Mastocytosis presenting with mast cell-mediator release-associated symptoms elicited by cyclo oxygenase inhibitors: prevalence, clinical, and laboratory features.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently avoided in mastocytosis, because of a potential increased risk for drug hypersensitivity reactions (DHRs) due to inhibition of cyclo-oxygenase (COX), subsequent depletion of prostaglandin E2 and release of leukotrienes. OBJECTIVES: Here, we aimed at determining the prevalence of mast cell (MC) mediator release symptoms triggered by NSAIDs in mastocytosis patients and the associated clinical and laboratory features of the disease. METHODS: Medical records from 418 adults to 223 pediatric mastocytosis patients were retrospectively reviewed. Patients were classified according to tolerance patterns to NSAIDs and other COX inhibitors (COXi) and compared for epidemiological, clinical and laboratory findings. RESULTS: Overall, 87% of adults and 91% of pediatric patients tolerated NSAIDs and other COXi. Among adult and pediatric patients presenting DHRs, 5% and 0% reacted to multiple NSAIDs, 4% and 0.7% were single reactors, and 3% and 8% were single reactors with known tolerance to paracetamol but unknown tolerance to other COXi, respectively. Among adults, hypersensitivity to ≥2 drugs was more frequent among females (p = 0.009), patients with prior history of anaphylaxis to triggers other than NSAIDs or other COXi and Hymenoptera venom (p = 0.009), presence of baseline flushing (p = 0.02), baseline serum tryptase ≥48 ng/ml (p = 0.005) and multilineage KIT mutation (p = 0.02). In contrast, tolerance to NSAIDs and other COXi was more frequent among males (p = 0.02), in patients with anaphylaxis caused by Hymenoptera venom (p = 0.02), among individuals who had skin lesions due to mastocytosis (p = 0.01), and in cases that had no baseline pruritus (p = 0.006). Based on these parameters, a score model was designed to stratify mastocytosis patients who have never received NSAIDs or other COXi apart from paracetamol, according to their risk of DHR. CONCLUSIONS: Our results suggest that despite the frequency of MC mediator related symptoms elicited by NSAIDs and other COXi apart from paracetamol is increased among mastocytosis patients versus the general population, it is lower than previously estimated and associated with unique disease features. Patients that tolerated NSAIDs and other COXi following disease onset should keep using them. In turn, adults with unknown tolerance to such drugs and a positive score should be challenged with a preferential/selective COX-2 inhibitor, while the remaining may be challenged with ibuprofen.

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

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.

Bone Marrow Mast Cell Antibody-Targetable Cell Surface Protein Expression Profiles in Systemic Mastocytosis.

Despite recent therapeutic advances, systemic mastocytosis (SM) remains an incurable disease due to limited complete remission (CR) rates even after novel therapies. To date, no study has evaluated the expression on SM bone marrow mast cells (BMMC) of large panel of cell surface suitable for antibody-targeted therapy. In this study, we analyzed the expression profile of six cell-surface proteins for which antibody-based therapies are available, on BMMC from 166 SM patients vs. 40 controls. Overall, variable patterns of expression for the markers evaluated were observed among SM BMMC. Thus, CD22, CD30, and CD123, while expressed on BMMC from patients within every subtype of SM, showed highly variable patterns with a significant fraction of negative cases among advanced SM (aggressive SM (ASM), ASM with an associated clonal non-MC lineage disease (ASM-AHN) and MC leukemia (MCL)), 36%, 46%, and 39%, respectively. In turn, CD25 and FcεRI were found to be expressed in most cases (89% and 92%) in virtually all BMMC (median: 92% and 95%) from both indolent and advanced SM, but with lower/absent levels in a significant fraction of MC leukemia (MCL) and both in MCL and well-differentiated SM (WDSM) patients, respectively. In contrast, CD33 was the only marker expressed on all BMMC from every SM patient. Thus, CD33 emerges as the best potentially targetable cell-surface membrane marker in SM, particularly in advanced SM.

