RARE DISEASE
Mastocytosis
Mastocytosis
Mastocytosis
Drug discovery
21
drugs
With orphan designations
Overview
Mastocytosis is a rare clonal disorder marked by abnormal proliferation and activation of mast cells, with systemic forms involving bone marrow and extracutaneous organs. It is classified into cutaneous (skin-limited) and systemic variants, the latter including indolent, aggressive, and mast cell leukemia subtypes [1][3][6]. Clinical manifestations stem from mast cell mediator release (histamine, tryptase) causing allergic-like symptoms (pruritus, flushing, anaphylaxis) and organ infiltration leading to hepatosplenomegaly, cytopenias, or osteoporosis [1][6][15]. Diagnosis requires bone marrow biopsy with CD25/CD2 staining and KIT D816V mutation testing [1][5].
Burden
Chronic symptoms (fatigue, abdominal pain) impair quality of life; 22–49% experience recurrent anaphylaxis [5][7][11].
Advanced subtypes confer reduced survival (median 2–4 years for mast cell leukemia) [7][12][14].
High healthcare utilization: Patients average 3–9 annual visits and delayed diagnosis (>8 months) [9][12].
Therapies
Symptom control: H1/H2 antihistamines, leukotriene inhibitors, and corticosteroids for mediator-related symptoms [1][13][17].
Disease-modifying agents: Tyrosine kinase inhibitors (midostaurin, avapritinib) for advanced subtypes; omalizumab reduces anaphylaxis risk [8][15][18].
Avoidance of triggers: Alcohol, NSAIDs, temperature extremes, and insect stings [3][6][13].
Categories: rare hematological diseases, rare neoplastic diseases
Research Papers
1,644 drug discovery papers about Mastocytosis, with 1 first-in-class and 21 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,644 drug discovery papers about Mastocytosis, with 1 first-in-class and 21 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-07 | Anesthetic Management of an Elective Cesarean Section in a Patient With Systemic Mastocytosis and Latex Allergy, Complicated by Incidental Intraoperative Wolff-Parkinson-White Pre-excitation: A Case Report.
Systemic mastocytosis (SM) is a rare clonal mast cell disorder in which physical, pharmacological, or emotional triggers can provoke massive mediator release and life-threatening anaphylactoid reactions. Pregnancy and delivery are recognized as high-risk periods that demand careful multidisciplinary planning. Cardiovascular manifestations of mast cell activation disease are increasingly recognized; however, their interplay with primary conduction abnormalities is poorly characterized, and the available evidence is largely limited to isolated case reports. We describe the elective cesarean delivery of a 40-year-old woman with indolent SM and documented latex allergy, managed within a multidisciplinary framework. After corticosteroid and antihistamine premedication in a latex-free operating room, spinal anesthesia was performed without intrathecal opioids; spinal-induced hypotension was treated with phenylephrine boluses, and postoperative analgesia relied on paracetamol alone, with nonsteroidal anti-inflammatory drugs (NSAIDs) deliberately avoided. Serial serum tryptase concentrations remained within the normal range throughout the perioperative period (baseline 7.9 µg/L; intraoperative 10.1 µg/L; early postoperative 9.3 µg/L), with no value reaching the consensus threshold for significant mast cell activation, supporting the effectiveness and safety of the adopted strategy. Unexpectedly, a new Wolff-Parkinson-White (WPW) pre-excitation pattern appeared intraoperatively in a patient with a normal antepartum tracing. She remained asymptomatic, and the subsequent cardiac workup was unremarkable, with outpatient electrophysiological follow-up arranged. This case highlights the value of a structured, prevention-oriented anesthetic strategy in SM, supports spinal anesthesia with hyperbaric bupivacaine as a reasonable preferred option when not contraindicated, and broadens the spectrum of perioperative electrocardiographic findings that may be observed in this population.
2026-08-02 | Non-immunoglobulin E-mediated mechanisms of anaphylaxis.
Anaphylaxis attributable to non-immunoglobulin E (IgE)-mediated mechanisms represents an increasingly recognized and clinically challenging subset of severe hypersensitivity reactions. This review synthesizes recent advances in the understanding of IgE-independent pathways, with emphasis on literature published in the last 18 months, and highlights their implications for precision diagnostics and therapeutic targeting. Major IgE-independent mechanisms have attracted substantial recent attention. First, the Mas-related G protein-coupled receptor X2 (MRGPRX2) has been consolidated as a central mediator of IgE-independent drug reactions, with new humanized knock-in mouse models revealing its capacity to amplify both IgE-dependent and IgE-independent systemic anaphylaxis. Second, clonal mast cell disorders-including systemic mastocytosis and monoclonal mast cell activation syndrome-are now recognized as major risk amplifiers for severe and fatal anaphylaxis, particularly following Hymenoptera venom exposure, reinforcing the role of the KIT D816V mutation in lowering the mast cell activation threshold. Third, a comprehensive biomarker meta-analysis confirms that tryptase, platelet-activating factor (PAF), and urinary prostaglandin D2 each contribute differentially to non-IgE reactions, with PAF and PAF-acetylhydrolase emerging as particularly relevant in IgE-independent severity pathways. Non-IgE-mediated anaphylaxis encompasses mechanistically distinct entities that demand tailored diagnostic algorithms. Recognizing MRGPRX2 activation, complement and IgG-dependent pathways, and clonal mast cell disease in the clinical work-up of unexplained or recurrent anaphylaxis is relevant. Emerging biomarkers and therapeutic targets - including MRGPRX2 antagonists - hold promise for transforming the management of this underdiagnosed condition.
2026-07-08 | Systemic Mastocytosis: Molecular Pathophysiology, WHO Diagnostic Framework, and KIT-Directed Targeted Therapies
Background: Systemic mastocytosis (SM) is a clonal mast cell (MC) neoplasm driven by somatically acquired activating mutations in the KIT receptor tyrosine kinase (CD117), resulting in pathological accumulation of morphologically atypical MCs in extracutaneous organs. The KIT D816V substitution is detectable in over 95% of cases by high-sensitivity next-generation sequencing (NGS) or allele-specific PCR. This gain-of-function variant confers ligand-independent receptor autophosphorylation, leading to constitutive activation of downstream signaling cascades that promote MC progenitor survival, clonal expansion, and resistance to apoptosis. Co-occurring somatic mutations in TET2, SRSF2, ASXL1, CBL, and RUNX1, increasingly identified in the context of clonal hematopoiesis of indeterminate potential, are associated with more aggressive phenotypes and independently confer adverse prognostic impact. Results: The 2022 WHO classification delineates indolent forms from advanced-phase SM, aggressive SM, SM with an associated hematologic neoplasm (SM-AHN), and MC leukemia, which produce progressive end-organ damage through both neoplastic tissue infiltration and uncontrolled mediator release. Formal diagnosis requires integration of histological criteria (multifocal bone marrow MC aggregates of ≥15 cells), immunophenotypic aberrancies (CD25, CD2, and/or CD30 coexpression on MCs by flow cytometry or immunohistochemistry), biochemical markers (baseline serum tryptase ≥ 20 ng/mL), and molecular confirmation of KIT D816V or equivalent pathogenic KIT mutation. The development of type I KIT inhibitors with selectivity for the D816V-mutant conformation has fundamentally restructured the therapeutic field of advanced SM. Conclusions: This review provides a thorough synthesis of SM pathobiology, WHO-defined diagnostic and classification criteria, validated prognostic tools, and the developing landscape of KIT-directed and combination therapies, with direct translational relevance for specialist practitioners managing this heterogeneous myeloid neoplasm.
2026-06-27 | Mast cell proteases and their significance in physiology, pathology, and therapeutic approaches.
Mast cells (MCs) are versatile, multifunctional immune cells with broad roles in physiological homeostasis and pathogenic processes. MCs are found in most tissues, including skin, lungs, intestines, and peritoneum, and they vary in numbers, types, and biological functions. MCs are implicated in host defense against various pathogens, including bacteria, viruses, and fungi. Additionally, MCs are crucial in protecting against toxins, including those present in venoms from multiple species, such as honeybees, snakes, scorpions, and lizards. Although MCs play an essential role in host defense, they are mostly known for their detrimental actions in allergic reactions, such as asthma, food allergy, anaphylaxis, mastocytosis, and various inflammatory skin conditions. Under such conditions, MCs are activated (via IgE-mediated or other mechanisms) and release a range of potent proinflammatory mediators, including tumor necrosis factor α. In addition to cytokines, they are major producers of histamine and various proteases, including chymase, tryptase, and carboxypeptidase A3. As a result, these mediators contribute to the pathological manifestations associated with inflammatory conditions and other disorders. This review focuses mainly on the biological role of MCs and their proteases, with a focus on chymase and tryptase, as well as their inhibitors as candidate therapies for MC-driven diseases. SIGNIFICANCE STATEMENT: Mast cells (MCs) and their proteases are central regulators of tissue homeostasis, barrier defense, and inflammation across multiple organs, but are also associated with numerous diseases. Ongoing research has shown that the function of MCs is highly dependent on their tissue location, where the local tissue environment shapes their phenotype, protease expression, and, consequently, their biological functions. However, further investigation is required to more precisely understand the physiological conditions governing the transition of MCs from maintaining tissue homeostasis to acquiring pathogenic functions, particularly with respect to their protease-dependent activities. By profiling MC heterogeneity using multiomics approaches to map protease-driven signaling networks, it will be possible to gain deeper insight into their functional roles and establish a conceptual framework to guide the development of next-generation, mechanism-based therapeutics that selectively modulate MC activity in human diseases.
2026-06-26 | Unmasking Indolent Systemic Mastocytosis in Patients with Unexplained or Treatment-Refractory Osteoporosis: A Case Series with Diagnostic and Therapeutic Implications.
