small molecules

2026-08-24 | Diffuse osteosclerosis in a patient with systemic mastocytosis.

Osteosclerosis refers to an abnormal increase in bone density resulting from excessive bone formation and/or reduced bone resorption. We present a case of a 31-year-old woman with acute-on-chronic abdominal pain, flushing, and diarrhea. Diffuse, mottled sclerosis involving the entire axial and appendicular skeleton was incidentally identified on imaging. Diagnostic investigations for osteosclerosis revealed a raised tryptase, leading to a bone marrow and trephine analysis. This demonstrated abnormally spindle-shaped mast cells, more than 15 in a group, with positive staining for tryptase which was consistent with systemic mastocytosis (SM). In the absence of "C" findings, a diagnosis of indolent SM complicated by diffuse osteosclerosis was made. Treatment with a histamine type-2 receptor antagonist provided mild symptomatic relief. In this report, we discuss the differential causes of osteosclerosis and the pathogenesis of bone manifestations related to SM, along with subtype-specific SM treatment options.

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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.

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2026-07-23 | Case Report: aleukemic mast cell leukemia with KIT p.V559G mutation, CD25-negative immunophenotype, and complex karyotype.

Mast cell leukemia (MCL), the most aggressive and often fatal subtype of systemic mastocytosis, is predominantly driven by KIT mutations, with the KIT p.D816V mutation being the most prevalent. Rare noncanonical KIT mutations remain poorly characterized, particularly when combined with a CD25-negative immunophenotype and high-risk cytogenetics. Through this case report, we aimed to enrich the molecular spectrum of MCL, emphasize the value of integrated diagnosis, and provide a reference for individualized treatment of older patients with high-risk MCL. This case involves an 81-year-old woman, with aleukemic MCL, who presented with dizziness and back pain. Severe pancytopenia was present, with 3% of atypical mast cells in the peripheral blood and 69.5% of abnormal mast cells in the bone marrow. Flow cytometry revealed a unique CD117bri, CD9bri, CD203c+, CD2+, CD25-, and HLA-DR- immunophenotypes. Karyotyping revealed complex clonal abnormalities, including monosomy 7. Next-generation sequencing identified a rare activating KIT p.V559G mutation (variant allele frequency, 42%), which is uncommon in MCL. Despite advanced age, life-threatening complications (sepsis, gastrointestinal bleeding, and myocardial infarction), and dismal prognostic features, the patient achieved clinical improvement with partial hematologic recovery on low-dose imatinib plus intensive supportive care and remained stable without evidence of disease progression during a four month follow-up period. This case represents a rare instance of aleukemic MCL cases with a KIT p.V559G mutation, CD25 negativity, and a complex karyotype, underscoring the importance of a comprehensive diagnostic workup and expands the clinical and molecular spectrum of MCL. Individualized low-intensity targeted therapy may offer short-term disease control in older patients with high-risk MCL, though long-term survival benefit remains unproven.

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2026-07-07 | 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.

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2026-06-29 | Hidden in Plain Sight: Systemic Mastocytosis Manifesting as Isolated Hepatosplenomegaly in the Absence of Cutaneous and Classical Manifestations-A Case Report and Literature Review.

Systemic mastocytosis (SM) is a rare clonal myeloproliferative neoplasm typically characterized by cutaneous lesions and mediator-release symptoms. Presentations dominated by visceral organ involvement without skin findings are uncommon and pose a significant diagnostic challenge, often mimicking hematologic malignancies. We report a 50-year-old male presenting with generalized weakness, fatigue, and progressive abdominal distension. Examination revealed significant hepatosplenomegaly with no cutaneous manifestations. Investigations demonstrated severe leukocytosis (peak WBC 112.8 × 103/μL) with a leucoerythroblastic picture, persistently elevated alkaline phosphatase, and anemia. Initial bone marrow morphology suggested chronic myeloid leukemia (CML), showing marked hypercellularity (95-100%) and granulocytic hyperplasia (M:E ratio 32:1). Cytogenetics revealed a normal male karyotype (46, XY), and BCR-ABL1 testing was negative, excluding CML. Comprehensive molecular profiling identified a pathogenic KIT p.D816V mutation, confirming systemic mastocytosis with an associated hematologic neoplasm (SM-AHN). The patient was treated with cladribine (40 mg over five days) followed by maintenance hydroxyurea (300 mg twice daily), with significant clinical improvement at eight-week follow-up. This case underscores that SM-AHN can present with isolated hepatosplenomegaly and profound leukocytosis without cutaneous signs, and highlights the critical role of integrated molecular profiling, including KIT mutation analysis, in the diagnostic workup of atypical hematologic presentations.

