Mast cells and tryptase. Modern aspects

The present review considers the role of mast cells (MC) and tryptase levels in various pathological conditions in children and adults. The main causes of hypertryptasemia are presented, as well as a list of the most important stimuli that can cause activation of MC. Cliical allergologists should focus their clinical practice on the patients with anaphylaxia and suspected MC activation syndromes. Moreover, hypertryptasemia (> 20 ng/ml) is considered an additional diagnostic criterion for systemic mastocytosis, according to the WHO recommendations. As a rule, the level of tryptase is constantly elevated in most patients with systemic mastocytosis, whereas it is undergo changes in acute IgE-mediated hypersensitivity reactions. In cases of anaphylaxia, tryptase concentration should be determined in the patients during the first hours following onset of acute allergic reaction, and 24-48 hours later. Recommendations are given for determining tryptase levels in blood serum of the patients (basal and peak values), and algorithms are provided for usage of these indexes in various diseases. The article also provides the assessed threshold values of tryptase when diagnosing anaphylaxia, MC activation syndromes, and a novel disorder – alpha-tryptasemia. In the diagnosis of hereditary alpha-tryptasemia, as well as MC activation syndromes (primary and secondary), clinical manifestations in the patient and time dynamics of tryptase levels should be taken into account. The accumulated experience allowed to consider, first of all, frequency of severe allergic reactions (most often as anaphylaxia) in the patients with suspected MC activation syndromes. The syndrome of MC activation is characterized by excessive release of their granule contents without signs of clonal proliferation, which in many cases may be due to gene allele duplication, especially, TPSAB1 α-tryptase gene. For patients with hereditary alpha-tryptasemia, the most characteristic manifestations are represented by vegetative-vascular dystonia (orthostatic tachycardia), joint hypermobility, etc. Hence, determination of tryptase level (especially in time course) should be given more attention in the practice of clinicians. Difficulties with interpretation of the results arise in cases when tryptase concentration remains within normal range (up to 11.4 ng/ml), and the patient has clinically evident mastocytosis, or MC activation syndromes. If the patient has a history of anaphylaxia, especially after bites of hymenoptera insects, the TC activation syndromes should be excluded.

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Systemic mastocytosis: Case report with literature review

Srpski arhiv za celokupno lekarstvo ◽

10.2298/sarh1202100m ◽

2012 ◽

Vol 140 (1-2) ◽

pp. 100-103

Author(s):

Mirjana Mitrovic ◽

Maja Perunicic-Jovanovic ◽

Aleksandra Sokic-Milutinovic ◽

Sladjana Andrejevic ◽

Nada Suvajdzic

Keyword(s):

Mast Cells ◽

Systemic Mastocytosis ◽

Clinical Signs ◽

Signs And Symptoms ◽

Grey Zone ◽

Tryptase Level ◽

History Of ◽

Clinical Signs And Symptoms ◽

Longterm Survival ◽

Indolent Disease

Introduction. Mastocytosis is a clonal neoplastic disorder of the mast cells. The clinical signs and symptoms of mastocytosis are heterogeneous ranging from indolent disease with a longterm survival to a highly aggressive neoplasm with survival of about 6 months. Systemic mastocytosis (SM) is characterized by mastocyte infiltration of one or more organs, with or without skin involvment. Case Outline. The presented patient presents a highly challenging diagnostic and therapeutic case. A 46-year-old man was referred to our Centre due to the 7-year-long history of hepatosplenomegaly and mild thrombocytopenia. Ultrasound examination showed hepatosplenomegaly (liver 170 mm; spleen 200 mm), platelet count was 90C109/L, serum tryptase level was elevated and bone marrow biopsy showed infiltration with mast cells (CD117, CD25 and mast cell tryptase positive). Our patient was diagnosed with aggressive systemic mastocytosis (SM) according to WHO Classification (2008), although the clinical course of the disease was indolent, without complications for more than 7 years. Because of the ?intermediate? course, this patient was referred to as smouldering or intermediate SM and was not treated with cytostatics. Conclusion. Utilizing the established criteria, indolent SM can be discriminated from the aggressive subvariants of SM in most cases. However, a small group of patients, like our case belongs to the ?grey zone?. Therapeutic approach to these patients is individual and prognosis is uncertain.