Indolent systemic mastocytosis (ISM) is an under-recognised cause of secondary osteoporosis, and skeletal fragility may be the only presenting feature, delaying diagnosis. We describe four adults referred to a tertiary endocrinology service for unexplained osteoporosis or low-trauma fractures, in whom systemic mastocytosis (SM) was identified during work-up. All had elevated basal serum tryptase (41.4-87.0 µg/L), bone-marrow biopsy showing atypical mast cells and the KIT D816V variant; cutaneous lesions were absent in every case. Three patients fulfilled WHO 2022 criteria for ISM. The fourth had coexistent JAK2 V617F-positive post-essential-thrombocythaemia myelofibrosis and was classified as SM with associated haematological neoplasm (SM-AHN); his mast cell clone (tryptase 43.7 µg/L; KIT D816V VAF 0.391%) behaved indolently and contributed clinically through osteoporosis alone, illustrating that an indolent mast cell component can be overlooked when a chronic myeloid neoplasm dominates the picture. Presentations ranged from an isolated low-energy L5 fracture in a 55-year-old man, to multiple vertebral compression fractures despite denosumab in a 71-year-old woman with primary hyperparathyroidism, to severe wasp-sting anaphylaxis in a 43-year-old man. After multidisciplinary review, all received intravenous zoledronic acid with vitamin D repletion; KIT-targeted therapy is under consideration in selected patients. Although causal inferences cannot be drawn from four retrospectively identified cases, the series illustrates how ISM may be missed in unexplained or treatment-refractory osteoporosis-particularly in younger men, those with prior severe anaphylaxis, and those fracturing on antiresorptive therapy-and supports combining basal serum tryptase with high-sensitivity peripheral-blood KIT D816V testing, in line with the WHO/ICC/AIM-ECNM 2022-2024 criteria. Prospective studies are needed.
vaccines
2023-12-01 | Post‐COVID‐19 Vaccination Trimester Evaluation in Mastocytosis: A Single‐Center Real‐Life Experience
Objective:The aim of this study was to evaluate the long-term impact of Coronavirus Disease 2019 (COVID-19) vaccination on mastocytosis. Materials and Methods:Patients with mastocytosis were divided into two groups as those who received COVID-19 vaccination (Group 1) and those who did not (Group 2).In group 1, the history of symptoms related to mast cell activation was obtained for the three-month periods before and after vaccination.Psychological status of both groups was assessed using the Depression, Anxiety, and Stress Scale (DASS-21).A modified Fear of COVID-19 Scale was employed to evaluate the fear of COVID-19 vaccination.Results: Fifty-three patients were included in the study, with six patients not receiving vaccination.The Fear of COVID-19 vaccination score was higher in group 2 (p=0.031).Among the vaccinated patients, 70.2% experienced non-allergic adverse reactions.Only one patient experienced anaphylaxis within 20 minutes after the first dose.None of the vaccinated patients reported any change in the frequency of anaphylaxis episodes after vaccination. Conclusion:To conclude, this study suggested that the COVID-19 vaccine can be safe for patients with mastocytosis in both early and late stages.While, further detailed studies on long-term outcomes are necessary, it is recommended to administer the COVID-19 vaccine to patients with mastocytosis while taking the necessary precautions in accordance with the provided recommendations.
2021-09-15 | Risk factors in bee and Vespula venom allergy: state of the art
Summary Background Correct recognition of risk factors enables individualized management and treatment of venom allergic patients. Methods Systematic research and review of current literature regarding the risk of (1) severe sting-induced anaphylaxis, (2) anaphylactic adverse event during venom immunotherapy (VIT), and (3) treatment failure. Results and discussion (1) Mastocytosis is the most important risk factor for severe sting-induced anaphylaxis. Hereditary α‑tryptasemia was recently identified as a genetic predictor of severe reactions. Older age is clearly associated with an increased risk; the respective impact of defined cardiovascular comorbidities has yet to be determined. Recent data do not support an aggravation of venom-induced anaphylaxis by intake of β‑blockers or angiotensin-converting enzyme (ACE) inhibitors. A higher risk in men can be attributed to more intensive exposure to stinging insects. (2) Anaphylactic side effects of VIT are most common during the buildup phase, particularly in the course of (ultra-)rush protocols involving a high number of injections and high cumulative daily doses. They are significantly more frequent during honeybee compared to Vespula VIT. Data supporting a negative effect of mastocytosis on the tolerability of VIT are scarce. Older age and cardiovascular medication are not associated with a higher incidence of VIT-induced anaphylaxis. (3) Relapsing anaphylactic reactions to both field and challenge stings are significantly more common during and after honeybee compared to Vespula VIT. Reports of severe field-sting reactions in mastocytosis patients suggest an increased risk of treatment failure which may be overcome by higher maintenance doses and longer duration of VIT.
2021-07-05 | Venom immunotherapy in indolent systemic mastocytosis with high serum tryptase level.
Mastocytosis is a rare group of disorders characterized by abnormal accumulation of mast cells in the skin, bone marrow, and internal organs. In particular, patients with systemic mastocytosis are at an increased risk of frequent and severe episodes of anaphylaxis. Hymenoptera venom allergy is the most common trigger of anaphylaxis in these patients. Immunotherapy is an effective and safe therapy recommended for patients with mastocytosis and venom allergy. Although this therapy can be administered according to different protocols, the preferred protocol for patients with mastocytosis remains unclear. Systemic side effects can occur, in particular, during the up-dosing phase of immunotherapy, making progression to the maintenance phase of therapy challenging. This case report presents the diagnosis and ultrarush immunotherapy process ended with anaphylaxis of a 33-y-old male patient with Apis mellifera allergy.
2021-04-05 | COVID-19 Vaccination in Mastocytosis: Recommendations of the European Competence Network on Mastocytosis (ECNM) and American Initiative in Mast Cell Diseases (AIM)
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. 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.
2020-07-30 | Mastocytosis presenting as insect anaphylaxis: gender differences and natural history.
Currently, there is strong evidence about an association between hymenoptera venom anaphylaxis (HVA) and mastocytosis. This review is focused on the most relevant clinical and biological features of systemic mastocytosis associated with HVA. HVA is a relatively common complication that modifies the natural course of patients with mastocytosis, particularly men with indolent systemic mastocytosis without skin lesions (ISMs-) in whom HVA can be the presenting symptom in up to around one-half of the cases. Patients with ISMs- associated with HVA are typically males with cardiovascular symptoms in the absence of itching, urticaria, and angioedema during anaphylaxis. Noteworthy, ISMs- is characterized by a low bone marrow mast cell load and a low risk for disease progression. Early and more recent studies support that specific venom immunotherapy (VIT) is a well-tolerated and effective treatment in patients with mastocytosis. VIT should be given life-long to all patients with mastocytosis and proven immunoglobulin E (IgE)-mediated HVA. In patients with negative venom skin test and undetectable IgE antibodies, additional studies such as component-based allergy testing might contribute to confirm an IgE-mediated mechanism of anaphylaxis in some cases, thus providing the indication of VIT.
proteins
2026-03-03 | P015 | Filling the gaps: PEG-interferon in the under-treated world of systemic mastocytosis
Unlike advanced forms of Systemic Mastocytosis (SM) - which may respond to tyrosine kinase inhibitors such as midostaurin or avapritinib - indolent and smoldering subtypes (ISM and SSM) typically lack indications for cytoreductive treatment. Their management remains largely symptomatic, focusing on mediator blockade with antihistamines leukotriene inhibitors, and mast cell stabilizers. The absence of disease-modifying therapies in non-advanced SM highlights an unmet need, particularly for patients with debilitating symptoms or complications such as osteoporosis and fractures, where current options offer limited disease control. While traditionally recognized for its antiviral and immunomodulatory properties, peg-interferon-alfa2a (peg-IFN-α) has been reported to show an effective role in osteoporosis associated with mast cell disorders. In a cohort of 12 patients currently under follow-up at Azienda Ospedaliera Universitaria Pisana (F:M= 1.2, median age of 54 years old) diagnosed with ISM or SMM (according to WHO 2022) and presenting with osteoporosis, treatment with low-dose peg-IFN-α (90–135 µg subcutaneously per week) was started in association with bisphosphonates over a median follow-up of 59 months. All patients had experienced at least one prior fragility fracture or presented with osteolytic lesions at baseline. The medium tryptase level at diagnosis was 63.8 mcg/L. Following initiation of peg-IFN-α, no new fractures were documented in 11 patients. The evaluation through Bone Mineral Densitometry (BMD) revealed a stabilization of the osteolytic lesions in 5 patients and a regression of the osteoporosis pattern in 3 patients (median Z-score at diagnosis -3.6 vs median Z-score after 24 months -3.1). Bone turnover markers, including serum alkaline phosphatase, showed significant reductions, suggesting decreased osteoclastic activity. Moreover, patients reported reduced bone pain and improved physical function. Only one patient showed progression of disease and was started on cytoreductive treatment. While adverse effects such as mild flu-like symptoms and fatigue were reported in a subset of patients, treatment was generally well tolerated. Only one patient presented cardiac arrhythmias, which brought to the suspension of the treatment in order to perform surgical atrial correction. Another patient discontinued the treatment for recurrent fungal respiratory infection. The medium tryptase level at 24 months was 28.6 µg/L. These preliminary findings support the potential of peg-IFN-α as a disease-modifying strategy to prevent progression of bone damage in selected patients with ISM and SSM who exhibit refractory or high-risk bone involvement. Unlike osteoporosis, where it appears to reduce osteoclastic activity, its impact on osteoblastic hyperactivity or sclerotic bone lesions has not been systematically studied. These outcomes suggest that peg-IFN-α may play a protective role in halting skeletal deterioration in non-advanced SM, likely by reducing mast cell burden and suppressing the release of bone-resorptive mediators.
2026-02-23 | Soluble FcεRI is increased in advanced mastocytosis and acts as a negative regulator of mast cell expansion and activation.
The soluble alpha chain of FcεRI (sFcεRI) is released during receptor cross-linking on mast cells (MCs) and serves as an acceptor site for circulating IgE. Recent data suggest that sFcεRI counteracts MC activation in allergic patients. We measured the levels of sFcεRI and its effect in cutaneous mastocytosis and systemic mastocytosis (SM). sFcεRI levels were quantified by ELISA in 114 patients with mastocytosis, including cutaneous mastocytosis (n = 12), indolent SM (n = 67), smoldering SM (n = 5), SM with associated hematologic neoplasm (n = 17), aggressive SM (n = 9), and MC leukemia (n = 4). We measured sFcεRI levels at diagnosis and during follow-up and established correlations with the SM variant, prognostic parameters, and survival. Moreover, we assessed sFcεRI effects on proliferation of neoplastic MCs and IgE-dependent activation and histamine release in basophils obtained from SM patients. Compared to healthy controls, sFcεRI levels were within normal range in most patients with cutaneous mastocytosis and indolent SM, whereas in most patients with advanced SM, especially those with aggressive SM, increased sFcεRI levels were detected. Moreover, we found that a clearly elevated sFcεRI level in SM correlates with poor survival and a lower risk of vascular instability. sFcεRI levels did not correlate with serum tryptase levels, total IgE levels, or the presence of hereditary α-tryptasemia. In in vitro experiments, sFcεRI suppressed anti-IgE-induced CD63 expression and histamine release in basophils and growth of neoplastic MCs. sFcεRI is often elevated in patients with advanced SM and acts as negative regulator of growth and activation of neoplastic MCs.
2023-11-24 | Nerve Growth Factor and Autoimmune Diseases.