Adverse reactions to drugs and biologics in patients with clonal mast cell disorders: A Work Group Report of the Mast Cells Disorder Committee, American Academy of Allergy, Asthma & Immunology.

Providers caring for patients with mastocytosis are tasked with the decision to consider therapeutic options. This can come with some trepidation because information available in the public domain lists numerous mast cell (MC) activators based on data that do not discriminate between primates, rodents, and MC lines; do not consider dosage; and do not take into account previous exposure and resultant clinical findings. This being said, there is support in the literature for an enhanced MC response in some patients with mastocytosis and in cases in which there is a greater incidence of adverse reactions associated with certain antigens, such as venoms and drugs. Thus this report provides a comprehensive guide for those providers who must decide on therapeutic options in the management of patients with clonal MC disease.

Impact of somatic and germline mutations on the outcome of systemic mastocytosis.

Systemic mastocytosis (SM) is a highly heterogeneous disease with indolent and aggressive forms, with the mechanisms leading to malignant transformation still remaining to be elucidated. Here, we investigated the presence and frequency of genetic variants in 34 SM patients with multilineal KIT D816V mutations. Initial screening was performed by targeted sequencing of 410 genes in DNA extracted from purified bone marrow cells and hair from 12 patients with nonadvanced SM and 8 patients with advanced SM, followed by whole-genome sequencing (WGS) in 4 cases. Somatic mutations were further investigated in another 14 patients with advanced SM. Despite the fact that no common mutation other than KIT D816V was found in WGS analyses, targeted next-generation sequencing identified 67 nonsynonymous genetic variants involving 39 genes. Half of the mutations were somatic (mostly multilineal), whereas the other half were germline variants. The presence of ≥1 multilineal somatic mutation involving genes other than KIT D816V, ≥3 germline variants, and ≥1 multilineal mutation in the SRSF2, ASXL1, RUNX1, and/or EZH2 genes (S/A/R/E genes), in addition to skin lesions, splenomegaly, thrombocytopenia, low hemoglobin levels, and increased alkaline phosphatase and ß2-microglobulin serum levels, were associated with a poorer patient outcome. However, the presence of ≥1 multilineal mutation, particularly involving S/A/R/E genes, was the only independent predictor for progression-free survival and overall survival in our cohort.

KIT D816V Positive Acute Mast Cell Leukemia Associated with Normal Karyotype Acute Myeloid Leukemia.

INTRODUCTION: Mast cell (MC) leukemia (MCL) is extremely rare. We present a case of MCL diagnosed concomitantly with acute myeloblastic leukemia (AML). CASE REPORT: A 41-year-old woman presented with asthenia, anorexia, fever, epigastralgia, and diarrhea. She had a maculopapular skin rash, hepatosplenomegaly, retroperitoneal adenopathies, pancytopenia, 6% blast cells (BC) and 20% MC in the peripheral blood, elevated lactate dehydrogenase, cholestasis, hypoalbuminemia, hypogammaglobulinemia, and increased serum tryptase (184 µg/L). The bone marrow (BM) smears showed 24% myeloblasts, 17% promyelocytes, and 16% abnormal toluidine blue positive MC, and flow cytometry revealed 12% myeloid BC, 34% aberrant promyelocytes, a maturation blockage at the myeloblast/promyelocyte level, and 16% abnormal CD2-CD25+ MC. The BM karyotype was normal, and the KIT D816V mutation was positive in BM cells. The diagnosis of MCL associated with AML was assumed. The patient received corticosteroids, disodium cromoglycate, cladribine, idarubicin and cytosine arabinoside, high-dose cytosine arabinoside, and hematopoietic stem cell transplantation (HSCT). The outcome was favorable, with complete hematological remission two years after diagnosis and one year after HSCT. CONCLUSIONS: This case emphasizes the need of an exhaustive laboratory evaluation for the concomitant diagnosis of MCL and AML, and the therapeutic options.