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antibodies

2026-09-29 | The SCF/KIT signaling pathway in multisystem diseases: Mechanisms and therapeutic targeting.

The stem cell factor (SCF)/KIT signaling axis regulates the survival, proliferation, differentiation, and migration of hematopoietic stem and progenitor cells, mast cells, interstitial cells of Cajal, germ cells, and melanocytes through multiple downstream pathways, including PI3K/AKT and RAS/MAPK. Its biological and pathological effects are determined by cell lineage, ligand presentation, and mutational context. At the pathway level, SCF expression and processing, KIT abundance, and activating mutations determine signal initiation and intensity, whereas CBL-mediated receptor degradation and SHP-1-mediated dephosphorylation limit signal duration. This narrative review critically examines representative multisystem diseases for which SCF/KIT involvement is supported by genetic, functional, or therapeutic evidence and distinguishes established treatments from investigational approaches. Activating KIT mutations drive gastrointestinal stromal tumors (GISTs) and systemic mastocytosis. Clinically established KIT-directed tyrosine kinase inhibitors, including imatinib for mutation-sensitive GIST and midostaurin or avapritinib for advanced systemic mastocytosis, have transformed disease management. By contrast, increased local SCF availability and KIT-dependent mast cell persistence may amplify inflammatory diseases, whereas impaired signaling is associated with gastrointestinal dysmotility, reproductive dysfunction, and pigmentary abnormalities. Emerging anti-KIT antibodies are being investigated as a strategy to deplete mast cells in chronic urticaria, whereas recombinant SCF-based mobilization has largely historical clinical relevance and regenerative applications remain experimental. Mutation-dependent drug sensitivity, polyclonal secondary resistance, multikinase-related toxicity, and on-target effects in normal KIT-dependent tissues remain major challenges. A disease-, genotype-, and cell-specific framework is therefore essential for translating SCF/KIT biology into safe and effective precision therapies.

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2026-09-26 | The Clinical and Molecular Characteristics of Systemic Mastocytosis with Associated Non-Mast Cell Myeloid Neoplasm.

Background: Systemic mastocytosis (SM) with associated non-mast cell myeloid neoplasm is a rare condition, defined by the presence of both SM and a clonal non-mast cell neoplasm. Due to its rarity, the demographic and molecular characteristics are poorly understood. This study investigated seven patients diagnosed with this condition at our institution. Methods: Our institutional database was searched for "systemic mastocytosis" from 1 January 2020, to 31 December 2025. Each case was annotated to identify the primary cohort of this study, systemic mastocytosis with associated non-mast cell myeloid neoplasm (SM-AHN). Demographic characteristics, outcome, hematologic features at diagnosis, cytogenetics, and molecular characteristics were annotated. Eight cases of isolated SM diagnosed during the same period were also analyzed for comparison. All patients in the database were followed until their death or until 31 December 2025. All data were exported to SPSS v. 28 (IBM, Armonk, NY, USA®). Results: A total of seven patients were diagnosed with SM-AHN. Compared to isolated SM, SM-AHN patients showed older age at presentation, poorer hematologic values (increased anemia and thrombocytopenia), higher mutational burden, and poorer outcomes. KIT mutations were most common, predominantly D816V, with other variants like D816Y and L576F also observed. Additional frequent mutations included DNMT3A, TET2, ASXL1, SF3B1, EZH2, JAK2, NRAS, and SRSF2. Conclusions: Our findings, though limited by a small sample size, suggest that SM with associated myeloid neoplasm presents with distinct clinical and molecular features compared to isolated SM. This combined disorder is associated with older age, worse hematologic parameters, a higher mutational burden, and poorer prognosis. The frequent co-occurrence of mutations in other genes, in addition to KIT mutations, highlights the complex molecular landscape.

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2026-09-04 | Barzolvolimab blocks stem cell factor-enhanced IgE activation without inducing apoptosis in KITD816V mast cells.