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Change In Mast Cell Bone Marrow Burden and In Serum Tryptase Level Are Not Accurate Markers of Response In Patients with Systemic Mastocytosis

Blood ◽

10.1182/blood.v116.21.3073.3073 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3073-3073

Author(s):

Alfonso QuintÁs-Cardama, ◽

Matjaz Sever ◽

Jorge E. Cortes ◽

Hagop M. Kantarjian ◽

Srdan Verstovsek

Keyword(s):

Bone Marrow ◽

Mast Cell ◽

Mast Cells ◽

Systemic Mastocytosis ◽

Median Number ◽

Response To Therapy ◽

Serum Tryptase ◽

Bone Marrow Biopsies ◽

Tryptase Level ◽

Bone Marrow Mast Cell

Abstract Abstract 3073 Background: Bone marrow involvement, with or without cutaneous or visceral involvement, is almost universal in patients with systemic mastocytosis (SM). The KITD816V mutation is present in most patients with SM, thus confirming its clonal nature. Patients with ASM are usually managed with cytoreductive agents such as hydroxyurea (HU), cladribine (2CDA), or interferon-alpha (IFN-α), although the activity of these therapies is limited as they do not target specifically the malignant clone. Response assessment in SM relies on symptom improvement and reduction in serum tryptase levels and visceral and/or bone marrow mast cell burden (percent mast cell involvement). We contend that the later two relatively objective metrics may not be appropriate markers of response because serum tryptase levels may vary significantly at different time-points in the same patient in the absence of intervention, do not correlate accurately with mast cell burden, and bone marrow mast cell burden determination is subject to sampling bias given the patchy infiltration observed in many cases of SM. Objectives: To assess the utility of bone marrow mast cell burden reduction and serum tryptase level reduction as criteria for response in patients with SM. Patients and Therapy: We studied a cohort of 50 patients with SM for whom at least 2 sequential bone marrow biopsies and 2 serum tryptase level determinations were available at our center. The KITD816V mutation was present in 20 (59%) of 34 assessable patients. No patient carried the JAK2V617F mutation or the FIP1L1-PDGFRA rearrangement. Patients had a diagnosis of indolent SM (ISM, n=25), aggressive SM (ASM, n=16), or SM-AHNMD (n=9). All but 1 patient received SM-directed therapy (median number of therapies 2, range 1–5), including: imatinib (n=16), dasatinib (n=23), RAD001 (n=8), denileukin diftitox (n=7). The median number of bone marrow biopsies available per patient was 4 (range, 2–14) and the median number of tryptase measurements was 6 (range, 2–18), which were obtained both on and off SM-directed therapies. Results: Four patients had a bone marrow complete response: 1 with imatinib, 2 with dasatinib, and 1 with decitabine (with SM-MDS). However none of the responders normalized their tryptase levels. We used the coefficient of variation (CV) as a normalized measure of dispersion of a probability distribution for the percentage of mast cells in bone marrow biopsies and serum tryptase levels. In this manner, the CV summarizes/describes the variation in tryptase levels and bone marrow mast cell percentage from the baseline (first recorded value) in the patients evaluated. We found that among the 49 treated patients, the percentage of bone marrow mast cells varied significantly with a CV ranging from 6 – 173% and an average of 65%. Forty-four percent of patients had a CV equal or higher to the average. Similar results were observed regarding tryptase levels, with an average CV of 19% that ranged from 0 to 96%. Thirty-six percent of patients had a CV higher than average. Conclusion: While most patients fail to respond to currently available SM-directed therapies, sequential bone marrow biopsies and tryptase level determinations exhibit remarkable variation both during and in the absence of SM-directed therapy. Therefore, it seems that single time point measurements of these values do not represent proper tools to assess accurately response to therapy. Disclosures: No relevant conflicts of interest to declare.

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Anti CD-30 Antibody-Drug Conjugate Brentuximab Vedotin (ADCETRIS®) May Be a Promising Treatment Option for Systemic Mastocytosis (SM).