Multiple large osteolytic lesions in a patient with systemic mastocytosis: a challenging diagnosis.

Patients with advanced variants of Systemic Mastocytosis may develop destructive bone lesions when massive mast cell (MC) infiltrates are present. Finding of large osteolyses in indolent systemic mastocytosis, typically characterized by low MC burden, should prompt investigations for an alternative explanation.

Imatinib in systemic mastocytosis: a phase IV clinical trial in patients lacking exon 17 KIT mutations and review of the literature.

Resistance to imatinib has been recurrently reported in systemic mastocytosis (SM) carrying exon 17 KIT mutations. We evaluated the efficacy and safety of imatinib therapy in 10 adult SM patients lacking exon 17 KIT mutations, 9 of which fulfilled criteria for well-differentiated SM (WDSM). The World Health Organization 2008 disease categories among WDSM patients were mast cell (MC) leukemia (n = 3), indolent SM (n = 3) and cutaneous mastocytosis (n = 3); the remainder case had SM associated with a clonal haematological non-MC disease. Patients were given imatinib for 12 months -400 or 300 mg daily depending on the presence vs. absence of > 30% bone marrow (BM) MCs and/or signs of advanced disease-. Absence of exon 17 KIT mutations was confirmed in highly-purified BM MCs by peptide nucleic acid-mediated PCR, while mutations involving other exons were investigated by direct sequencing of purified BM MC DNA. Complete response (CR) was defined as resolution of BM MC infiltration, skin lesions, organomegalies and MC-mediator release-associated symptoms, plus normalization of serum tryptase. Criteria for partial response (PR) included ≥ 50% reduction in BM MC infiltration and improvement of skin lesions and/or organomegalies. Treatment was well-tolerated with an overall response rate of 50%, including early and sustained CR in four patients, three of whom had extracellular mutations of KIT, and PR in one case. This later patient and all non-responders (n = 5) showed wild-type KIT. These results together with previous data from the literature support the relevance of the KIT mutational status in selecting SM patients who are candidates for imatinib therapy.

Systemic mastocytosis with KIT V560G mutation presenting as recurrent episodes of vascular collapse: response to disodium cromoglycate and disease outcome.

BACKGROUND: Mastocytosis are rare diseases characterized by an accumulation of clonal mast cells (MCs) in one or multiple organs or tissues. Patients with systemic mastocytosis (SM), whose MCs frequently arbor the activating D816V KIT mutation, may have indolent to aggressive diseases, and they may experience MC mediator related symptoms. Indolent SM with recurrent anaphylaxis or vascular collapse in the absence of skin lesions, ISMs(-), is a specific subtype indolent SM (ISM), and this clonal MC activation disorder represents a significant fraction of all MC activation syndromes. The V560G KIT mutation is extremely rare in patients with SM and its biological and prognostic impact remains unknown. CASE PRESENTATION: A 15-year old boy was referred to our hospital because of repeated episodes of flushing, hypotension and syncope since the age of 3-years, preceded by skin lesions compatible with mastocytosis on histopathology that had disappeared in the late-early childhood. Diagnosis of ISM, more precisely the ISMs(-) variant, was confirmed based on the clinical manifestations together with increased baseline serum tryptase levels and the presence of morphologically atypical, mature appearing (CD117+high, FcεRI+) phenotypically aberrant (CD2+, CD25+) MCs, expressing activation-associated markers (CD63, CD69), in the bone marrow. Molecular genetic studies revealed the presence of the KIT V560G mutation in bone marrow MCs, but not in other bone marrow cells, whereas the screening for mutations in codon 816 of KIT was negative. The patient was treated with oral disodium cromoglycate and the disease had a favorable outcome after an eleven-year follow-up period, during which progressively lower serum tryptase levels together with the fully disappearance of all clinical manifestations was observed. CONCLUSIONS: To the best of our knowledge this first report of a patient with ISM, whose bone marrow MCs carry the KIT V560G activating mutation, manifesting as recurrent spontaneous episodes of flushing and vascular collapse in the absence of skin lesions at the time of diagnosis, in whom disodium cromoglycate had led to long term clinical remission.

