Mast cell activation syndrome (MCAS) is a rare condition defined by a severe systemic reaction to mast cell (MC)-derived mediators. Most cases present with clinical signs of anaphylaxis, and some ...have an underlying IgE-dependent allergy. A primary MC disease (mastocytosis) may also be detected. Severe recurrent MCAS episodes requiring intensive care or even resuscitation are typically found in patients who suffer from both mastocytosis and allergy against certain triggers, such as hymenoptera venom components. A less severe form and a local form of MC activation (MCA) also exist. For these patients, diagnostic criteria are lacking. Moreover, a number of different, unrelated, conditions with overlapping symptoms may be confused with MCAS. As a result, many patients believe that they are suffering from MCAS but have in fact a less severe form of MCA or another underlying disease. In the current article, we review the potential differential diagnoses of MCA and MCAS and discuss available diagnostic criteria and diagnostic tools. These criteria and assays may be useful in daily practice and help avoid unnecessary referrals and unjustified fears in patients.
Treatment strategies in mastocytosis Siebenhaar, Frank; Akin, Cem; Bindslev-Jensen, Carsten ...
Immunology and allergy clinics of North America,
05/2014, Letnik:
34, Številka:
2
Journal Article
Recenzirano
Treatment recommendations for mastocytosis are based mostly on expert opinion rather than evidence obtained from controlled clinical trials. In this article, treatment options for mastocytosis are ...presented, with a focus on the control of mediator-related symptoms in patients with indolent disease.
Mutations in the proto-oncogene c-kit cause constitutive kinase activity of its product, KIT protein, and are associated with human mastocytosis and gastrointestinal stromal tumors (GISTs). Although ...currently available tyrosine kinase inhibitors are effective in the treatment of GISTs, there has been limited success in the treatment of mastocytosis. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), a benzoquinoid ansamycin antibiotic, which binds to heat shock protein 90 (hsp90) causes destabilization of various hsp90-dependent kinases important in oncogenesis. Treatment with 17-AAG of the mast cell line HMC-1.2, harboring the Asp816Val and Val560Gly KIT mutations, and the cell line HMC-1.1, harboring a single Val560Gly mutation, causes both the level and activity of KIT and downstream signaling molecules AKT and STAT3 to be down-regulated following drug exposure. These data were validated using Cos-7 cells transfected with wild-type and mutated KIT. 17-AAG promotes cell death of both HMC mast cell lines. In addition, neoplastic mast cells isolated from patients with mastocytosis, incubated with 17-AAG ex vivo, are selectively sensitive to the drug compared to the mononuclear fraction. These data provide compelling evidence that 17-AAG may be effective in the treatment of c-kit-related diseases including mastocytosis, GISTs, mast cell leukemia, subtypes of acute myelogenous leukemia, and testicular cancer. (Blood. 2004;103:1078-1084)
Indolent systemic mastocytosis (ISM) is the most prevalent form of systemic mastocytosis. Many patients with ISM suffer from mast cell (MC) mediator-related symptoms. In a small number of patients, ...hematologic progression is seen in the follow-up. In some patients with ISM, symptoms arising from MC-derived mediators including gastrointestinal symptoms, anaphylaxis, and neuropsychiatric symptoms are kept under control with conventional mediator-targeting drugs or MC-stabilizing agents. However, in a substantial number of patients, the symptoms are refractory to such conventional therapy. For these patients, novel drugs and targeted approaches are considered. One reasonable approach may be to apply tyrosine kinase inhibitors directed against KIT and other key kinase targets expressed in neoplastic MCs in ISM. Because MCs in more than 90% of all patients with typical ISM display the KIT D816V mutant receptor, clinically effective KIT-targeting drugs have to be active against this mutant form of KIT. The 2 such most effective and well-studied agents currently available are midostaurin and avapritinib. Other KIT-targeting drugs, such as imatinib or masitinib, are less effective or even noneffective against KIT D816V and are thus recommended for use only in patients with other KIT mutant forms (noncodon 816 mutations) or with wild-type KIT. In the present article, we review the current state in the treatment of ISM with tyrosine kinase inhibitors, with special emphasis on treatment responses and potential adverse effects. In fact, all of these agents also have unique and common adverse effects, and their use to treat patients with ISM should be balanced against their toxicity and short- and long-term safety.