Blood ◽

10.1182/blood.v120.21.2857.2857 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2857-2857 ◽

Cited By ~ 4

Author(s):

Amitkumar Mehta ◽

Vishnu V B Reddy ◽

Uma Borate

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Systemic Mastocytosis ◽

White Male ◽

Brentuximab Vedotin ◽

Antibody Drug Conjugate ◽

Antimitotic Agent ◽

Drug Conjugate ◽

Tryptase Level ◽

Antibody Drug

Abstract Abstract 2857 Mastocytosis is a clonal proliferation of abnormal mast cells in single or multiple organs leading to clinical syndromes ranging from a benign self-resolving cutaneous disease to the highly aggressive malignancy, mast cell leukemia (MCL). Mastocytosis is categorized under myeloproliferative neoplasms in the 2008 World Health Organization (WHO) classification of hematopoietic and lymphoid diseases. In almost all cases of SM, the bone marrow (BM) is involved by atypical mast cells. The characteristic Asp816Val (D816V) mutation in the KIT gene present in most cases gives the atypical mast cells a survival advantage that leads to treatment resistance with tyrosine kinase inhibitor (TKIs) like imatinib. According to the 2008 WHO classification, 1 major and 1 minor or 3 minor criterion are required for the diagnosis of systemic mastocytosis (Fig. 1a). Systemic Mastocytosis (SM) is subcategorized into four distinct categories in order of indolent to highly aggressive disease: Indolent Systemic Mastocytosis (ISM), SM with an associated hematologic non-MC-lineage disease (SM-AHNMD), aggressive SM (ASM) and MCL. SM with C findings categorized as ASM (Fig. 1b) is treated with cytoreductive chemotherapy such as interferon 2α or 2-chlorodeoxyadenosine (2-CdA). The overall response rate (ORR) with these agents is 40–50% with significant chemotherapy-related toxicity and short durable responses. The majority of patients with ASM and MCL relapse within a year with a very poor prognosis. The CD30 (Ki-1) antigen is expressed in the majority of ASM cases. Thus, CD30 can serve as a potential therapeutic target as well as a reliable tumor marker to follow disease status. Brentuximab vedotin is an antibody-drug conjugate compound consisting of a chimeric monoclonal antibody against CD30 linked to the antimitotic agent monomethyl auristatin E (MMAE). Here we report evidence of anti-tumor activity in two patients with CD30-positive ASM treated with brentuximab vedotin. Case #1: A 62 year old white male with significant medical history of rheumatoid arthritis, diabetes mellitus and coronary artery disease was evaluated for pancytopenia and hepatomegaly. His initial BM aspiration and biopsy revealed multifocal dense mast cell infiltrate (30–40% involvement with tryptase and CD117 positivity). His initial serum tryptase level was 276 ng/ml. He was treated with 2-CdA continuous infusion for three cycles with no significant response and substantial toxicities. He was subsequently enrolled in a clinical trial with brentuximab vedotin given every 3 weeks at 1.8 mg/kg after confirmation of CD30 positivity on BM aspirate and biopsy (Fig. 2). His peripheral blood counts started to improve after the 5thcycle and he had a durable partial response as assessed by his peripheral blood counts and BM biopsies (Fig 2). Importantly, his sequential bone marrow biopsies showed a decrease in mast cell involvement and CD30 intensity with improved normal marrow cellularity (Fig 2). His only treatment-related toxicities were grade II neuropathy and neutropenia for which his dose was reduced to 1.2 mg/kg. He is currently asymptomatic with ECOG performance status of 0 and does not require any growth factor support at Cycle 12 of this regimen. Case #2: A 79 yr old white male with significant medical history of hypertension, obstructive sleep apnea, coronary artery disease s/p CABG was referred for new diagnosis of ASM on BM biopsy (60–70% marrow involvement with 3+ mast cell density). His initial tryptase level was 224ng/ml. He was enrolled on the same clinical protocol as described above. His sequential BM biopsies revealed significant reduction in mast cell density with mild improvement in overall normal cellularity after 3 cycles of treatment. (Fig 3). Conclusion: Brentuximab vedotin is a promising targeted therapy for SM and needs to be confirmed further by a prospective multicenter clinical trial. In two patients reported here treatment is well tolerated, targets the malignant mast cells and seems to prevent disease progression in a rare disorder with few treatment options and limited response rates. Disclosures: Off Label Use: Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate compound consisting of a chimeric monoclonal antibody against CD30 linked to the antimitotic agent monomethyl auristatin E (MMAE). It is not FDA approved for use in Mastocytosis.