KITD816V drives constitutive mast cell (MC) signaling and is central to the pathogenesis of clonal MC activation disorders, including systemic mastocytosis. These conditions may present with severe anaphylaxis despite low KITD816V mutation burden. Because neoplastic MCs may coexpress mutant and wild-type (WT) KIT, the functional relevance of ligand-dependent signaling and activation remains incompletely understood. Barzolvolimab has demonstrated efficacy in WT MC-driven diseases, but its effects on KIT-mutated MCs remain unclear. We assessed the effects of barzolvolimab on KITD816V-mutated MCs. We established and characterized primary-like human MC models, including isogenic human induced pluripotent stem cell-derived WT and heterozygous KITD816V MCs, peripheral CD34+ stem cell-derived MCs, and HMC-1.2 cell line. Barzolvolimab effects on apoptosis, KIT signaling, and IgE-mediated activation were investigated by flow cytometry, Western blot analysis, and functional degranulation assays. Barzolvolimab induced dose-dependent apoptosis and inhibited stem cell factor-induced KIT signaling in WT MCs, but it had no effect on mutant MC viability or signaling. Notably, barzolvolimab effectively suppressed stem cell factor-enhanced IgE-mediated MC activation across all primary-like models, including KITD816V MCs, as evidenced by reduced β-hexosaminidase release and CD63 expression. This inhibitory effect occurred at low nanomolar concentrations and was independent of cytotoxicity. A functional dissociation between KIT-dependent survival and activation pathways occurs in mutated MCs. Barzolvolimab does not reduce the viability of KIT-mutated MCs, but it effectively suppresses stem cell factor-dependent amplification of IgE-mediated activation, thus supporting its potential as a therapeutic option for symptomatic patients harboring KIT mutations, particularly for the control of mediator-related symptoms.

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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.

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2026-08-01 | EP239 - ECE_2410 - Coexisting causes of secondary osteoporosis: systemic mastocytosis and partial hypogonadism in a male patient with Y-chromosome mosaicism

Abstract Introduction Osteoporosis is a global health problem. Among men with osteoporosis, 50%-80% have secondary osteoporosis, which is frequently under-recognized. Male hypogonadism may represent a cause of secondary osteoporosis. Systemic mastocytosis is another uncommon but clinically significant cause and may present with severe skeletal involvement. We report a patient with known hypogonadism in whom the assessment for secondary osteoporosis revealed systemic mastocytosis. Case presentation A 62-year-old man with a medical history οf hypertension, nephrolithiasis, previous knee arthroplasty and Y chromosome mosaicism presented with acute back pain following minimal trauma after lifting a 15-kg weight. Cytogenetic investigation due to azoospermia revealed a rare mosaic karyotype pattern of 45,X/46,XY/ 47,XY, +mar (Y). The molecular analysis of Y-chromosome markers (DYS1, DYS222, DAZ) confirmed loss of Y chromosomal material. He had previously received testosterone replacement therapy during puberty. The imaging revealed a vertebral fracture at L1 and kyphoplasty was performed. Nine days later, he experienced sudden back pain and further imaging demonstrated new vertebral fractures at T12, L4, and L5. Thus, he underwent an additional kyphoplasty. Given the occurrence of multiple low-trauma vertebral fractures, the patient was evaluated for secondary causes of osteoporosis other than his partial hypogonadism (testosterone levels = 2.33 ng/ml (normal range: 1.93-7.40)). The workup revealed elevated serum tryptase levels (34.9 μg/L) and hypothyroidism. The patient underwent a bone marrow biopsy, which together with serum tryptase levels, confirmed the diagnosis of systemic mastocytosis. Treatment with levothyroxine, and midostaurin was initiated. Although bisphosphonates remain the cornerstone of therapy for mastocytosis-associated osteoporosis, the patient expressed significant concern regarding the risk of acute phase reactions when informed of bisphosphonates’ side effects. Therefore, denosumab therapy was initiated, considering evidence suggesting it may also reduce serum tryptase levels. New bone mineral density measurements will be evaluated in February 2026, one year after the treatment initiation. Conclusions This case highlights the importance of investigating secondary causes of osteoporosis in patients presenting with osteoporosis, as more than one contributing factors may coexist.

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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.

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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.

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2022-03-31 | Human diamine oxidase cellular binding and internalization in vitro and rapid clearance in vivo are not mediated by N-glycans but by heparan sulfate proteoglycan interactions.

