its prevalence in the United Kingdom and France is reportedly 5%-6%; its prevalence in Germany is unknown. Symptomatic persons with HAT suffer from a complex constellation of symptoms. As described in this review, HAT is an important differential diagnosis in interdisciplinary practice.
METHODS
This review is based on publications about HAT retrieved by a selective search in PubMed, on relevant presentations at scientific meetings, and on our clinical experience. We also collected our own data on the prevalence and clinical manifestations of HAT.
RESULTS
According to the literature, HAT is very common among patients in medical centers with BST values of 8 μg/L or above (64-74%). HAT is most commonly associated with neuropsychiatric symptoms such as exhaustion (85%), depressive episodes (59%), sleep disturbances (69%), and memory impairment (59%-68%), followed by gastrointestinal symptoms such as irritable bowel (30%-60%), nausea (51%), and reflux (49%-77%). Typical mast cell-mediated symptoms, such as flushing (47%), itch (69%), urticaria (37%), and anaphylaxis (14%-28%), are reported as well. Less commonly reported are cardio vascular manifestations, such as hypotonia, dizziness, and tachycardia (34%), and joint hyper - mobility (28%). HAT is more common among patients with systemic mastocytosis (SM; 12%-21%). It is often associated with severe anaphylaxis induced by insect toxins or unknown triggers. The therapeutic options include treatment with antihistamines, mastcell stabilizers, or IgE antibodies.
CONCLUSION
A diagnosis of hereditary alphatryptasemia can be strongly suspected on the basis of thorough history-taking and BST measurement and then confirmed by molecular genetic testing.
Topics: Humans; Tryptases; Diagnosis, Differential; Prevalence; Genetic Predisposition to Disease; Mastocytosis; Germany
PubMed: 38260947
DOI: 10.3238/arztebl.m2023.0287 -
The Journal of Allergy and Clinical... Aug 2022Mast cell activation (MCA) is common and occurs in a number of pathologic conditions, including IgE-dependent and independent allergic reactions, atopic disorders,...
Mast cell activation (MCA) is common and occurs in a number of pathologic conditions, including IgE-dependent and independent allergic reactions, atopic disorders, autoimmune processes, and mastocytosis. In a subset of patients, no underlying disease and no known trigger of MCA are found. When the symptoms are severe, systemic, and recurrent, and accompanied by a diagnostic increase in the serum tryptase level or other mast cell mediators, an MCA syndrome (MCAS) may be diagnosed. In these patients, the symptoms typically respond to drugs suppressing MCA, mediator production in mast cells, or mediator effects. In each case, diagnostic consensus criteria must be fulfilled to diagnose MCAS. In other patients, MCA may be local, less severe, or less acute, or may be suspected but not confirmed, so that the diagnostic criteria of MCAS are not fulfilled. In these patients, it may be difficult to prove MCA, for example, by measuring multiple mast cell mediators or basophil activation, the latter as a surrogate of IgE-dependent hypersensitivity. However, validated diagnostic criteria for implicating suspected MCA behind such conditions are lacking, even if some of these conditions have recently been assigned to an International Classification of Diseases-10-Clinical Modification code (ICD-10-CM). In this article, we discuss diagnostic features and criteria and propose a ICD-10-CM-adjusted classification for disorders associated with MCA, herein referred to as MCA disorders (MCADs), with special emphasis on the delineation between confirmed MCAS, MCAD not fulfilling MCAS criteria, and suspected MCAD that is not present. In addition, we discuss the discrimination between overt MCAD and predisposing conditions, such as atopic states, mastocytosis, and hereditary alpha tryptasemia.
Topics: Humans; Hypersensitivity, Immediate; Immunoglobulin E; International Classification of Diseases; Mast Cell Activation Disorders; Mast Cells; Mastocytosis; Tryptases
PubMed: 35623575
DOI: 10.1016/j.jaip.2022.05.007 -
Cancers Jul 2022Evidence in the recent literature suggests that the presentation spectrum of mast cell neoplasms is broad. In this article, we elaborate on recent data pertaining to... (Review)
Review
Evidence in the recent literature suggests that the presentation spectrum of mast cell neoplasms is broad. In this article, we elaborate on recent data pertaining to minor diagnostic criteria of systemic mastocytosis (SM), including sensitive testing methods for detection of activating mutations in the gene or its variants, and adjusted serum tryptase levels in cases with hereditary α-tryptasemia. We also summarize entities that require differential diagnosis, such as the recently reclassified SM subtype named bone marrow mastocytosis, mast cell leukemia (an SM subtype that can be acute or chronic); the rare morphological variant of all SM subtypes known as well-differentiated systemic mastocytosis; the extremely rare myelomastocytic leukemia and its differentiating features from mast cell leukemia; and mast cell activation syndrome. In addition, we provide a concise clinical update of the latest adjusted risk stratification model incorporating genomic data to define prognosis in SM and new treatments that were approved for advanced SM (midostaurin, avapritinib).
PubMed: 35884535
DOI: 10.3390/cancers14143474