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Familial Mastocytosis: Identification Of KIT K509I Mutation and Its In Vitro Sensitivity To Imatinib, Dasatinib and PKC412

Blood ◽

10.1182/blood.v122.21.5267.5267 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5267-5267 ◽

Cited By ~ 2

Author(s):

Paula De Melo Campos ◽

João Agostinho Machado-Neto ◽

Adriana Silva Santos Duarte ◽

Renata Scopim-Ribeiro ◽

Flavia Fonseca de Carvalho Barra ◽

...

Keyword(s):

Bone Marrow ◽

Mast Cells ◽

Tyrosine Kinase ◽

Bone Marrow Cells ◽

Systemic Mastocytosis ◽

History Of ◽

Primary Bone ◽

Primary Bone Marrow ◽

Apoptosis Ratio

Abstract Background Mast cell diseases are myeloproliferative neoplasms characterized by an abnormal proliferation and accumulation of mast cells in different tissues. The clinical presentation of mastocytosis is heterogeneous, ranging from skin-limited disease to more aggressive variants that may be associated with multiorgan dysfunction/failure and shortened survival. In a relatively high proportion of cases, the clonal nature of the disease can be established on the basis of the demonstration of gain-of-function mutations involving the tyrosine kinase (TK) domain of KIT in skin lesions and BM cells and by the factor-independent proliferation and transforming abilities of these mutations. The tyrosine kinase inhibitor Imatinib is a treatment available for mastocytosis patients; however, some KIT mutations, specially KIT D816V, confer resistance to this drug. Aims To characterize the clinical phenotype and molecular mutations of 2 relatives with diagnosis of systemic mastocytosis (WHO 2008). We also aimed to test the in vitro sensitivity of primary bone marrow (BM) cells from both patients to tyrosine kinase inhibitors. Patients and methods Four individuals were included in the study; two patients (case 1 [mother], and case 2 [daughter]), and the parents of case 1. DNA samples were obtained from total BM cells, CD3+ BM cells and oral mucosa of patients, and from peripheral blood of all individuals. KIT (exons 1 to 21) was submitted for Sanger sequencing analysis. Primary bone marrow cells (5X104) from the 2 patients were cultured and treated with Imatinib (5uM), Dasatinib (80nM) and PKC 412 (100nM) or with vehicle only (control cells) and submitted for proliferation (MTT) and apoptosis assays (Annexin-V/PI) at days 4, 8 and 12 of culture. Results Case 1 was a 33 year-old woman with a chronic history of pruritic skin rash who was referred to our outpatient service for evaluation of massive splenomegaly (25 centimeters in length) and pancytopenia. She had neither comorbidities nor any familial history of hematological malignancies. The patient had no siblings and had only one daughter (case 2). At biopsy, she showed extensive skin and bone marrow infiltration by mast cells. During follow up, the patient presented with spontaneous splenic rupture and had to undergo splenectomy, which led to the resolution of pancytopenia. She was diagnosed with Aggressive Systemic Mastocytosis. Her daughter (case 2), a 17 year-old woman, was also evaluated for an insidious history of diffuse skin rash. Skin and bone marrow biopsies showed massive infiltration by atypical mast cells and a diagnosis of Indolent Systemic Mastocytosis was made. The rare KIT K509I mutation was found in all DNA samples obtained from both patients, but not from the parents of case 1. This suggests that the KIT K509I was a germ line mutation acquired de novo by patient 1 that was subsequently transmitted to her daughter (patient 2). In vitro treatment of primary bone marrow cells harboring the KIT K509I mutation from patients 1 and 2 resulted in variable clinical response rates according to the drug used and the treatment duration. Imatinib treatment resulted in a significant reduction in proliferation (days 4, 8 and 12 of culture) and an increase in apoptosis (days 8 and 12) in cases 1 and 2 (all p≤0.03). Although Dasatinib resulted in decreased proliferation in both patients at day 12 (all p≤0.008), a significantly higher apoptosis ratio was observed only for patient 1 at day 12 of culture (p=0.03). PKC412 had a negative effect over cell growth in patient 1 (days 4 and 8) and in patient 2 (day 4) (all p≤0.03); however, no effect in apoptosis ratio was seen. Conclusions We herein provide a report of a KIT K509I mutation in familial mastocytosis. This mutation has been previously described in the literature in one case of familial mastocytosis. Although rare, the screening for KIT K509I mutation should be considered in all cases of familial mastocytosis. Based on in vitro studies, mastocytosis patients harboring the KIT K509I mutation could benefit from treatment with Imatinib, Dasatinib and PKC 412. However, Imatinib may be more effective in inducing neoplastic mast cells apoptosis. Both patients described were started on Imatinib in June 2013. Disclosures: No relevant conflicts of interest to declare.