NGF plays a crucial immunomodulatory role and increased levels are found in numerous tissues during autoimmune states. NGF directly modulates innate and adaptive immune responses of B and T cells and causes the release of neuropeptides and neurotransmitters controlling the immune system activation in inflamed tissues. Evidence suggests that NGF is involved in the pathogenesis of numerous immune diseases including autoimmune thyroiditis, chronic arthritis, multiple sclerosis, systemic lupus erythematosus, mastocytosis, and chronic granulomatous disease. Furthermore, as NGF levels have been linked to disease severity, it could be considered an optimal early biomarker to identify therapeutic approach efficacy. In conclusion, by gaining insights into how these molecules function and which cells they interact with, future studies can devise targeted therapies to address various neurological, immunological, and other disorders more effectively. This knowledge may pave the way for innovative treatments based on NGF manipulation aimed at improving the quality of life for individuals affected by diseases involving neurotrophins.
2022-01-06 | Darier's sign
A 38-year-old Caucasian male presented with a ten-year history of back pains, dyspepsia and allergic rhinitis and conjunctivitis treated with non-steroidal antirheumatic drugs and on-demand antihystamines. During this time, slowly progressive brownish freckles and patches on the trunk and the extremities began to occur. Because the patient was an entrepreneur with a busy working schedule, he did not pursue any further medical workup. However, due to increasing back pains, he underwent regular massages, and after these treatments, the skin on the back usually became swollen, itchy and red (Fig. 1A), necessitating the use of antihystamines. The patient was eventually referred to a dermatologist. Except for the rash, the clinical status of the patient was unremarkable. Blood counts were also normal. What is the diagnosis? The biopsy of involved skin demonstrated numerous spindle-shaped CD117+ mast cells infiltrating the dermis (Figs. 1B and 1C). Serum tryptase levels were 35 ng/mL and the c-KIT (D816V) mutation was detected by real-time polymerase chain reaction in the bone marrow, finally confirming the diagnosis of indolent systemic mastocytosis [[1]Pardanani A. Systemic mastocytosis in adults–2021 update on diagnosis, risk stratification and management.Am J Hematol. 2021; 96: 508-525Google Scholar]. Due to bone pains, the patient was additionally treated with pegylated interferon. After six months of treatment, complete resolution of back pains, rhinitis, conjunctivitis and dyspepsia was noted, with a minor regression of the skin lesions. Systemic mastocytosis is a heterogeneous disorder characterized by accumulation of the neoplastic mast cells in different organs [[1]Pardanani A. Systemic mastocytosis in adults–2021 update on diagnosis, risk stratification and management.Am J Hematol. 2021; 96: 508-525Google Scholar]. Unlike children, where mastocytosis is usually limited to the skin and can spontaneously regress, the disorder in adults is typically systemic with an almost universal involvement of the skin and bone marrow [[2]Berezowska S. Flaig M.J. Ruëff F. et al.Adult-onset mastocytosis in the skin is highly suggestive of systemic mastocytosis.Mod Pathol. 2014; 27: 19-29Google Scholar]. The Darier's sign is pathognomonic of cutaneous mastocytosis and refers to mast cell degranulation with subsequent hystamine release in parts of the skin infiltrated by mast cells. However, the Darier's sign must not be confused with other forms of dermographism where rubbing of the uninvolved skin also produces urtication. This 'mast cell activation syndrome' is also responsible for the systemic symptoms associated with the disease, such as rhinitis, conjunctivitis, dyspepsia, osteoporosis and anaphylaxis [[1]Pardanani A. Systemic mastocytosis in adults–2021 update on diagnosis, risk stratification and management.Am J Hematol. 2021; 96: 508-525Google Scholar]; therefore, when this constellation of symptoms is present, the clinicians should always remember to look for systemic mastocytosis. None. The patient provided informed consent for this report.
2021-04-30 | Protein 4.1R negatively regulates P815 cells proliferation by inhibiting C-Kit-mediated signal transduction.
The proliferation of mast cells (MCs) plays a crucial role in either physiological or pathological progression of human physical. C-Kit-mediated signaling pathway has been confirmed to play a key role in MCs proliferation, and the regulatory mechanisms of C-Kit-mediated MCs proliferation need to be further explored. Our previous study found that protein 4.1R could negatively regulate T cell receptor (TCR) mediated signal pathways in CD4+ T cells. Little is known about the function of 4.1R in C-Kit-mediated proliferation of MCs. In this study, P815-4.1R-/- cells were constructed by using CRISPR/Cas9 technique. Lack of 4.1R significantly enhanced P815 cells proliferation by accelerating the progression of cell cycle. 4.1R could also significantly alleviate the clinical symptoms of systemic mastocytosis (SM) and improve the overall survival of SM mice. Further study showed that 4.1R could interact directly with C-Kit to inhibit the activation of C-Kit-mediated Ras-Raf-MAPKs and PI3K-AKT signal pathways. Taken together, our findings demonstrate that protein 4.1R, a novel negative regulator, negatively regulates MCs proliferation by inhibiting C-Kit-mediated signal transduction, which maybe provide a potential target to the prevention and treatment of abnormal MCs proliferation-related diseases.
antibodies
2026-08-12 | Bone fragility in mastocytosis: Clinical insights from a 5-patient retrospective case series.
ObjectiveThis retrospective case series aimed to describe 36-month skeletal, biochemical, safety, and patient-reported outcomes in five postmenopausal women with mastocytosis treated with denosumab.MethodsA technical expert panel (TEP) retrospectively evaluated five consecutive eligible patients with osteoporosis associated with indolent systemic mastocytosis. All subjects underwent physiatric assessment, DXA assessment, and Mini-Osteoporosis Quality of Life (Mini-OQoL) evaluation using the validated Italian version of the questionnaire. Data collected at baseline (T0), 18 months (T1), and 36 months (T2) following initiation of denosumab 60 mg every 6 months, combined with cholecalciferol and calcium supplementation according to individual requirements, were descriptively analyzed.ResultsOver 36 months, femoral and lumbar spine T-scores showed modest improvement/stabilization. Mean femoral T-score improved from -3.9 ± 0.3 at baseline to -3.5 ± 0.3 at 36 months, while lumbar spine T-score improved from -4.3 ± 0.5 SD to -3.9 ± 0.4. Vitamin D levels normalized during follow-up, and Mini-OQoL scores improved from 54.2 ± 9 to 67.3 ± 6. However, BMD remained within the osteoporotic range and one vertebral fracture was documented at 36 months. No severe adverse events were recorded.ConclusionsIn this case series, denosumab was associated with stabilization or modest improvement of BMD and improvement in patient-reported quality of life over 36 months in women with osteoporosis secondary to indolent systemic mastocytosis. These preliminary observations should be interpreted cautiously because of the small sample size, lack of a comparator, and occurrence of one new vertebral fracture during follow-up. Thus, larger multicenter prospective studies are required.
2026-06-05 | Efficacy and safety evaluation of gilvetmab in dogs with melanoma and mast cell tumor.
Immune checkpoint inhibitors (ICIs) have transformed oncology in human medicine, providing clinical benefit in a broad spectrum of cancers. Widely available ICIs for dogs are lacking. Evaluate efficacy and safety of gilvetmab, a caninized anti-PD-1 monoclonal antibody. Fifty-one client-owned dogs were evaluated, 25 with stages II-III melanoma and 26 with stages I-III mast cell tumor (MCT). Fifteen dogs with stages III-V lymphoma were also evaluated. Multi-institutional, open-label study. Enrolled dogs were treated with gilvetmab IV at 6 mg/kg q28d or 10 mg/kg q14d; 8 dogs receiving the lower dosage underwent dose escalation with their owners' consent. Safety was evaluated by physical examinations, laboratory testing, and clinical observations made by veterinarians or the dogs' owners. Efficacy was assessed by objective response rate (ORR) and time to progression (TTP) using cRECIST v1.0 and lymphoma response criteria. For melanoma, the ORR was 20% (95% confidence interval [CI], 7%-41%) and median TTP was 56 days. For MCT, the ORR was 46% (95% CI, 27%-67%) and median TTP was not reached. No objective responses were observed in dogs with lymphoma. Serious adverse events of anaphylaxis, hypotension, or tumor hemorrhage occurred in 3 dogs (3/51, 5.9%). Tumor enlargement before regression, consistent with possible pseudoprogression, was observed in 2 dogs with melanoma. Gilvetmab has a reasonable expectation of efficacy and an acceptable preliminary safety profile in dogs with MCT stages I-III and melanoma stages II and III.
2026-04-13 | A successful treatment of urticaria pigmentosa with omalizumab in a pediatric patient: a case report.
Cutaneous mastocytosis (CM) is a rare disorder characterized by abnormal mast cell proliferation limited to the skin. Conventional treatments including antihistamines and corticosteroids often provide suboptimal symptom control, with less than 50% of patients responding adequately to H1-antihistamine therapy. Omalizumab, a humanized monoclonal antibody that inhibits immunoglobulin E (IgE) binding to mast cells, represents a promising therapeutic alternative for refractory cases. We report a 14-year-old Middle Eastern female with a 1-year history of intensely pruritic, hyperpigmented macules significantly impacting her quality of life. Physical examination revealed widespread excoriated erythematous and brown macules with positive Darier's sign. Histopathological examination showed CD117-positive mast cells, confirming CM diagnosis. Laboratory investigations were normal except for mildly elevated IgE (217 IU/mL). Conventional management with antihistamines, corticosteroids, and Montelukast provided minimal improvement, with persistent urticarial attacks requiring systemic steroid pulses. Omalizumab was initiated at 150 mg monthly subcutaneously and increased to 300 mg monthly due to relapses. Following dose optimization, the patient achieved complete symptom resolution and improved quality of life without adverse events. This represents the first documented pediatric CM case in Saudi Arabia successfully treated with omalizumab. The treatment demonstrated remarkable efficacy when conventional therapies failed, with excellent safety profile. Omalizumab may serve as a viable therapeutic alternative for pediatric patients with refractory CM. Further clinical trials are needed to establish optimal treatment protocols.
2026-03-29 | Honeybee venom immunotherapy: An Australian Centre experience over 15 years.
Honeybee venom is a leading cause of anaphylaxis, and venom immunotherapy (VIT) reduces the risk of future severe reactions to stings. To retrospectively evaluate treatment practices and outcomes of honeybee VIT (HB-VIT) in an Australian centre. Patients who underwent HB-VIT between July 2010 and July 2025 were identified, and data on demographics, Brown anaphylaxis grade, tryptase level, specific IgE, HB-VIT protocol: ultra-rush (UR) or semi-rush (SR), adverse reactions and field sting reactions during and following HB-VIT were recorded. One hundred and sixty-seven patients received HB-VIT, the majority were of male gender (n=126, 75.4%), with a median age of 48 years (IQR 36.0-59.0). Most patients had Brown Grade 2 (n=86, 51.5%) or 3 (n=71, 42.5%) anaphylaxis at index reaction. Three patients had indolent systemic mastocytosis (SM). Ninety-nine patients (59.3%) had SR protocol. UR was more common than SR among those from regional or rural residence (48 vs 18; p < 0.05). Of the 87 allergic adverse reactions (ARs) in 58 patients (34.7%), all occurred during HB-VIT buildup; large localised reactions were most frequent (n=25, 15.0%). Ten patients (6%) developed systemic allergic reactions (SARs). Omalizumab was prescribed and successful in preventing further SARs in two of these patients (one with indolent SM). There were no significant differences in frequency and severity of ARs between protocols. Thirty patients experienced field stings during or after HB-VIT completion; three (10%) developed SARs (n=3). This retrospective study demonstrates the effectiveness of HB-VIT and the tolerability of both SR and UR protocols.