Advances in the Classification and Treatment of Mastocytosis: Current Status and Outlook toward the Future.

Mastocytosis is a term used to denote a heterogeneous group of conditions defined by the expansion and accumulation of clonal (neoplastic) tissue mast cells in various organs. The classification of the World Health Organization (WHO) divides the disease into cutaneous mastocytosis, systemic mastocytosis, and localized mast cell tumors. On the basis of histomorphologic criteria, clinical parameters, and organ involvement, systemic mastocytosis is further divided into indolent systemic mastocytosis and advanced systemic mastocytosis variants, including aggressive systemic mastocytosis and mast cell leukemia. The clinical impact and prognostic value of this classification has been confirmed in numerous studies, and its basic concept remains valid. However, refinements have recently been proposed by the consensus group, the WHO, and the European Competence Network on Mastocytosis. In addition, new treatment options are available for patients with advanced systemic mastocytosis, including allogeneic hematopoietic stem cell transplantation and multikinase inhibitors directed against KIT D816V and other key signaling molecules. Our current article provides an overview of recent advances in the field of mastocytosis, with emphasis on classification, prognostication, and emerging new treatment options in advanced systemic mastocytosis. Cancer Res; 77(6); 1261-70. ©2017 AACR.

Advances in the understanding and clinical management of mastocytosis and clonal mast cell activation syndromes.

Clonal mast cell activation syndromes and indolent systemic mastocytosis without skin involvement are two emerging entities that sometimes might be clinically difficult to distinguish, and they involve a great challenge for the physician from both a diagnostic and a therapeutic point of view. Furthermore, final diagnosis of both entities requires a bone marrow study; it is recommended that this be done in reference centers. In this article, we address the current consensus and guidelines for the suspicion, diagnosis, classification, treatment, and management of these two entities.

Diagnosis and classification of mastocytosis in non-specialized versus reference centres: a Spanish Network on Mastocytosis (REMA) study on 122 patients.

The diagnosis of 'rare diseases', such as mastocytosis, remains a challenge. Despite this, the precise benefits of referral of mastocytosis patients to highly specialized reference centres are poorly defined and whether patients should be managed at non-specialized versus reference centres remains a matter of debate. To evaluate the quality and efficiency of diagnostic procedures performed at the reference centres for mastocytosis in Spain (REMA) versus other non-reference centres, we retrospectively analysed a series of 122 patients, for the overall degree of agreement obtained for the World Health Organization (WHO) diagnostic and classification criteria betwen the referring and REMA centres. Our results showed that not all WHO diagnostic criteria were frequently investigated at the referring centres. Among the five WHO diagnostic criteria, the highest degree of agreement was obtained for serum tryptase levels [median 90% (95% confidence interval 84-96%)]; in turn, the overall agreement was significantly lower for the major histopathological criterion [80% (72-89%)], and the other three minor criteria: cytomorphology [68% (56-80%)] immunophenotyping of BM mast cells [75% (62-87%)] and detection of the KIT mutation [34% (8-60%)]. Referral of patients with diagnostic suspicion of mastocytosis to a multidisciplinary reference centre improves diagnostic efficiency and quality.

Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology.