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Adults with possible food protein-induced enterocolitis syndrome with crustacean ingestion

Allergy Asthma & Clinical Immunology ◽

10.1186/s13223-020-00497-z ◽

2020 ◽

Vol 16 (1) ◽

Author(s):

Daniel H. Li ◽

Andrew Wong-Pack ◽

Andrea Leilani Macikunas ◽

Harold Kim

Keyword(s):

Time Course ◽

Immunoglobulin E ◽

Gastrointestinal Symptoms ◽

Case Series ◽

Retrospective Chart Review ◽

Food Protein ◽

Female Predominance ◽

Adolescents And Adults ◽

History Of ◽

Ige Mediated

Abstract Background Food protein-induced enterocolitis (FPIES), an entity previously thought to only affect children, has been increasingly described in adults. In this study, we report a Canadian cohort of 19 adolescents and adults with recurrent non-immunoglobulin E (IgE)-mediated gastrointestinal symptoms after crustacean ingestion, consistent with FPIES. Methods We conducted a retrospective chart review of patients in an outpatient allergy clinic from January 2005 to May 2020. Electronic records were searched using keywords for crustaceans and for symptoms consistent with FPIES. We included patients with gastrointestinal symptoms specifically to crustaceans on more than one occasion, who were 14 years or older at the time of index reaction. Exclusion criteria included symptoms suggestive of an IgE-mediated anaphylactic reaction or a likely alternative diagnosis. We identified 19 patients for our cohort who met the criteria. Results Our cohort was 68.4% female (13) and 32.6% (6) male. The average age at first reaction to crustaceans was 34 years old with a range of 14–68 years (median = 28 years; IQR = 32 years). Time from ingestion to beginning of symptoms ranged from 3 min to 6.5 h, with an average of 2.8 h (median = 2 h; IQR = 3.25 h). Duration of reaction ranged from less than a minute to over 48 h, with a mean of 9.4 h (median = 4 h; IQR = 7.75 h). Patients had 4.8 reactions on average; however, number of reactions ranged from 2 to 12.5 (median = 3, IQR = 3). All patients identified a “trigger” food in the crustacean group, and 12 subjects identified additional reactions to other seafood. Conclusions This case series will better characterize and advance our understanding of this disease entity in adults. There are key differences in the presentation of FPIES in adults compared to children, namely female predominance, difference in solid food trigger, and unpredictable time course. Future studies are needed to examine the pathophysiology and natural history of adult FPIES. Specific guidelines should be developed for the diagnosis and management in adults. Trial registration: retrospectively registered.

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Systemic mastocytosis: variable manifestations can lead to a challenging diagnostic process

BMJ Case Reports ◽

10.1136/bcr-2019-229967 ◽

2019 ◽

Vol 12 (8) ◽

pp. e229967 ◽

Cited By ~ 1

Author(s):

Susanna Nallamilli ◽

Aideen O’Neill ◽

Andrew Wilson ◽

Mallika Sekhar ◽

Jonathan Lambert

Keyword(s):

Quality Of Life ◽

Bone Marrow ◽

Cell Clone ◽

Systemic Mastocytosis ◽

Clinical Manifestations ◽

Skin Lesions ◽

Diagnostic Process ◽

Histamine Antagonists ◽

History Of

Systemic mastocytosis results from proliferation and activation of an abnormal mast cell clone. It is a heterogeneous disorder with clinical manifestations ranging from skin lesions alone to aggressive multi-organ infiltration and decreased survival. Given these varied manifestations, diagnosis can be difficult. We describe the case of a woman who presented with rash and diarrhoea and had a history of anaphylactic reactions. Over a protracted period, the patient’s symptoms were investigated by a number of specialties including gastroenterology, dermatology, immunology and haematology. Morphological, immunohistochemical and molecular analysis of bone marrow samples ultimately led to a diagnosis of systemic mastocytosis. Management with leukotriene and histamine antagonists resulted in significant improvement in symptoms and quality of life. The case serves to highlight the protean manifestations of systemic mastocytosis, the tests available to diagnose it and the agents available to treat it.

