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
950 drug discovery papers related to Systemic mastocytosis, with 4 first-in-class and 11 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
950 drug discovery papers related to Systemic mastocytosis, with 4 first-in-class and 11 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
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.
2026-06-26 | 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.
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.
2026-06-26 | 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.
Access all drug discovery articles and probability of success in trials forecasts:
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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 |
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