2026-03-19 | Characterization of CD123 expression by mast cells in systemic mastocytosis with multicolor flow cytometry.
Systemic mastocytosis (SM) is a clonal mast cell (MC) disorder characterized by aberrant immunophenotypes, including expression of CD25, CD2, and occasionally CD30. CD123, the α-subunit of the interleukin-3 receptor, is a therapeutic target in hematologic malignancies and has been reported to be expressed on neoplastic MCs by immunohistochemistry (IHC) with prognostic implications. This study aims to characterize CD123 expression in SM by flow cytometry. We retrospectively analyzed 142 bone marrow samples from 79 SM patients (81 diagnostic samples) and 25 controls with normal MC immunophenotype. Flow cytometry was performed using a clinically validated 9-color mast cell tube which included CD123. Data collected included SM subtype, clinical and laboratory features, MC burden, and marker expression. Statistical analyses were performed in R. CD123 was expressed on MCs in 91% of SM cases (ISM 92%, SM-AHN 94%, SSM 100%, ASM 100%, MCL 50%). Median percentage of MCs positive for CD123 was 53.9% (IQR 8.1-83.4). Compared to prior IHC data (overall 64% positivity), flow cytometry demonstrated more cases with CD123 expression by MCs. No significant correlations were observed between CD123 expression and serum tryptase, KIT D816V allele burden, or MC burden. CD123 is frequently expressed on neoplastic MCs in SM by flow cytometry, across all subtypes. These findings support further investigation of CD123 as a therapeutic target and warrant correlation with IHC and clinical outcomes in larger cohorts.
other
2026-05-08 | CAR T-cells targeting CD117 effectively eliminate mast cells in preclinical models of advanced systemic mastocytosis.
Systemic mastocytosis (SM) is characterized by uncontrolled expansion of neoplastic mast cells (MCs) and their accumulation in various tissues and organs, ranging from indolent variants to more advanced forms (advSM). Although several MC- and SM-expressed cell surface antigens have been identified, no immune therapy has been developed for advSM so far. The receptor tyrosine kinase KIT (CD117) is highly expressed on MCs, exceeding the levels of expression on hematopoietic stem and progenitor cells (HSPC). Therefore, targeting CD117 in advSM could be of therapeutic value. In this study, we assessed the therapeutic potential of anti-CD117 chimeric antigen receptor (CAR) T-cells to target neoplastic MCs in SM. In vitro, anti-CD117-CAR T-cells efficiently lysed several SM-related human MC cell lines, MCs differentiated from SM patient-derived induced pluripotent stem (iPS) cells, and neoplastic bone marrow cells obtained from SM patients. Furthermore, in immunocompromised mice engrafted with an advSM-like MC cell line, repetitive applications of anti-CD117-CAR T-cells were able to inhibit MC expansion. These data may pave the way for the development of anti-CD117-CAR T-cell therapies in advSM.
2026-02-24 | A Wolf in Sheep's clothing: Mastocytosis lurking under favorable risk AML
Systemic Mastocytosis associated with hematologic neoplasms (SM-AHN) is exceedingly rare in children posing diagnostic and therapeutic challenge. We report a 5-year-old girl with AML-M2 with RUNX1::RUNX1T1 and mutations in ASXL1 and NRAS. After first cycle of chemotherapy bone marrow was in complete remission but revealed the mast cell aggregates confirming SM-AHN. She had inadequate log reduction of RUNX1::RUNXITI fusion transcript and persisting mast cell aggregates even after 3 cycles of chemotherapy. Hence she was upstaged to high risk and underwent HLA haploidentical hematopoietic stem cell transplantation (HSCT). After two years from allogenic HSCT she remained in complete remission with 4.8-log reduction in RUNX1::RUNX1T1 fusion transcripts and complete clearance of mast cells. Identification of SM-AHN is crucial and allogeneic HSCT offers potential cure. Molecular detection of RUNXI::RUNXIT1 fusion transcripts is essential for monitoring therapy response, screening early relapse and pre-emptive therapeutic decisions. • Underlying Mast cells can be masked by the blasts at diagnosis of Acute Myeloid Leukemia that can be spotted out by detailed immunophenotyping • Early therapy intensification is mandatory in AML associated with Mastocytosis even when associated with good risk genetics • Following log reduction in real time PCR of RUNX1::RUNX1T1 fusion transcript helps identify response to therapy and early relapse.
2025-09-23 | Allogeneic haematopoietic cell transplantation in advanced systemic mastocytosis in the new era: A CIBMTR study.
We investigated the outcomes of patients with advanced systemic mastocytosis (AdvSM) undergoing allogeneic haematopoietic cell therapy (alloHCT) in the US. Twenty-seven adult (median age, 58 years) patients with AdvSM received alloHCT from 2014 to 2021. Most patients were white (93%), male (63%) and had systemic mastocytosis (SM) with associated haematological neoplasm (SM-AHN, 70%), received peripheral blood grafts (89%) and non-myeloablative regimens. KIT mutation was detected in 14 of the reported 16 patients (87.5%). Post-transplantation cyclophosphamide (PTCy) was used in approximately 50% of the cohort. Approximately 1 year after alloHCT, median bone marrow mast cell burden decreased from 15% pre-alloHCT to 1.5% (range 0-8) at 1 year post-alloHCT. The median serum tryptase decreased from 55 ng/mL (range 3-400 ng/mL) pre-alloHCT to 18 ng/mL (range 0-481 ng/mL) at 1 year post-alloHCT. At 1 year, progression-free survival (PFS) and overall survival (OS) were 59% (95% confidence interval [CI], 41%-77%) and 74% (95% CI, 56%-89%) respectively. In the subset of patients with SM-AHN, 1-year PFS and OS were 74% (52%-91%) and 79% (95% CI, 58%-94%) respectively. The cumulative incidence of relapse/progression for the entire population of patients with SM (n = 27) was 4% (95% CI, 0-14) at 100 days and 15% (95% CI, 4-31) at 1 year. For the subset of patients with AHN, the cumulative incidence was 11% (95% CI, 1-28) at 100 days and 21% (95% CI, 6-42) at 1 year. Relapse/progression was the cause of death in six of 12 patients (5 died of AHN and 1 died of SM progression). Eighteen and nine patients received a KIT inhibitor before alloHCT and after alloHCT respectively. In addition, six patients received a KIT inhibitor for the treatment of relapse/progression of SM after alloHCT. Although it is difficult to delineate the exact effect of alloHCT and KIT inhibitors because of the size of the study in this era, the use of alloHCT and KIT inhibitors pre- and post- alloHCT is increasing. In the near future, larger studies are required to provide further insights into this subject.
2025-03-07 | Establishment and characterisation of a novel canine mast cell tumour cell line (C18).
Mast cell tumour (MCT) is a life-threatening neoplasm commonly found in dogs worldwide. The outcome of treatment for dogs with cutaneous MCT is currently poor, mainly because of the tumour's aggressiveness and the heterogeneity in tumour behaviour. This study established a novel canine MCT cell line and compared with three reference canine MCT cell lines (CMMC, VIMC and CoMS) in terms of their characteristics and tumour sensitivity to immune cell-mediated cytotoxicity. Of 18 MCT samples, only one cell line derived from high grade cutaneous MCT was established and referred to as C18 cell line. The C18 cell line could be maintained for over 100 passages while they still exhibited c-kit, tryptase, FcεRIα and FcεRIβ expression. The C18 had the longest doubling time and smallest tumour spheroid size when compared to the other three reference cell lines. The C18 also had c-kit internal tandem duplication (ITD) in exon 11 and nine single nucleotide polymorphisms (SNPs) in five genes, namely c-kit, HYAL4, SEL1L, SPAM1 and TRAF3. For a comparison of tumour sensitivity to immune cell-mediated cytotoxicity, the percentages of early and total apoptotic cells were significantly increased in all four cell lines. However, the percentages of viable cells were significantly decreased only in C18. In conclusion, a novel canine cutaneous MCT cell line was successfully established, in terms of its characteristics, growth behavior and interaction with PBMCs. The C18 cell line holds a potential promise for advancing studies and developing new therapeutic strategies.
2024-04-08 | Allogeneic haematopoietic cell transplantation for advanced systemic mastocytosis: Best practice recommendations on behalf of the EBMT Practice Harmonisation and Guidelines Committee.
Systemic Mastocytosis (SM) is a multifaceted clinically heterogeneous disease. Advanced SM (AdvSM) comprises three entities: aggressive SM (ASM), mast cell leukaemia (MCL) and SM with an associated hematologic neoplasm (SM-AHN), the latter accounting for 60-70% of all AdvSM cases. Detection of a disease-triggering mutation in the KIT gene (esp. KIT D816V) in >90% of the patients with ASM or SM-AHN has led to a significant improvement in therapeutic options by the implementation of two KIT-targeting kinase inhibitors: midostaurin and avapritinib. Although complete remissions have been reported, neither of these targeted agents is 'curative' in all patients and the duration of responses varies. The median overall survival, depending on the WHO subtype and scoring result, is approximately 1 to 4 years. Although the European Competence Network on Mastocytosis (ECNM) and American Initiative in Mast Cell Diseases (AIM) consensus groups recommend allogeneic haematopoietic cell transplantation (allo-HCT) in drug-resistant and other high-risk patients, there is a relative lack of information to guide clinicians on which patients with AdvSM should be considered for transplant, and how KIT inhibitors may fit into the transplant algorithm, including their use pre- and post-transplant to optimise outcomes. Following the generation of an expert panel with a specialist interest in allo-HCT and mastocytosis, these best practice recommendations were generated according to the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonisation and guidelines and ECNM methodology. We aim to provide a practical, clinically relevant and up-to-date framework to guide allo-HCT in AdvsM in 2024 and beyond.
small molecules
2026-08-07 | Anesthetic Management of an Elective Cesarean Section in a Patient With Systemic Mastocytosis and Latex Allergy, Complicated by Incidental Intraoperative Wolff-Parkinson-White Pre-excitation: A Case Report.