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Hypersensitivity Reactions and Anaphylaxis

10.2310/em.4259 ◽

2020 ◽

Author(s):

Kristopher K. Ford ◽

Timothy M. Loftus ◽

Joseph J. Moellman

Keyword(s):

Mast Cells ◽

Clinical Manifestations ◽

Allergic Reactions ◽

Hypersensitivity Reactions ◽

Life Threatening ◽

Vasopressor Agents ◽

Ige Mediated ◽

Criteria For Diagnosis ◽

Key Words Allergy

Allergic reactions vary in intensity from mild rash or allergic rhinitis to devastating anaphylactic shock. Anaphylaxis, often underrecognized and undertreated, can be a life-threatening syndrome leading to multiorgan dysfunction. This review covers the etiology, pathophysiology, and treatment of severe allergic reactions and anaphylaxis. It is precipitated by exposure to particular allergens—commonly food, medications, insect stings, and environmental exposures—in a previously sensitized individual. Symptoms develop from an IgE-mediated immune response leading to degranulation of mast cells and basophils and the release of preformed mediators, lipid-derived metabolites, and inflammatory cytokines. First-line treatment for anaphylaxis involves epinephrine. Secondary treatments are antihistamines and corticosteroids. Further treatments for patients refractory to standard therapies involve vasopressor agents, nebulized albuterol, and glucagon. Frequency and duration of biphasic reactions are variable, limiting the development of consensus guidelines for monitoring of anaphylactic reactions. Figures show the immune activity and inflammatory pathways in allergic responses, mast cell degranulation, and a depiction of common organs involved and corresponding clinical manifestations. Tables list the criteria for diagnosis of anaphylaxis, classification of hypersensitivity reactions, common clinical manifestations, and etiology and mediators of anaphylaxis. This review contains 4 highly rendered figures, 11 tables, and 43 references. Key words: allergy, anaphylaxis, antihistamine, corticosteroid, epinephrine, mast cells

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In aggressive forms of mastocytosis, TET2 loss cooperates with c-KITD816V to transform mast cells

Blood ◽

10.1182/blood-2011-12-397588 ◽

2012 ◽

Vol 120 (24) ◽

pp. 4846-4849 ◽

Cited By ~ 64

Author(s):

Erinn Soucie ◽

Katia Hanssens ◽

Thomas Mercher ◽

Sophie Georgin-Lavialle ◽

Gandhi Damaj ◽

...

Keyword(s):

Mast Cells ◽

Systemic Mastocytosis ◽

Clinical Manifestations ◽

Competitive Growth ◽

Wild Type ◽

Cell Disease ◽

Murine Bone Marrow ◽

Potential Marker ◽

Tet2 Mutation ◽

Mast Cell Disease

Abstract Although a role for oncogenic KIT in driving mast cell disease is clear, the mechanisms driving the multiple phenotypic and clinical manifestations of this disorder are not well elucidated. We now show, using a large cohort of mastocytosis patients, including an almost equal number of aggressive and nonaggressive cases of systemic mastocytosis, that in contrast to the oncogenic KITD816V, TET2 mutation statistically associates with aggressive forms of the disease. By infecting primary murine bone marrow–derived mast cells with KITD816V, we also observe a significant and competitive growth advantage for KITD816V in Tet2-nullizygous compared with wild-type cells. TET2-deficient cells display increased proliferation and can survive in the absence of cytokines. Taken together, these data demonstrate a oncogenic cooperation in mast cells and reveal TET2 mutation as a potential marker to diagnose and predict severe forms of mastocytosis.