Cutaneous lesions in patients with mastocytosis are highly heterogeneous and encompass localized and disseminated forms. Although a classification and criteria for cutaneous mastocytosis (CM) have been proposed, there remains a need to better define subforms of cutaneous manifestations in patients with mastocytosis. To address this unmet need, an international task force involving experts from different organizations (including the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology) met several times between 2010 and 2014 to discuss the classification and criteria for diagnosis of cutaneous manifestations in patients with mastocytosis. This article provides the major outcomes of these meetings and a proposal for a revised definition and criteria. In particular, we recommend that the typical maculopapular cutaneous lesions (urticaria pigmentosa) should be subdivided into 2 variants, namely a monomorphic variant with small maculopapular lesions, which is typically seen in adult patients, and a polymorphic variant with larger lesions of variable size and shape, which is typically seen in pediatric patients. Clinical observations suggest that the monomorphic variant, if it develops in children, often persists into adulthood, whereas the polymorphic variant may resolve around puberty. This delineation might have important prognostic implications, and its implementation in diagnostic algorithms and future mastocytosis classifications is recommended. Refinements are also suggested for the diagnostic criteria of CM, removal of telangiectasia macularis eruptiva perstans from the current classification of CM, and removal of the adjunct solitary from the term solitary mastocytoma.

KIT D816V-mutated bone marrow mesenchymal stem cells in indolent systemic mastocytosis are associated with disease progression.

Multilineage involvement of bone marrow (BM) hematopoiesis by the somatic KIT D816V mutation is present in a subset of adult indolent systemic mastocytosis (ISM) patients in association with a poorer prognosis. Here, we investigated the potential involvement of BM mesenchymal stem cells (MSCs) from ISM patients by the KIT D816V mutation and its potential impact on disease progression and outcome. This mutation was investigated in highly purified BM MSCs and other BM cell populations from 83 ISM patients followed for a median of 116 months. KIT D816V-mutated MSCs were detected in 22 of 83 cases. All MSC-mutated patients had multilineage KIT mutation (100% vs 30%, P = .0001) and they more frequently showed involvement of lymphoid plus myeloid BM cells (59% vs 22%; P = .03) and a polyclonal pattern of inactivation of the X-chromosome of KIT-mutated BM mast cells (64% vs 0%; P = .01) vs other multilineage ISM cases. Moreover, presence of KIT-mutated MSCs was associated with more advanced disease features, a greater rate of disease progression (50% vs 17%; P = .04), and a shorter progression-free survival (P ≤ .003). Overall, these results support the notion that ISM patients with mutated MSCs may have acquired the KIT mutation in a common pluripotent progenitor cell, prior to differentiation into MSCs and hematopoietic precursor cells, before the X-chromosome inactivation process occurs. From a clinical point of view, acquisition of the KIT mutation in an earlier BM precursor cell confers a significantly greater risk for disease progression and a poorer outcome.

Clinical, immunophenotypic, and molecular characteristics of well-differentiated systemic mastocytosis.

BACKGROUND: Well-differentiated systemic mastocytosis (WDSM) is a rare variant of systemic mastocytosis (SM) characterized by bone marrow (BM) infiltration by mature-appearing mast cells (MCs) often lacking exon 17 KIT mutations. Because of its rarity, the clinical and biological features of WDSM remain poorly defined. OBJECTIVE: We sought to determine the clinical, biological, and molecular features of a cohort of 33 patients with mastocytosis in the skin in association with BM infiltration by well-differentiated MCs and to establish potential diagnostic criteria for WDSM. METHODS: Thirty-three patients with mastocytosis in the skin plus BM aggregates of round, fully granulated MCs lacking strong CD25 and CD2 expression in association with clonal MC features were studied. RESULTS: Our cohort of patients showed female predominance (female/male ratio, 4:1) and childhood onset of the disease (91%) with frequent familial aggregation (39%). Skin involvement was heterogeneous, including maculopapular (82%), nodular (6%), and diffuse cutaneous (12%) mastocytosis. KIT mutations were detected in only 10 (30%) of 33 patients, including the KIT D816V (n = 5), K509I (n = 3), N819Y (n = 1), and I817V (n = 1) mutations. BM MCs displayed a unique immunophenotypic pattern consisting of increased light scatter features, overexpression of cytoplasmic carboxypeptidase, and aberrant expression of CD30, together with absent (79%) or low (21%) positivity for CD25, CD2, or both. Despite only 9 (27%) of 33 patients fulfilling the World Health Organization criteria for SM, our findings allowed us to establish the systemic nature of the disease, which fit with the definition of WDSM. CONCLUSIONS: WDSM represents a rare clinically and molecularly heterogeneous variant of SM that requires unique diagnostic criteria to avoid a misdiagnosis of cutaneous mastocytosis per current World Health Organization criteria.