Systemic mastocytosis (SM) is a rare clonal mast cell disorder in which physical, pharmacological, or emotional triggers can provoke massive mediator release and life-threatening anaphylactoid reactions. Pregnancy and delivery are recognized as high-risk periods that demand careful multidisciplinary planning. Cardiovascular manifestations of mast cell activation disease are increasingly recognized; however, their interplay with primary conduction abnormalities is poorly characterized, and the available evidence is largely limited to isolated case reports. We describe the elective cesarean delivery of a 40-year-old woman with indolent SM and documented latex allergy, managed within a multidisciplinary framework. After corticosteroid and antihistamine premedication in a latex-free operating room, spinal anesthesia was performed without intrathecal opioids; spinal-induced hypotension was treated with phenylephrine boluses, and postoperative analgesia relied on paracetamol alone, with nonsteroidal anti-inflammatory drugs (NSAIDs) deliberately avoided. Serial serum tryptase concentrations remained within the normal range throughout the perioperative period (baseline 7.9 µg/L; intraoperative 10.1 µg/L; early postoperative 9.3 µg/L), with no value reaching the consensus threshold for significant mast cell activation, supporting the effectiveness and safety of the adopted strategy. Unexpectedly, a new Wolff-Parkinson-White (WPW) pre-excitation pattern appeared intraoperatively in a patient with a normal antepartum tracing. She remained asymptomatic, and the subsequent cardiac workup was unremarkable, with outpatient electrophysiological follow-up arranged. This case highlights the value of a structured, prevention-oriented anesthetic strategy in SM, supports spinal anesthesia with hyperbaric bupivacaine as a reasonable preferred option when not contraindicated, and broadens the spectrum of perioperative electrocardiographic findings that may be observed in this population.
2026-08-02 | Non-immunoglobulin E-mediated mechanisms of anaphylaxis.
Anaphylaxis attributable to non-immunoglobulin E (IgE)-mediated mechanisms represents an increasingly recognized and clinically challenging subset of severe hypersensitivity reactions. This review synthesizes recent advances in the understanding of IgE-independent pathways, with emphasis on literature published in the last 18 months, and highlights their implications for precision diagnostics and therapeutic targeting. Major IgE-independent mechanisms have attracted substantial recent attention. First, the Mas-related G protein-coupled receptor X2 (MRGPRX2) has been consolidated as a central mediator of IgE-independent drug reactions, with new humanized knock-in mouse models revealing its capacity to amplify both IgE-dependent and IgE-independent systemic anaphylaxis. Second, clonal mast cell disorders-including systemic mastocytosis and monoclonal mast cell activation syndrome-are now recognized as major risk amplifiers for severe and fatal anaphylaxis, particularly following Hymenoptera venom exposure, reinforcing the role of the KIT D816V mutation in lowering the mast cell activation threshold. Third, a comprehensive biomarker meta-analysis confirms that tryptase, platelet-activating factor (PAF), and urinary prostaglandin D2 each contribute differentially to non-IgE reactions, with PAF and PAF-acetylhydrolase emerging as particularly relevant in IgE-independent severity pathways. Non-IgE-mediated anaphylaxis encompasses mechanistically distinct entities that demand tailored diagnostic algorithms. Recognizing MRGPRX2 activation, complement and IgG-dependent pathways, and clonal mast cell disease in the clinical work-up of unexplained or recurrent anaphylaxis is relevant. Emerging biomarkers and therapeutic targets - including MRGPRX2 antagonists - hold promise for transforming the management of this underdiagnosed condition.
2026-07-08 | Systemic Mastocytosis: Molecular Pathophysiology, WHO Diagnostic Framework, and KIT-Directed Targeted Therapies
Background: Systemic mastocytosis (SM) is a clonal mast cell (MC) neoplasm driven by somatically acquired activating mutations in the KIT receptor tyrosine kinase (CD117), resulting in pathological accumulation of morphologically atypical MCs in extracutaneous organs. The KIT D816V substitution is detectable in over 95% of cases by high-sensitivity next-generation sequencing (NGS) or allele-specific PCR. This gain-of-function variant confers ligand-independent receptor autophosphorylation, leading to constitutive activation of downstream signaling cascades that promote MC progenitor survival, clonal expansion, and resistance to apoptosis. Co-occurring somatic mutations in TET2, SRSF2, ASXL1, CBL, and RUNX1, increasingly identified in the context of clonal hematopoiesis of indeterminate potential, are associated with more aggressive phenotypes and independently confer adverse prognostic impact. Results: The 2022 WHO classification delineates indolent forms from advanced-phase SM, aggressive SM, SM with an associated hematologic neoplasm (SM-AHN), and MC leukemia, which produce progressive end-organ damage through both neoplastic tissue infiltration and uncontrolled mediator release. Formal diagnosis requires integration of histological criteria (multifocal bone marrow MC aggregates of ≥15 cells), immunophenotypic aberrancies (CD25, CD2, and/or CD30 coexpression on MCs by flow cytometry or immunohistochemistry), biochemical markers (baseline serum tryptase ≥ 20 ng/mL), and molecular confirmation of KIT D816V or equivalent pathogenic KIT mutation. The development of type I KIT inhibitors with selectivity for the D816V-mutant conformation has fundamentally restructured the therapeutic field of advanced SM. Conclusions: This review provides a thorough synthesis of SM pathobiology, WHO-defined diagnostic and classification criteria, validated prognostic tools, and the developing landscape of KIT-directed and combination therapies, with direct translational relevance for specialist practitioners managing this heterogeneous myeloid neoplasm.
2026-06-27 | Mast cell proteases and their significance in physiology, pathology, and therapeutic approaches.
Mast cells (MCs) are versatile, multifunctional immune cells with broad roles in physiological homeostasis and pathogenic processes. MCs are found in most tissues, including skin, lungs, intestines, and peritoneum, and they vary in numbers, types, and biological functions. MCs are implicated in host defense against various pathogens, including bacteria, viruses, and fungi. Additionally, MCs are crucial in protecting against toxins, including those present in venoms from multiple species, such as honeybees, snakes, scorpions, and lizards. Although MCs play an essential role in host defense, they are mostly known for their detrimental actions in allergic reactions, such as asthma, food allergy, anaphylaxis, mastocytosis, and various inflammatory skin conditions. Under such conditions, MCs are activated (via IgE-mediated or other mechanisms) and release a range of potent proinflammatory mediators, including tumor necrosis factor α. In addition to cytokines, they are major producers of histamine and various proteases, including chymase, tryptase, and carboxypeptidase A3. As a result, these mediators contribute to the pathological manifestations associated with inflammatory conditions and other disorders. This review focuses mainly on the biological role of MCs and their proteases, with a focus on chymase and tryptase, as well as their inhibitors as candidate therapies for MC-driven diseases. SIGNIFICANCE STATEMENT: Mast cells (MCs) and their proteases are central regulators of tissue homeostasis, barrier defense, and inflammation across multiple organs, but are also associated with numerous diseases. Ongoing research has shown that the function of MCs is highly dependent on their tissue location, where the local tissue environment shapes their phenotype, protease expression, and, consequently, their biological functions. However, further investigation is required to more precisely understand the physiological conditions governing the transition of MCs from maintaining tissue homeostasis to acquiring pathogenic functions, particularly with respect to their protease-dependent activities. By profiling MC heterogeneity using multiomics approaches to map protease-driven signaling networks, it will be possible to gain deeper insight into their functional roles and establish a conceptual framework to guide the development of next-generation, mechanism-based therapeutics that selectively modulate MC activity in human diseases.
2026-06-26 | Unmasking Indolent Systemic Mastocytosis in Patients with Unexplained or Treatment-Refractory Osteoporosis: A Case Series with Diagnostic and Therapeutic Implications.
Indolent systemic mastocytosis (ISM) is an under-recognised cause of secondary osteoporosis, and skeletal fragility may be the only presenting feature, delaying diagnosis. We describe four adults referred to a tertiary endocrinology service for unexplained osteoporosis or low-trauma fractures, in whom systemic mastocytosis (SM) was identified during work-up. All had elevated basal serum tryptase (41.4-87.0 µg/L), bone-marrow biopsy showing atypical mast cells and the KIT D816V variant; cutaneous lesions were absent in every case. Three patients fulfilled WHO 2022 criteria for ISM. The fourth had coexistent JAK2 V617F-positive post-essential-thrombocythaemia myelofibrosis and was classified as SM with associated haematological neoplasm (SM-AHN); his mast cell clone (tryptase 43.7 µg/L; KIT D816V VAF 0.391%) behaved indolently and contributed clinically through osteoporosis alone, illustrating that an indolent mast cell component can be overlooked when a chronic myeloid neoplasm dominates the picture. Presentations ranged from an isolated low-energy L5 fracture in a 55-year-old man, to multiple vertebral compression fractures despite denosumab in a 71-year-old woman with primary hyperparathyroidism, to severe wasp-sting anaphylaxis in a 43-year-old man. After multidisciplinary review, all received intravenous zoledronic acid with vitamin D repletion; KIT-targeted therapy is under consideration in selected patients. Although causal inferences cannot be drawn from four retrospectively identified cases, the series illustrates how ISM may be missed in unexplained or treatment-refractory osteoporosis-particularly in younger men, those with prior severe anaphylaxis, and those fracturing on antiresorptive therapy-and supports combining basal serum tryptase with high-sensitivity peripheral-blood KIT D816V testing, in line with the WHO/ICC/AIM-ECNM 2022-2024 criteria. Prospective studies are needed.
vaccines
2023-12-01 | Post‐COVID‐19 Vaccination Trimester Evaluation in Mastocytosis: A Single‐Center Real‐Life Experience
Objective:The aim of this study was to evaluate the long-term impact of Coronavirus Disease 2019 (COVID-19) vaccination on mastocytosis. Materials and Methods:Patients with mastocytosis were divided into two groups as those who received COVID-19 vaccination (Group 1) and those who did not (Group 2).In group 1, the history of symptoms related to mast cell activation was obtained for the three-month periods before and after vaccination.Psychological status of both groups was assessed using the Depression, Anxiety, and Stress Scale (DASS-21).A modified Fear of COVID-19 Scale was employed to evaluate the fear of COVID-19 vaccination.Results: Fifty-three patients were included in the study, with six patients not receiving vaccination.The Fear of COVID-19 vaccination score was higher in group 2 (p=0.031).Among the vaccinated patients, 70.2% experienced non-allergic adverse reactions.Only one patient experienced anaphylaxis within 20 minutes after the first dose.None of the vaccinated patients reported any change in the frequency of anaphylaxis episodes after vaccination. Conclusion:To conclude, this study suggested that the COVID-19 vaccine can be safe for patients with mastocytosis in both early and late stages.While, further detailed studies on long-term outcomes are necessary, it is recommended to administer the COVID-19 vaccine to patients with mastocytosis while taking the necessary precautions in accordance with the provided recommendations.