Human diamine oxidase (hDAO) rapidly inactivates histamine by deamination. No pharmacokinetic data are available to better understand its potential as a new therapeutic modality for diseases with excess local and systemic histamine, like anaphylaxis, urticaria or mastocytosis. After intravenous administration of recombinant hDAO to rats and mice, more than 90% of the dose disappeared from the plasma pool within 10 min. Human DAO did not only bind to various endothelial and epithelial cell lines in vitro, but was also unexpectedly internalized and visible in granule-like structures. The uptake of rhDAO into cells was dependent on neither the asialoglycoprotein-receptor (ASGP-R) nor the mannose receptor (MR) recognizing terminal galactose or mannose residues, respectively. Competition experiments with ASGP-R and MR ligands did not block internalization in vitro or rapid clearance in vivo. The lack of involvement of N-glycans was confirmed by testing various glycosylation mutants. High but not low molecular weight heparin strongly reduced the internalization of rhDAO in HepG2 cells and HUVECs. Human DAO was readily internalized by CHO-K1 cells, but not by the glycosaminoglycan- and heparan sulfate-deficient CHO cell lines pgsA-745 and pgsD-677, respectively. A docked heparin hexasaccharide interacted well with the predicted heparin binding site 568RFKRKLPK575. These results strongly imply that rhDAO clearance in vivo and cellular uptake in vitro is independent of N-glycan interactions with the classical clearance receptors ASGP-R and MR, but is mediated by binding to heparan sulfate proteoglycans followed by internalization via an unknown receptor.

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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.

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2021-12-21 | Metabolome and lipidome derangements during a severe mast cell activation event in a patient with indolent systemic mastocytosis.

The number of mast cells in various organs is elevated manifold in individuals with systemic mastocytosis. Degranulation can lead to life-threatening symptomatology. No data about the alterations of the metabolome and lipidome during an attack have been published. Our aim was to analyze changes in metabolomics and lipidomics during the acute phase of a severe mast cell activation event. A total of 43 metabolites and 11 lipid classes comprising 200 subvariants from multiple plasma samples in duplicate, covering 72 hours of a severe mast cell activation attack with nausea and vomiting, were compared with 2 baseline samples by using quantitative liquid chromatography-mass spectrometry. A strong enterocyte dysfunction reflected in an almost 20-fold reduction in the functional small bowel length was extrapolated from strongly reduced ornithine and citrulline concentrations and was very likely secondary to severe endothelial cell dysfunction with hypoperfusion and extensive vascular leakage. Highly increased histamine and lactate concentrations accompanied the peak in clinical symptoms. Elevated asymmetric and symmetric dimethylarginine levels combined with reduced arginine levels compromised endothelial nitric oxide synthase activity and nitric oxide signaling. Specific and extensive depletion of many lysophosphatidylcholine variants indicates localized autotaxin activation and lysophosphatidic acid release. A strong correlation of clinical parameters with histamine concentrations and symptom reduction after 100-fold elevated plasma diamine oxidase concentrations implies that histamine is the key driver of the acute phase. Rapid elimination of elevated histamine concentrations through use of recombinant human diamine oxidase, supplementation of lysophosphatidylcholine for immunomodulation, inhibition of autotaxin activity, and/or blockade of lysophosphatidic acid receptors might represent new treatment options for life-threatening mast cell activation events.

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cell therapies

2026-08-21 | Subtype-specific outcome after allogeneic hematopoietic cell transplantation in advanced systemic mastocytosis: a registry study of the European competence network on mastocytosis.

Advanced systemic mastocytosis (AdvSM), comprising aggressive systemic mastocytosis, mast cell leukemia, and systemic mastocytosis with an associated hematological neoplasm, is a heterogeneous myeloid neoplasm with poor prognosis. Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only potentially curative treatment, yet its benefit across AdvSM subtypes in the era of KIT-targeted tyrosine kinase inhibitors (TKIs) such as midostaurin and avapritinib remains unclear. To identify patient subgroups benefiting from allo-HCT and to define prognostic factors for post-transplant survival, we analyzed 631 AdvSM patients from the European Competence Network on Mastocytosis registry, including 69 who underwent allo-HCT. Treatment effects were assessed using time-dependent Cox regression in a transplant-eligible complete-case cohort (n = 419). In this cohort, allo-HCT showed no overall survival (OS) benefit (hazard ratio [HR] 1.21, 95% CI 0.80-1.84; p = 0.37), whereas TKI response emerged as a strong independent predictor of survival (HR 0.42; p<0.001). Subtype-stratified analysis revealed an allo-HCT benefit exclusively in patients with systemic mastocytosis associated with acute myeloid leukemia (n = 30; HR 0.20; p = 0.020). Among the 69 transplanted patients, median OS was 49.6 months with 2-year and 5-year survival of 63% and 46%, respectively. The International Prognostic Scoring System for Mastocytosis (IPSM) at transplantation independently predicted both OS (HR per category 1.68; p = 0.026) and progression-free survival (HR 1.99; p = 0.003), whereas the Mutation-Adjusted Risk Score and diagnostic subtype did not reach statistical significance. Competing risk analysis demonstrated that higher IPSM captured both relapse-related and transplant-related mortality. These findings suggest that the survival benefit of allo-HCT in AdvSM is driven primarily by control of the associated myeloid neoplasm. Accordingly, allo-HCT should be prioritized in patients with SM-AML, whereas TKI-directed strategies may be preferred in other subtypes, with IPSM at transplantation potentially guiding transplant selection and timing.

