RARE DISEASE
Systemic mastocytosis
Systemic mastocytosis
Systemic mastocytosis
Drug discovery
1
drug
With orphan designation
Overview
Systemic mastocytosis (SM) is a rare myeloproliferative disorder driven by KIT mutations (often D816V), causing pathological mast cell accumulation in tissues like bone marrow, skin, and gastrointestinal organs. Diagnosis requires bone marrow biopsy demonstrating mast cell clusters with CD25/CD2 co-expression and elevated serum tryptase (>20 ng/mL) [1][11]. Clinical manifestations range from indolent subtypes (urticaria pigmentosa, mediator-related symptoms) to aggressive forms with organ dysfunction [1][16]. Anaphylaxis risk is elevated, particularly with hypotension [5][11].
Population
Prevalence: 13.94–27.43 per 100,000 adults, with indolent SM (ISM) comprising 48–82% of cases [2][7][16].
Median age at diagnosis: 49 years (ISM); advanced subtypes (e.g., aggressive SM) occur in older adults (median ~67 years) [2][7].
Predominantly affects Caucasians; slight female predominance overall, but males are overrepresented in advanced subtypes [2][7][17].
Burden
Median 14 symptoms/patient (fatigue, GI distress, bone pain), with 30% experiencing ER visits for anaphylaxis annually [4][9].
ISM patients report SF-12 scores below population norms (Physical: 46.7; Mental: 47.6 vs. 50) [9].
Diagnostic delays average >5 years; 18% progress from indolent to advanced SM over ~7 years [6][14].
Therapies
Symptom control: H1/H2 antihistamines, leukotriene inhibitors, cromolyn sodium; epinephrine for anaphylaxis [3][13][18].
Advanced disease: Tyrosine kinase inhibitors (midostaurin: 50–75% response; avapritinib: 75–100% response) [3][13]. Bisphosphonates for osteoporosis [13][18].
Emerging therapies: Omalizumab for IgE-mediated anaphylaxis (84% efficacy in symptom reduction) [3][5].
Categories: rare hematological diseases, rare neoplastic diseases
Research Papers
953 drug discovery papers about Systemic mastocytosis, with 4 first-in-class and 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
953 drug discovery papers about Systemic mastocytosis, with 4 first-in-class and 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
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.
2026-08-02 | 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.
2026-07-23 | 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.
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.
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.
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.
2026-08-02 | 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.
2026-07-23 | 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.
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.
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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for Systemic mastocytosis, including 1 approved therapy.
1 orphan drug designation for Systemic mastocytosis, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Imatinib mesylate [Gleevec] | small molecules | FDA | 2005-09-09 | 2006-10-19 | Novartis Pharmaceuticals Corporation |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI's forecasts to outperform average preclinical success rates. Whether you're expanding your R&D pipeline, evaluating a partnership, or simply have a question — we'd love to hear from you.