2021-09-15 | Risk factors in bee and Vespula venom allergy: state of the art
Summary Background Correct recognition of risk factors enables individualized management and treatment of venom allergic patients. Methods Systematic research and review of current literature regarding the risk of (1) severe sting-induced anaphylaxis, (2) anaphylactic adverse event during venom immunotherapy (VIT), and (3) treatment failure. Results and discussion (1) Mastocytosis is the most important risk factor for severe sting-induced anaphylaxis. Hereditary α‑tryptasemia was recently identified as a genetic predictor of severe reactions. Older age is clearly associated with an increased risk; the respective impact of defined cardiovascular comorbidities has yet to be determined. Recent data do not support an aggravation of venom-induced anaphylaxis by intake of β‑blockers or angiotensin-converting enzyme (ACE) inhibitors. A higher risk in men can be attributed to more intensive exposure to stinging insects. (2) Anaphylactic side effects of VIT are most common during the buildup phase, particularly in the course of (ultra-)rush protocols involving a high number of injections and high cumulative daily doses. They are significantly more frequent during honeybee compared to Vespula VIT. Data supporting a negative effect of mastocytosis on the tolerability of VIT are scarce. Older age and cardiovascular medication are not associated with a higher incidence of VIT-induced anaphylaxis. (3) Relapsing anaphylactic reactions to both field and challenge stings are significantly more common during and after honeybee compared to Vespula VIT. Reports of severe field-sting reactions in mastocytosis patients suggest an increased risk of treatment failure which may be overcome by higher maintenance doses and longer duration of VIT.
2021-07-05 | Venom immunotherapy in indolent systemic mastocytosis with high serum tryptase level.
Mastocytosis is a rare group of disorders characterized by abnormal accumulation of mast cells in the skin, bone marrow, and internal organs. In particular, patients with systemic mastocytosis are at an increased risk of frequent and severe episodes of anaphylaxis. Hymenoptera venom allergy is the most common trigger of anaphylaxis in these patients. Immunotherapy is an effective and safe therapy recommended for patients with mastocytosis and venom allergy. Although this therapy can be administered according to different protocols, the preferred protocol for patients with mastocytosis remains unclear. Systemic side effects can occur, in particular, during the up-dosing phase of immunotherapy, making progression to the maintenance phase of therapy challenging. This case report presents the diagnosis and ultrarush immunotherapy process ended with anaphylaxis of a 33-y-old male patient with Apis mellifera allergy.
2021-04-05 | COVID-19 Vaccination in Mastocytosis: Recommendations of the European Competence Network on Mastocytosis (ECNM) and American Initiative in Mast Cell Diseases (AIM)
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. 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.
2020-07-30 | Mastocytosis presenting as insect anaphylaxis: gender differences and natural history.
Currently, there is strong evidence about an association between hymenoptera venom anaphylaxis (HVA) and mastocytosis. This review is focused on the most relevant clinical and biological features of systemic mastocytosis associated with HVA. HVA is a relatively common complication that modifies the natural course of patients with mastocytosis, particularly men with indolent systemic mastocytosis without skin lesions (ISMs-) in whom HVA can be the presenting symptom in up to around one-half of the cases. Patients with ISMs- associated with HVA are typically males with cardiovascular symptoms in the absence of itching, urticaria, and angioedema during anaphylaxis. Noteworthy, ISMs- is characterized by a low bone marrow mast cell load and a low risk for disease progression. Early and more recent studies support that specific venom immunotherapy (VIT) is a well-tolerated and effective treatment in patients with mastocytosis. VIT should be given life-long to all patients with mastocytosis and proven immunoglobulin E (IgE)-mediated HVA. In patients with negative venom skin test and undetectable IgE antibodies, additional studies such as component-based allergy testing might contribute to confirm an IgE-mediated mechanism of anaphylaxis in some cases, thus providing the indication of VIT.
proteins
2026-03-03 | P015 | Filling the gaps: PEG-interferon in the under-treated world of systemic mastocytosis
Unlike advanced forms of Systemic Mastocytosis (SM) - which may respond to tyrosine kinase inhibitors such as midostaurin or avapritinib - indolent and smoldering subtypes (ISM and SSM) typically lack indications for cytoreductive treatment. Their management remains largely symptomatic, focusing on mediator blockade with antihistamines leukotriene inhibitors, and mast cell stabilizers. The absence of disease-modifying therapies in non-advanced SM highlights an unmet need, particularly for patients with debilitating symptoms or complications such as osteoporosis and fractures, where current options offer limited disease control. While traditionally recognized for its antiviral and immunomodulatory properties, peg-interferon-alfa2a (peg-IFN-α) has been reported to show an effective role in osteoporosis associated with mast cell disorders. In a cohort of 12 patients currently under follow-up at Azienda Ospedaliera Universitaria Pisana (F:M= 1.2, median age of 54 years old) diagnosed with ISM or SMM (according to WHO 2022) and presenting with osteoporosis, treatment with low-dose peg-IFN-α (90–135 µg subcutaneously per week) was started in association with bisphosphonates over a median follow-up of 59 months. All patients had experienced at least one prior fragility fracture or presented with osteolytic lesions at baseline. The medium tryptase level at diagnosis was 63.8 mcg/L. Following initiation of peg-IFN-α, no new fractures were documented in 11 patients. The evaluation through Bone Mineral Densitometry (BMD) revealed a stabilization of the osteolytic lesions in 5 patients and a regression of the osteoporosis pattern in 3 patients (median Z-score at diagnosis -3.6 vs median Z-score after 24 months -3.1). Bone turnover markers, including serum alkaline phosphatase, showed significant reductions, suggesting decreased osteoclastic activity. Moreover, patients reported reduced bone pain and improved physical function. Only one patient showed progression of disease and was started on cytoreductive treatment. While adverse effects such as mild flu-like symptoms and fatigue were reported in a subset of patients, treatment was generally well tolerated. Only one patient presented cardiac arrhythmias, which brought to the suspension of the treatment in order to perform surgical atrial correction. Another patient discontinued the treatment for recurrent fungal respiratory infection. The medium tryptase level at 24 months was 28.6 µg/L. These preliminary findings support the potential of peg-IFN-α as a disease-modifying strategy to prevent progression of bone damage in selected patients with ISM and SSM who exhibit refractory or high-risk bone involvement. Unlike osteoporosis, where it appears to reduce osteoclastic activity, its impact on osteoblastic hyperactivity or sclerotic bone lesions has not been systematically studied. These outcomes suggest that peg-IFN-α may play a protective role in halting skeletal deterioration in non-advanced SM, likely by reducing mast cell burden and suppressing the release of bone-resorptive mediators.
2026-02-23 | Soluble FcεRI is increased in advanced mastocytosis and acts as a negative regulator of mast cell expansion and activation.
The soluble alpha chain of FcεRI (sFcεRI) is released during receptor cross-linking on mast cells (MCs) and serves as an acceptor site for circulating IgE. Recent data suggest that sFcεRI counteracts MC activation in allergic patients. We measured the levels of sFcεRI and its effect in cutaneous mastocytosis and systemic mastocytosis (SM). sFcεRI levels were quantified by ELISA in 114 patients with mastocytosis, including cutaneous mastocytosis (n = 12), indolent SM (n = 67), smoldering SM (n = 5), SM with associated hematologic neoplasm (n = 17), aggressive SM (n = 9), and MC leukemia (n = 4). We measured sFcεRI levels at diagnosis and during follow-up and established correlations with the SM variant, prognostic parameters, and survival. Moreover, we assessed sFcεRI effects on proliferation of neoplastic MCs and IgE-dependent activation and histamine release in basophils obtained from SM patients. Compared to healthy controls, sFcεRI levels were within normal range in most patients with cutaneous mastocytosis and indolent SM, whereas in most patients with advanced SM, especially those with aggressive SM, increased sFcεRI levels were detected. Moreover, we found that a clearly elevated sFcεRI level in SM correlates with poor survival and a lower risk of vascular instability. sFcεRI levels did not correlate with serum tryptase levels, total IgE levels, or the presence of hereditary α-tryptasemia. In in vitro experiments, sFcεRI suppressed anti-IgE-induced CD63 expression and histamine release in basophils and growth of neoplastic MCs. sFcεRI is often elevated in patients with advanced SM and acts as negative regulator of growth and activation of neoplastic MCs.
2023-11-24 | Nerve Growth Factor and Autoimmune Diseases.
NGF plays a crucial immunomodulatory role and increased levels are found in numerous tissues during autoimmune states. NGF directly modulates innate and adaptive immune responses of B and T cells and causes the release of neuropeptides and neurotransmitters controlling the immune system activation in inflamed tissues. Evidence suggests that NGF is involved in the pathogenesis of numerous immune diseases including autoimmune thyroiditis, chronic arthritis, multiple sclerosis, systemic lupus erythematosus, mastocytosis, and chronic granulomatous disease. Furthermore, as NGF levels have been linked to disease severity, it could be considered an optimal early biomarker to identify therapeutic approach efficacy. In conclusion, by gaining insights into how these molecules function and which cells they interact with, future studies can devise targeted therapies to address various neurological, immunological, and other disorders more effectively. This knowledge may pave the way for innovative treatments based on NGF manipulation aimed at improving the quality of life for individuals affected by diseases involving neurotrophins.
2022-01-06 | Darier's sign
A 38-year-old Caucasian male presented with a ten-year history of back pains, dyspepsia and allergic rhinitis and conjunctivitis treated with non-steroidal antirheumatic drugs and on-demand antihystamines. During this time, slowly progressive brownish freckles and patches on the trunk and the extremities began to occur. Because the patient was an entrepreneur with a busy working schedule, he did not pursue any further medical workup. However, due to increasing back pains, he underwent regular massages, and after these treatments, the skin on the back usually became swollen, itchy and red (Fig. 1A), necessitating the use of antihystamines. The patient was eventually referred to a dermatologist. Except for the rash, the clinical status of the patient was unremarkable. Blood counts were also normal. What is the diagnosis? The biopsy of involved skin demonstrated numerous spindle-shaped CD117+ mast cells infiltrating the dermis (Figs. 1B and 1C). Serum tryptase levels were 35 ng/mL and the c-KIT (D816V) mutation was detected by real-time polymerase chain reaction in the bone marrow, finally confirming the diagnosis of indolent systemic mastocytosis [[1]Pardanani A. Systemic mastocytosis in adults–2021 update on diagnosis, risk stratification and management.Am J Hematol. 2021; 96: 508-525Google Scholar]. Due to bone pains, the patient was additionally treated with pegylated interferon. After six months of treatment, complete resolution of back pains, rhinitis, conjunctivitis and dyspepsia was noted, with a minor regression of the skin lesions. Systemic mastocytosis is a heterogeneous disorder characterized by accumulation of the neoplastic mast cells in different organs [[1]Pardanani A. Systemic mastocytosis in adults–2021 update on diagnosis, risk stratification and management.Am J Hematol. 2021; 96: 508-525Google Scholar]. Unlike children, where mastocytosis is usually limited to the skin and can spontaneously regress, the disorder in adults is typically systemic with an almost universal involvement of the skin and bone marrow [[2]Berezowska S. Flaig M.J. Ruëff F. et al.Adult-onset mastocytosis in the skin is highly suggestive of systemic mastocytosis.Mod Pathol. 2014; 27: 19-29Google Scholar]. The Darier's sign is pathognomonic of cutaneous mastocytosis and refers to mast cell degranulation with subsequent hystamine release in parts of the skin infiltrated by mast cells. However, the Darier's sign must not be confused with other forms of dermographism where rubbing of the uninvolved skin also produces urtication. This 'mast cell activation syndrome' is also responsible for the systemic symptoms associated with the disease, such as rhinitis, conjunctivitis, dyspepsia, osteoporosis and anaphylaxis [[1]Pardanani A. Systemic mastocytosis in adults–2021 update on diagnosis, risk stratification and management.Am J Hematol. 2021; 96: 508-525Google Scholar]; therefore, when this constellation of symptoms is present, the clinicians should always remember to look for systemic mastocytosis. None. The patient provided informed consent for this report.