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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.

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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.

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2025-06-18 | Different clearance of KITD816V mutation and tryptase levels after haematopoietic cell transplantation in patients with systemic mastocytosis with associated haematological neoplasm.

The patterns of tryptase normalization, KITD816V clearance and establishment of donor cell chimerism were analysed in 13 patients with systemic mastocytosis and associated haematological neoplasm (AHN) after haematopoietic cell transplantation (HCT). The molecular marker of systemic mastocytosis (SM) (KITD816V) simultaneously disappeared (median + 36 days) with the establishment of donor chimerism (median: +31 days post-HCT; Pearson correlation: -0.99, p < 0.001). In contrast, tryptase normalized median of +228 days after HCT with significant delay to KITD816V clearance (p = 0.01) and full donor chimerism (p = 0.04). Faster normalization was observed after radiation-based conditioning and removal of an infiltrated spleen, while persistence was not associated with relapse of AHN.

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2024-03-06 | Allogeneic Hematopoietic Cell Transplantation in Advanced Systemic Mastocytosis: A retrospective analysis of the DRST and GREM registries

Abstract We identified 71 patients with AdvSM (aggressive SM [ASM], SM with an associated hematologic neoplasm [SM-AHN, e.g., acute myeloid leukemia, SM-AML], mast cell leukemia [MCL]) in two national registries (DRST/GREM) who received an allogeneic hematopoietic cell transplantation (alloHCT) performed in Germany from 1999–2021. Median overall survival (OS) of ASM/SM-AHN ( n = 30, 45%), SM-AML ( n = 28, 39%) and MCL ± AHN ( n = 13, 19%) was 9.0, 3.3 and 0.9 years ( P = 0.007). Improved median OS was associated with response of SM (17/41, 41%; HR 0.4 [0.2–0.9], P = 0.035) and/or of AHN (26/43, 60%, HR 0.3 [0.1–0.7], P = 0.004) prior to alloHCT. Adverse predictors for OS included absence of KIT D816V (10/61, 16%, HR 2.9 [1.2–6.5], P < 0.001) and a complex karyotype (9/60, 15%, HR 4.2 [1.8–10.0], P = 0.016). HLA-match, conditioning type or transplantation at centers reporting above-average alloHCTs (≥7) had no impact on OS. Taking into account competing events at years 1, 3 and 5, relapse-related mortality and non-relapse mortality rate were 15%/23%, 20%/30% and 23%/35%, respectively. Irrespective of subtype, subsequent treatment response was achieved in 13/30 (43%) patients and was highest on midostaurin/avapritinib (7/9, 78%). We conclude that outcome of alloHCT in AdvSM is more affected by disease phenotype and treatment response prior to transplant than by transplant characteristics.

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2025-07-17 | Repeated anaphylactic shocks during bee venom immunotherapy and successful continuation of treatment after vaccine change

The study aims to investigate potential causes of repeated anaphylactic reactions during immunotherapy and to analyze possible measures to be taken in such a situation. The reported patient experienced an anaphylactic reaction after taking a maintenance dose of immunotherapy. Despite changing the antihypertensive drug from an angiotensin-converting-enzyme inhibitor, during an attempt to restart immunotherapy, another anaphylactic reaction occurred. Systemic mastocytosis was excluded. Implementing immunotherapy with a different vaccine was successful. In the case of generalized anaphylactic reactions occurring during immunotherapy, it is advisable to analyze what other drugs the patient is taking and, if suspected, perform testing for systemic mastocytosis. The tolerance of the second vaccine may have been due to the presence of an aluminum hydroxide adjuvant, which allows for a slower release of the allergen. In some cases, changing the immunotherapy vaccine may be crucial due to potential sensitivity to non-venom components.