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Response Criteria in Advanced Systemic Mastocytosis: Evolution in the Era of KIT Inhibitors

International Journal of Molecular Sciences ◽

10.3390/ijms22062983 ◽

2021 ◽

Vol 22 (6) ◽

pp. 2983

Author(s):

William Shomali ◽

Jason Gotlib

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Systemic Mastocytosis ◽

Myeloproliferative Neoplasms ◽

Organ Damage ◽

Response Criteria ◽

Molecular Response ◽

Tryptase Level ◽

Hematologic Neoplasm ◽

Kit D816v

Systemic mastocytosis (SM) is a rare clonal hematologic neoplasm, driven, in almost all cases, by the activating KIT D816V mutation that leads to the growth and accumulation of neoplastic mast cells. While patients with advanced forms of SM have a poor prognosis, the introduction of KIT inhibitors (e.g., midostaurin, and avapritinib) has changed their outlook. Because of the heterogenous nature of advanced SM (advSM), successive iterations of response criteria have tried to capture different dimensions of the disease, including measures of mast cell burden (percentage of bone marrow mast cells and serum tryptase level), and mast cell-related organ damage (referred to as C findings). Historically, response criteria have been anchored to reversion of one or more organ damage finding(s) as a minimal criterion for response. This is a central principle of the Valent criteria, Mayo criteria, and International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG-MRT-ECNM) consensus criteria. Irrespective of the response criteria, an ever-present challenge is how to apply response criteria in patients with SM and an associated hematologic neoplasm, where the presence of both diseases complicates assignment of organ damage and adjudication of response. In the context of trials with the selective KIT D816V inhibitor avapritinib, pure pathologic response (PPR) criteria, which rely solely on measures of mast cell burden and exclude consideration of organ damage findings, are being explored as more robust surrogate of overall survival. In addition, the finding that avapritinib can elicit complete molecular responses of KIT D816V allele burden, establishes a new benchmark for advSM and motivates the inclusion of definitions for molecular response in future criteria. Herein, we also outline how the concept of PPR can inform a proposal for new response criteria which use a tiered evaluation of pathologic, molecular, and clinical responses.

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Histamine Intolerance: Clinical Characterization and Determination of Serum Diamine Oxidase (Dao) in a Series of Cases and Controls

10.21203/rs.3.rs-60226/v1 ◽

2020 ◽

Author(s):

Peralta Teresa ◽

Bastías Carla ◽

Camila Beltran-Ortiz ◽

Durán Magdalena ◽

Ramos Verónica ◽

...

Keyword(s):

Diamine Oxidase ◽

Clinical Manifestations ◽

Histamine Intolerance ◽

Significant Difference ◽

History Of ◽

Ige Mediated ◽

Average Serum ◽

Excessive Accumulation

Abstract Introduction. Histamine intolerance (HIT) is a pathology with an estimated prevalence of 1% in which there is an imbalance between the intake of histamine via the digestive tract and the body's ability to degrade it. This results in an excessive accumulation of histamine that determines the appearance of gastrointestinal, skin, respiratory and neurological symptoms. The enzyme responsible for degrading histamine in the extracellular space is diamine oxidase (DAO); therefore, HIT is caused due to a deficit in the concentration and/or in the activity of this enzyme. Because histamine is the main mediator of the classic symptoms of IgE-mediated allergic reactions, it is difficult to differentiate a true allergy from HIT since it has basically the same clinical manifestations. Objectives. The objective of this study was to perform a clinical characterization of patients with HIT and to determine the usefulness of quantifying serum DAO concentration in the diagnosis of HIT. Method: Twenty-two patients over the age of 18 with a history of histamine intolerance were recruited, in whom IgE-mediated food allergy was ruled out, and 22 healthy patients. Both groups were surveyed and serum DAO concentration was determined. Results: Middle-aged women predominated in the population with HIT. They described a wide variety of symptoms, with a dominance of abdominal pain, bloating, diarrhea, flushing, urticaria, itching, headache and dysmenorrhea. When comparing the average serum DAO concentration in the population with HIT (10.686 U/ml) with the average obtained in the control population (20.664 U/ml), there was a significant difference (p < 0.003). Conclusion. The determination of serum DAO concentration is a useful tool for the diagnosis of HIT.

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