2021-04-30 | Protein 4.1R negatively regulates P815 cells proliferation by inhibiting C-Kit-mediated signal transduction.
The proliferation of mast cells (MCs) plays a crucial role in either physiological or pathological progression of human physical. C-Kit-mediated signaling pathway has been confirmed to play a key role in MCs proliferation, and the regulatory mechanisms of C-Kit-mediated MCs proliferation need to be further explored. Our previous study found that protein 4.1R could negatively regulate T cell receptor (TCR) mediated signal pathways in CD4+ T cells. Little is known about the function of 4.1R in C-Kit-mediated proliferation of MCs. In this study, P815-4.1R-/- cells were constructed by using CRISPR/Cas9 technique. Lack of 4.1R significantly enhanced P815 cells proliferation by accelerating the progression of cell cycle. 4.1R could also significantly alleviate the clinical symptoms of systemic mastocytosis (SM) and improve the overall survival of SM mice. Further study showed that 4.1R could interact directly with C-Kit to inhibit the activation of C-Kit-mediated Ras-Raf-MAPKs and PI3K-AKT signal pathways. Taken together, our findings demonstrate that protein 4.1R, a novel negative regulator, negatively regulates MCs proliferation by inhibiting C-Kit-mediated signal transduction, which maybe provide a potential target to the prevention and treatment of abnormal MCs proliferation-related diseases.
antibodies
2026-08-12 | Bone fragility in mastocytosis: Clinical insights from a 5-patient retrospective case series.
ObjectiveThis retrospective case series aimed to describe 36-month skeletal, biochemical, safety, and patient-reported outcomes in five postmenopausal women with mastocytosis treated with denosumab.MethodsA technical expert panel (TEP) retrospectively evaluated five consecutive eligible patients with osteoporosis associated with indolent systemic mastocytosis. All subjects underwent physiatric assessment, DXA assessment, and Mini-Osteoporosis Quality of Life (Mini-OQoL) evaluation using the validated Italian version of the questionnaire. Data collected at baseline (T0), 18 months (T1), and 36 months (T2) following initiation of denosumab 60 mg every 6 months, combined with cholecalciferol and calcium supplementation according to individual requirements, were descriptively analyzed.ResultsOver 36 months, femoral and lumbar spine T-scores showed modest improvement/stabilization. Mean femoral T-score improved from -3.9 ± 0.3 at baseline to -3.5 ± 0.3 at 36 months, while lumbar spine T-score improved from -4.3 ± 0.5 SD to -3.9 ± 0.4. Vitamin D levels normalized during follow-up, and Mini-OQoL scores improved from 54.2 ± 9 to 67.3 ± 6. However, BMD remained within the osteoporotic range and one vertebral fracture was documented at 36 months. No severe adverse events were recorded.ConclusionsIn this case series, denosumab was associated with stabilization or modest improvement of BMD and improvement in patient-reported quality of life over 36 months in women with osteoporosis secondary to indolent systemic mastocytosis. These preliminary observations should be interpreted cautiously because of the small sample size, lack of a comparator, and occurrence of one new vertebral fracture during follow-up. Thus, larger multicenter prospective studies are required.
2026-06-05 | Efficacy and safety evaluation of gilvetmab in dogs with melanoma and mast cell tumor.
Immune checkpoint inhibitors (ICIs) have transformed oncology in human medicine, providing clinical benefit in a broad spectrum of cancers. Widely available ICIs for dogs are lacking. Evaluate efficacy and safety of gilvetmab, a caninized anti-PD-1 monoclonal antibody. Fifty-one client-owned dogs were evaluated, 25 with stages II-III melanoma and 26 with stages I-III mast cell tumor (MCT). Fifteen dogs with stages III-V lymphoma were also evaluated. Multi-institutional, open-label study. Enrolled dogs were treated with gilvetmab IV at 6 mg/kg q28d or 10 mg/kg q14d; 8 dogs receiving the lower dosage underwent dose escalation with their owners' consent. Safety was evaluated by physical examinations, laboratory testing, and clinical observations made by veterinarians or the dogs' owners. Efficacy was assessed by objective response rate (ORR) and time to progression (TTP) using cRECIST v1.0 and lymphoma response criteria. For melanoma, the ORR was 20% (95% confidence interval [CI], 7%-41%) and median TTP was 56 days. For MCT, the ORR was 46% (95% CI, 27%-67%) and median TTP was not reached. No objective responses were observed in dogs with lymphoma. Serious adverse events of anaphylaxis, hypotension, or tumor hemorrhage occurred in 3 dogs (3/51, 5.9%). Tumor enlargement before regression, consistent with possible pseudoprogression, was observed in 2 dogs with melanoma. Gilvetmab has a reasonable expectation of efficacy and an acceptable preliminary safety profile in dogs with MCT stages I-III and melanoma stages II and III.
2026-04-13 | A successful treatment of urticaria pigmentosa with omalizumab in a pediatric patient: a case report.
Cutaneous mastocytosis (CM) is a rare disorder characterized by abnormal mast cell proliferation limited to the skin. Conventional treatments including antihistamines and corticosteroids often provide suboptimal symptom control, with less than 50% of patients responding adequately to H1-antihistamine therapy. Omalizumab, a humanized monoclonal antibody that inhibits immunoglobulin E (IgE) binding to mast cells, represents a promising therapeutic alternative for refractory cases. We report a 14-year-old Middle Eastern female with a 1-year history of intensely pruritic, hyperpigmented macules significantly impacting her quality of life. Physical examination revealed widespread excoriated erythematous and brown macules with positive Darier's sign. Histopathological examination showed CD117-positive mast cells, confirming CM diagnosis. Laboratory investigations were normal except for mildly elevated IgE (217 IU/mL). Conventional management with antihistamines, corticosteroids, and Montelukast provided minimal improvement, with persistent urticarial attacks requiring systemic steroid pulses. Omalizumab was initiated at 150 mg monthly subcutaneously and increased to 300 mg monthly due to relapses. Following dose optimization, the patient achieved complete symptom resolution and improved quality of life without adverse events. This represents the first documented pediatric CM case in Saudi Arabia successfully treated with omalizumab. The treatment demonstrated remarkable efficacy when conventional therapies failed, with excellent safety profile. Omalizumab may serve as a viable therapeutic alternative for pediatric patients with refractory CM. Further clinical trials are needed to establish optimal treatment protocols.
2026-03-29 | Honeybee venom immunotherapy: An Australian Centre experience over 15 years.
Honeybee venom is a leading cause of anaphylaxis, and venom immunotherapy (VIT) reduces the risk of future severe reactions to stings. To retrospectively evaluate treatment practices and outcomes of honeybee VIT (HB-VIT) in an Australian centre. Patients who underwent HB-VIT between July 2010 and July 2025 were identified, and data on demographics, Brown anaphylaxis grade, tryptase level, specific IgE, HB-VIT protocol: ultra-rush (UR) or semi-rush (SR), adverse reactions and field sting reactions during and following HB-VIT were recorded. One hundred and sixty-seven patients received HB-VIT, the majority were of male gender (n=126, 75.4%), with a median age of 48 years (IQR 36.0-59.0). Most patients had Brown Grade 2 (n=86, 51.5%) or 3 (n=71, 42.5%) anaphylaxis at index reaction. Three patients had indolent systemic mastocytosis (SM). Ninety-nine patients (59.3%) had SR protocol. UR was more common than SR among those from regional or rural residence (48 vs 18; p < 0.05). Of the 87 allergic adverse reactions (ARs) in 58 patients (34.7%), all occurred during HB-VIT buildup; large localised reactions were most frequent (n=25, 15.0%). Ten patients (6%) developed systemic allergic reactions (SARs). Omalizumab was prescribed and successful in preventing further SARs in two of these patients (one with indolent SM). There were no significant differences in frequency and severity of ARs between protocols. Thirty patients experienced field stings during or after HB-VIT completion; three (10%) developed SARs (n=3). This retrospective study demonstrates the effectiveness of HB-VIT and the tolerability of both SR and UR protocols.
2026-03-19 | Characterization of CD123 expression by mast cells in systemic mastocytosis with multicolor flow cytometry.
Systemic mastocytosis (SM) is a clonal mast cell (MC) disorder characterized by aberrant immunophenotypes, including expression of CD25, CD2, and occasionally CD30. CD123, the α-subunit of the interleukin-3 receptor, is a therapeutic target in hematologic malignancies and has been reported to be expressed on neoplastic MCs by immunohistochemistry (IHC) with prognostic implications. This study aims to characterize CD123 expression in SM by flow cytometry. We retrospectively analyzed 142 bone marrow samples from 79 SM patients (81 diagnostic samples) and 25 controls with normal MC immunophenotype. Flow cytometry was performed using a clinically validated 9-color mast cell tube which included CD123. Data collected included SM subtype, clinical and laboratory features, MC burden, and marker expression. Statistical analyses were performed in R. CD123 was expressed on MCs in 91% of SM cases (ISM 92%, SM-AHN 94%, SSM 100%, ASM 100%, MCL 50%). Median percentage of MCs positive for CD123 was 53.9% (IQR 8.1-83.4). Compared to prior IHC data (overall 64% positivity), flow cytometry demonstrated more cases with CD123 expression by MCs. No significant correlations were observed between CD123 expression and serum tryptase, KIT D816V allele burden, or MC burden. CD123 is frequently expressed on neoplastic MCs in SM by flow cytometry, across all subtypes. These findings support further investigation of CD123 as a therapeutic target and warrant correlation with IHC and clinical outcomes in larger cohorts.
other
2026-05-08 | CAR T-cells targeting CD117 effectively eliminate mast cells in preclinical models of advanced systemic mastocytosis.