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2023-01-31 | The exon-skipping oligonucleotide, KitStop, depletes tissue-resident mast cells in vivo to ameliorate anaphylaxis

Introduction Anaphylaxis represents the most extreme and life-threatening form of allergic disease and is considered a medical emergency requiring immediate intervention. Additionally, some people with mastocytosis experience recurrent episodes of anaphylaxis during normal daily activities without exposure to known triggers. While acute therapy consists primarily of epinephrine and supportive care, chronic therapy relies mostly on desensitization and immunotherapy against the offending allergen, which is a time-consuming and sometimes unsuccessful process. These treatments also necessitate identification of the triggering allergen which is not always possible, and thus highlighting a need for alternative treatments for mast cell-mediated diseases. Methods The exon-skipping oligonucleotide KitStop was administered to mice intradermally, intraperitoneally, or systemically at a dose of 12.5 mg/kg. Local mast cell numbers were enumerated via peritoneal lavage or skin histology, and passive systemic anaphylaxis was induced to evaluate KitStop’s global systemic effect. A complete blood count and biochemistry panel were performed to assess the risk of acute toxicity following KitStop administration. Results Here, we report the use of an exon-skipping oligonucleotide, which we have previously termed KitStop, to safely reduce the severity and duration of the anaphylactic response via mast cell depopulation in tissues. KitStop administration results in the integration of a premature stop codon within the mRNA transcript of the KIT receptor—a receptor tyrosine kinase found primarily on mast cells and whose gain-of-function mutation can lead to systemic mastocytosis. Following either local or systemic KitStop treatment, mice had significantly reduced mast cell numbers in the skin and peritoneum. In addition, KitStop-treated mice experienced a significantly diminished anaphylactic response using a model of passive systemic anaphylaxis when compared with control mice. Discussion KitStop treatment results in a significant reduction in systemic mast cell responses, thus offering the potential to serve as a powerful additional treatment modality for patients that suffer from anaphylaxis.

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2022-04-07 | Targeting KIT by frameshifting mRNA transcripts as a therapeutic strategy for aggressive mast cell neoplasms.

Activating mutations in c-KIT are associated with the mast cell (MC) clonal disorders cutaneous mastocytosis and systemic mastocytosis and its variants, including aggressive systemic mastocytosis, MC leukemia, and MC sarcoma. Currently, therapies inhibiting KIT signaling are a leading strategy to treat MC proliferative disorders. However, these approaches may have off-target effects, and in some patients, complete remission or improved survival time cannot be achieved. These limitations led us to develop an approach using chemically stable exon skipping oligonucleotides (ESOs) that induce exon skipping of precursor (pre-)mRNA to alter gene splicing and introduce a frameshift into mature KIT mRNA transcripts. The result of this alternate approach results in marked downregulation of KIT expression, diminished KIT signaling, inhibition of MC proliferation, and rapid induction of apoptosis in neoplastic HMC-1.2 MCs. We demonstrate that in vivo administration of KIT targeting ESOs significantly inhibits tumor growth and systemic organ infiltration using both an allograft mastocytosis model and a humanized xenograft MC tumor model. We propose that our innovative approach, which employs well-tolerated, chemically stable oligonucleotides to target KIT expression through unconventional pathways, has potential as a KIT-targeted therapeutic alone, or in combination with agents that target KIT signaling, in the treatment of KIT-associated malignancies.

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2021-06-01 | 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.

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2011-01-28 | KIT signaling regulates MITF expression through miRNAs in normal and malignant mast cell proliferation

Abstract Activating mutations in codon D816 of the tyrosine kinase receptor, KIT, are found in the majority of patients with systemic mastocytosis. We found that the transcription factor, microphthalmia-associated transcription factor (MITF), is highly expressed in bone marrow biopsies from 9 of 10 patients with systemic mastocytosis and activating c-KIT mutations. In primary and transformed mast cells, we show that KIT signaling markedly up-regulates MITF protein. We demonstrate that MITF is required for the proliferative phenotype by inhibiting colony-forming units with sh-RNA knockdown of MITF. Furthermore, constitutively active KIT does not restore growth of primary MITF-deficient mast cells. MITF mRNA levels do not change significantly with KIT signaling, suggesting posttranscriptional regulation. An array screen from mast cells identified candidate miRNAs regulated by KIT signaling. We found that miR-539 and miR-381 are down-regulated by KIT signaling and they repressed MITF expression through conserved miRNA binding sites in the MITF 3′-untranslated region. Forced expression of these miRNAs suppressed MITF protein and inhibited colony-forming capacity of mastocytosis cell lines. This work demonstrates a novel regulatory pathway between 2 critical mast cell factors, KIT and MITF, mediated by miRNAs; dysregulation of this pathway may contribute to abnormal mast cell proliferation and malignant mast cell diseases.

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