Management of Anesthesia in Adult and Pediatric Mastocytosis: A Study of the Spanish Network on Mastocytosis (REMA) Based on 726 Anesthetic Procedures.

BACKGROUND: The role of anesthesia as an elicitor of mast cell (MC) mediator release symptoms in mastocytosis is poorly investigated. OBJECTIVE: To determine the frequency and type of MC mediator release symptoms during anesthetic procedures in mastocytosis patients. METHODS: Medical records were reviewed regarding the anesthetic techniques for 501 mastocytosis patients (459 adults and 42 children; 95 and 5% with systemic involvement, respectively) who were subjected to 676 and 50 anesthetic techniques, respectively. General, sedation, epidural, and local anesthetic techniques were used in 66 (10%), 67 (10%), 76 (11%), and 515 (76%) adult patients and in 24 (48%), 8 (16%), 2 (4%), and 25 (50%) pediatric patients. RESULTS: The frequency of perioperative MC mediator-related symptoms and anaphylaxis was 2 and 0.4% in the adult series and 4 and 2% among children. In the adult series, this frequency was significantly higher in patients who previously presented with anaphylaxis (p = 0.03), underwent major surgeries (p < 0.001) and general anesthesia (p = 0.02), and were not given prophylactic antimediator therapy (PAT) 1 h before the anesthesia (H1/H2 antihistamines and benzodiacepines; p = 0.002).Hypersensitivity and/or allergy to the involved drugs and latex allergy were ruled out in all but one symptomatic case; when PAT was given and sedation was added, some cases later tolerated the same anesthetic drugs. CONCLUSION: The frequency of perioperative anaphylaxis appears to be higher in mastocytosis patients than in the general population. Mastocytosis should not be a contraindication for anesthesia since PAT and adequate anesthetic management using the drugs with the safest profile appears to be effective in preventing/controlling MC mediator-associated symptoms.

Detection of the KIT D816V mutation in peripheral blood of systemic mastocytosis: diagnostic implications.

Recent studies have found the KIT D816V mutation in peripheral blood of virtually all adult systemic mastocytosis patients once highly sensitive PCR techniques were used; thus, detection of the KIT D816V mutation in peripheral blood has been proposed to be included in the diagnostic work-up of systemic mastocytosis algorithms. However, the precise frequency of the mutation, the biological significance of peripheral blood-mutated cells and their potential association with involvement of bone marrow hematopoietic cells other than mast cells still remain to be investigated. Here, we determined the frequency of peripheral blood involvement by the KIT D816V mutation, as assessed by two highly sensitive PCR methods, and investigated its relationship with multilineage involvement of bone marrow hematopoiesis. Overall, our results confirmed the presence of the KIT D816V mutation in peripheral blood of most systemic mastocytosis cases (161/190; 85%)--with an increasing frequency from indolent systemic mastocytosis without skin lesions (29/44; 66%) to indolent systemic mastocytosis with skin involvement (124/135; 92%), and more aggressive disease subtypes (11/11; 100%)--as assessed by the allele-specific oligonucleotide-qPCR method, which was more sensitive (P<.0001) than the peptide nucleic acid-mediated PCR approach (84/190; 44%). Although the presence of the KIT mutation in peripheral blood, as assessed by the allele-specific oligonucleotide-qPCR technique, did not accurately predict for multilineage bone marrow involvement of hematopoiesis, the allele-specific oligonucleotide-qPCR allele burden and the peptide nucleic acid-mediated-PCR approach did. These results suggest that both methods provide clinically useful and complementary information through the identification and/or quantification of the KIT D816V mutation in peripheral blood of patients suspected of systemic mastocytosis.