A 47-year-old man presented with loss of consciousness 5 minutes after being stung by a yellow jacket in his backyard. Epinephrine and fluids were required for resuscitation. Allergy evaluation ...revealed specific IgE to yellow jacket and honeybee, and the patient was started on venom immunotherapy. He had systemic reactions during buildup and a severe anaphylactic episode requiring 3 doses of intramuscular epinephrine at maintenance doses. Immunotherapy was discontinued. Serum tryptase level after 1 such episode was 29 ng/mL, with a baseline level of 25 ng/mL 4 weeks later. The physical examination was unremarkable including no skin lesions of cutaneous mastocytosis. Because of elevated baseline tryptase level, a bone marrow biopsy was performed, which revealed multifocal dense infiltrates of mast cells. A diagnosis of systemic mastocytosis was made. The patient was treated with omalizumab and was able to tolerate immunotherapy and is currently maintained on lifelong immunotherapy. He was restung in the field and has not had anaphylaxis.
Hereditary alpha tryptasemia (HαT) is found in approximately 7% of the population. Associations with a variety of clinical symptoms including gastric reflux, joint hypermobility, dysautonomia, ...flushing and pruritus, and hymenoptera allergy have variably been described in prior reports. However, our understanding of this genetic trait is limited by a paucity of published studies, referral bias, and conflicting findings at clinical presentation.
The purpose of this study was to assess the clinical phenotype of HαT in a random biorepository population and in patients with and without mastocytosis referred to the allergy clinic.
Tryptase copy number allele was assessed using digital droplet PCR. Participants with or without HαT were interviewed and examined by a clinician and surveyed regarding their medical history and symptomology.
HαT was identified in 7.5% of the random biorepository samples and in 18% of patients with mastocytosis. There was no difference in the clinical symptomology or medical history of individuals with HαT compared to controls. Average baseline serum tryptase was higher in individuals with HαT compared to controls, but there was no difference in urinary mast cell activation products.
Elevated baseline serum tryptase was the only consistent phenotypic marker for HαT in this study. There was a higher frequency of HαT in patients with mastocytosis than in the general population.
Background The broad and overlapping clinical manifestations of D816V KIT–associated systemic mastocytosis with eosinophilia and FIP1L1/PDGFRA-associated chronic eosinophilic leukemia (CEL), coupled ...with the increase in activated eosinophils and mast cells seen in both disorders, have led to confusion in the nomenclature. It is of paramount importance, however, to distinguish between these 2 groups of patients because of differences in clinical sequelae, prognoses, and selection of treatment. Objective We thus sought to identify clinical and laboratory features that could be used to distinguish these 2 diagnoses. Methods We compared 12 patients with D816V-positive systemic mastocytosis with eosinophilia with 17 patients with FIP1L1/PDGFRA-positive CEL. Distinguishing features were used to create a risk factor scoring system. Results This system correctly classified 16 of 17 FIP1L1/PDGFRA-positive patients with CEL and all 12 patients with systemic mastocytosis with eosinophilia. Thirty-four FIP1L1/PDGFRA-positive patients described in the literature were also classified using this system, and although a complete set of data was not available for any of the historical patients, 21 were correctly classified. Conclusion These results reinforce the hypothesis that the FIP1L1/PDGFRA gene fusion and D816V- KIT mutation cause distinct clinical syndromes. Clinical implications This novel diagnostic approach should prove helpful in clinical practice in the evaluation of patients with increased mast cells and peripheral eosinophilia.
PDF