Systemic mastocytosis (SM) is characterized by uncontrolled expansion of neoplastic mast cells (MCs) and their accumulation in various tissues and organs, ranging from indolent variants to more advanced forms (advSM). Although several MC- and SM-expressed cell surface antigens have been identified, no immune therapy has been developed for advSM so far. The receptor tyrosine kinase KIT (CD117) is highly expressed on MCs, exceeding the levels of expression on hematopoietic stem and progenitor cells (HSPC). Therefore, targeting CD117 in advSM could be of therapeutic value. In this study, we assessed the therapeutic potential of anti-CD117 chimeric antigen receptor (CAR) T-cells to target neoplastic MCs in SM. In vitro, anti-CD117-CAR T-cells efficiently lysed several SM-related human MC cell lines, MCs differentiated from SM patient-derived induced pluripotent stem (iPS) cells, and neoplastic bone marrow cells obtained from SM patients. Furthermore, in immunocompromised mice engrafted with an advSM-like MC cell line, repetitive applications of anti-CD117-CAR T-cells were able to inhibit MC expansion. These data may pave the way for the development of anti-CD117-CAR T-cell therapies in advSM.
2026-02-24 | A Wolf in Sheep's clothing: Mastocytosis lurking under favorable risk AML
Systemic Mastocytosis associated with hematologic neoplasms (SM-AHN) is exceedingly rare in children posing diagnostic and therapeutic challenge. We report a 5-year-old girl with AML-M2 with RUNX1::RUNX1T1 and mutations in ASXL1 and NRAS. After first cycle of chemotherapy bone marrow was in complete remission but revealed the mast cell aggregates confirming SM-AHN. She had inadequate log reduction of RUNX1::RUNXITI fusion transcript and persisting mast cell aggregates even after 3 cycles of chemotherapy. Hence she was upstaged to high risk and underwent HLA haploidentical hematopoietic stem cell transplantation (HSCT). After two years from allogenic HSCT she remained in complete remission with 4.8-log reduction in RUNX1::RUNX1T1 fusion transcripts and complete clearance of mast cells. Identification of SM-AHN is crucial and allogeneic HSCT offers potential cure. Molecular detection of RUNXI::RUNXIT1 fusion transcripts is essential for monitoring therapy response, screening early relapse and pre-emptive therapeutic decisions. • Underlying Mast cells can be masked by the blasts at diagnosis of Acute Myeloid Leukemia that can be spotted out by detailed immunophenotyping • Early therapy intensification is mandatory in AML associated with Mastocytosis even when associated with good risk genetics • Following log reduction in real time PCR of RUNX1::RUNX1T1 fusion transcript helps identify response to therapy and early relapse.
2025-09-23 | Allogeneic haematopoietic cell transplantation in advanced systemic mastocytosis in the new era: A CIBMTR study.
We investigated the outcomes of patients with advanced systemic mastocytosis (AdvSM) undergoing allogeneic haematopoietic cell therapy (alloHCT) in the US. Twenty-seven adult (median age, 58 years) patients with AdvSM received alloHCT from 2014 to 2021. Most patients were white (93%), male (63%) and had systemic mastocytosis (SM) with associated haematological neoplasm (SM-AHN, 70%), received peripheral blood grafts (89%) and non-myeloablative regimens. KIT mutation was detected in 14 of the reported 16 patients (87.5%). Post-transplantation cyclophosphamide (PTCy) was used in approximately 50% of the cohort. Approximately 1 year after alloHCT, median bone marrow mast cell burden decreased from 15% pre-alloHCT to 1.5% (range 0-8) at 1 year post-alloHCT. The median serum tryptase decreased from 55 ng/mL (range 3-400 ng/mL) pre-alloHCT to 18 ng/mL (range 0-481 ng/mL) at 1 year post-alloHCT. At 1 year, progression-free survival (PFS) and overall survival (OS) were 59% (95% confidence interval [CI], 41%-77%) and 74% (95% CI, 56%-89%) respectively. In the subset of patients with SM-AHN, 1-year PFS and OS were 74% (52%-91%) and 79% (95% CI, 58%-94%) respectively. The cumulative incidence of relapse/progression for the entire population of patients with SM (n = 27) was 4% (95% CI, 0-14) at 100 days and 15% (95% CI, 4-31) at 1 year. For the subset of patients with AHN, the cumulative incidence was 11% (95% CI, 1-28) at 100 days and 21% (95% CI, 6-42) at 1 year. Relapse/progression was the cause of death in six of 12 patients (5 died of AHN and 1 died of SM progression). Eighteen and nine patients received a KIT inhibitor before alloHCT and after alloHCT respectively. In addition, six patients received a KIT inhibitor for the treatment of relapse/progression of SM after alloHCT. Although it is difficult to delineate the exact effect of alloHCT and KIT inhibitors because of the size of the study in this era, the use of alloHCT and KIT inhibitors pre- and post- alloHCT is increasing. In the near future, larger studies are required to provide further insights into this subject.
2025-03-07 | Establishment and characterisation of a novel canine mast cell tumour cell line (C18).
Mast cell tumour (MCT) is a life-threatening neoplasm commonly found in dogs worldwide. The outcome of treatment for dogs with cutaneous MCT is currently poor, mainly because of the tumour's aggressiveness and the heterogeneity in tumour behaviour. This study established a novel canine MCT cell line and compared with three reference canine MCT cell lines (CMMC, VIMC and CoMS) in terms of their characteristics and tumour sensitivity to immune cell-mediated cytotoxicity. Of 18 MCT samples, only one cell line derived from high grade cutaneous MCT was established and referred to as C18 cell line. The C18 cell line could be maintained for over 100 passages while they still exhibited c-kit, tryptase, FcεRIα and FcεRIβ expression. The C18 had the longest doubling time and smallest tumour spheroid size when compared to the other three reference cell lines. The C18 also had c-kit internal tandem duplication (ITD) in exon 11 and nine single nucleotide polymorphisms (SNPs) in five genes, namely c-kit, HYAL4, SEL1L, SPAM1 and TRAF3. For a comparison of tumour sensitivity to immune cell-mediated cytotoxicity, the percentages of early and total apoptotic cells were significantly increased in all four cell lines. However, the percentages of viable cells were significantly decreased only in C18. In conclusion, a novel canine cutaneous MCT cell line was successfully established, in terms of its characteristics, growth behavior and interaction with PBMCs. The C18 cell line holds a potential promise for advancing studies and developing new therapeutic strategies.
2024-04-08 | Allogeneic haematopoietic cell transplantation for advanced systemic mastocytosis: Best practice recommendations on behalf of the EBMT Practice Harmonisation and Guidelines Committee.
Systemic Mastocytosis (SM) is a multifaceted clinically heterogeneous disease. Advanced SM (AdvSM) comprises three entities: aggressive SM (ASM), mast cell leukaemia (MCL) and SM with an associated hematologic neoplasm (SM-AHN), the latter accounting for 60-70% of all AdvSM cases. Detection of a disease-triggering mutation in the KIT gene (esp. KIT D816V) in >90% of the patients with ASM or SM-AHN has led to a significant improvement in therapeutic options by the implementation of two KIT-targeting kinase inhibitors: midostaurin and avapritinib. Although complete remissions have been reported, neither of these targeted agents is 'curative' in all patients and the duration of responses varies. The median overall survival, depending on the WHO subtype and scoring result, is approximately 1 to 4 years. Although the European Competence Network on Mastocytosis (ECNM) and American Initiative in Mast Cell Diseases (AIM) consensus groups recommend allogeneic haematopoietic cell transplantation (allo-HCT) in drug-resistant and other high-risk patients, there is a relative lack of information to guide clinicians on which patients with AdvSM should be considered for transplant, and how KIT inhibitors may fit into the transplant algorithm, including their use pre- and post-transplant to optimise outcomes. Following the generation of an expert panel with a specialist interest in allo-HCT and mastocytosis, these best practice recommendations were generated according to the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonisation and guidelines and ECNM methodology. We aim to provide a practical, clinically relevant and up-to-date framework to guide allo-HCT in AdvsM in 2024 and beyond.
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Drug Discovery Landscape
21 orphan drug designations for Mastocytosis, including 5 approved therapies.
21 orphan drug designations for Mastocytosis, including 5 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Bezuclastinib | small molecules | EMA | 2025-06-20 | — | FGK Representative Service GmbH |
highly selective inhibitor of the tyrosine kinase BTK | small molecules | FDA | 2025-02-25 | — | Telios Pharma, Inc. |
2-{4-[4-(4-{5-[(1S)-1-amino-1-(4-fluorophenyl) ethyl]pyrimidin-2-yl}piperazin-1-yl)pyrrolo[2,1-f] [1,2,4]triazin-6-yl]-1H-pyrazol-1-yl}ethan-1-ol | small molecules | EMA | 2023-04-21 | — | Blueprint Medicines (Netherlands) B.V. |
bezuclastinib | small molecules | FDA | 2023-03-17 | — | Cogent Biosciences, Inc. |
Selective KIT Inhibitor | small molecules | FDA | 2022-07-01 | — | Blueprint Medicines |
c-KIT-targeting, dendrimer-linked phosphorodiamidate morpholino oligonucleotide | oligonucleotides | FDA | 2022-03-10 | — | Hoth Therapeutics, Inc |
humanized non-fucosylated anti-Siglec-8 monoclonal antibody (IgG1) | antibodies | FDA | 2019-07-15 | — | Allakos Inc. |
Avapritinib [AYVAKYT] | small molecules | EMA | 2018-10-26 | 2022-03-25 | Blueprint Medicines (Netherlands) B.V. |
humanized IgG1 low affinity allergic reactivity inhibiting (LARI) monoclonal antibody | antibodies | FDA | 2018-02-15 | — | Sixal Inc. |
Lirentelimab | antibodies | EMA | 2017-10-16 | — | Turnkey Pharmaconsulting Ireland Limited |
avapritinib [Ayvakit] | small molecules | FDA | 2016-01-21 | 2021-06-16 | Blueprint Medicines Corporation |
cromolyn sodium for inhalation | small molecules | FDA | 2015-12-09 | — | Patara Pharma, LLC |
ketotifen | small molecules | FDA | 2015-02-25 | — | Valcrest Pharmaceuticals, LLC |
Recombinant human diamine oxidase | proteins | EMA | 2014-08-22 | — | Medical University of Vienna |
Cladribine | small molecules | EMA | 2013-08-05 | — | Lipomed GmbH |
Midostaurin [Rydapt] | small molecules | EMA | 2010-08-04 | 2017-09-20 | Novartis Europharm Limited |
midostaurin [Rydapt] | small molecules | FDA | 2010-04-30 | 2017-04-28 | Novartis Pharmaceuticals Corporation |
masitinib | small molecules | FDA | 2005-09-14 | — | AB Science |
Imatinib mesilate [Glivec] | small molecules | EMA | 2005-08-26 | — | Novartis Europharm Limited |
N-(methyl-diazacyclohexyl-methylbenzamide)-azaphenyl-aminothiopyrrole | small molecules | EMA | 2004-11-16 | — | AB Science S.A. |
Cromolyn sodium [Gastrocrom] | small molecules | FDA | 1984-03-08 | 1989-12-22 | Fisons Corporation |
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