Aggressive systemic mastocytosis

Summary

Aggressive systemic mastocytosis (MONDO:0020333) is a disease with 1 cohort gene and 8 clinical trials. Top therapeutic interventions include avapritinib, brentuximab vedotin, and ibrutinib.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 2
• Phenotypes (HPO): 39
• Clinical trials: 8

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000		Europe	Validated

Signs & symptoms

Clinical features (HPO)

39 HPO clinical features (Orphanet curated; top 39 by frequency):

HPO ID	Term	Frequency
HP:0100494	Abnormal mast cell morphology	Very frequent (80-99%)
HP:0000939	Osteoporosis	Frequent (30-79%)
HP:0000989	Pruritus	Frequent (30-79%)
HP:0001433	Hepatosplenomegaly	Frequent (30-79%)
HP:0001824	Weight loss	Frequent (30-79%)
HP:0001974	Leukocytosis	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002024	Malabsorption	Frequent (30-79%)
HP:0002027	Abdominal pain	Frequent (30-79%)
HP:0002039	Anorexia	Frequent (30-79%)
HP:0002615	Hypotension	Frequent (30-79%)
HP:0002653	Bone pain	Frequent (30-79%)
HP:0002716	Lymphadenopathy	Frequent (30-79%)
HP:0002829	Arthralgia	Frequent (30-79%)
HP:0003155	Elevated circulating alkaline phosphatase concentration	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0025142	Constitutional symptom	Frequent (30-79%)
HP:0031284	Flushing	Frequent (30-79%)
HP:0031408	Increased proportion of CD25+ mast cells	Frequent (30-79%)
HP:0031901	Increased serum mast cell beta-tryptase concentration	Frequent (30-79%)
HP:0032155	Abdominal cramps	Frequent (30-79%)
HP:0100845	Anaphylactic shock	Frequent (30-79%)
HP:0001025	Urticaria	Occasional (5-29%)
HP:0001409	Portal hypertension	Occasional (5-29%)
HP:0001410	Decreased liver function	Occasional (5-29%)
HP:0001541	Ascites	Occasional (5-29%)
HP:0001873	Thrombocytopenia	Occasional (5-29%)
HP:0001875	Decreased total neutrophil count	Occasional (5-29%)
HP:0001876	Pancytopenia	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0001909	Leukemia	Occasional (5-29%)
HP:0001971	Hypersplenism	Occasional (5-29%)
HP:0002239	Gastrointestinal hemorrhage	Occasional (5-29%)
HP:0002756	Pathologic fracture	Occasional (5-29%)
HP:0002797	Osteolysis	Occasional (5-29%)
HP:0004377	Hematological neoplasm	Occasional (5-29%)
HP:0008066	Abnormal blistering of the skin	Occasional (5-29%)
HP:0011121	Abnormal skin morphology	Occasional (5-29%)
HP:0040186	Maculopapular exanthema	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	aggressive systemic mastocytosis
Mondo ID	MONDO:0020333
Orphanet	98850
DOID	DOID:4798
ICD-10-CM	C96.21
ICD-11	870477963
NCIT	C9285
SNOMED CT	716655008
UMLS	C1112486
MedGen	206813
GARD	0019597
MedDRA	10056453
Is cancer (heuristic)	no

Also known as: aggressive systemic mastocytosis (morphologic abnormality) · ASM

Data availability: 2 ClinVar variants.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › hematopoietic and lymphoid system neoplasm › hematopoietic and lymphoid cell neoplasm › myeloid neoplasm › mast cell neoplasm › mastocytosis › systemic mastocytosis › aggressive systemic mastocytosis

Related subtypes (4): extracutaneous mastocytoma, indolent systemic mastocytosis, systemic mastocytosis with an associated clonal hematologic non-mast cell lineage disease, mast cell leukemia

Subtypes (1): lymphoadenopathic mastocytosis with eosinophilia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
409805	NM_001754.5(RUNX1):c.1253T>G (p.Met418Arg)	RUNX1	Uncertain significance	reviewed by expert panel
988867	NM_001754.5(RUNX1):c.1270T>G (p.Ser424Ala)	RUNX1	Uncertain significance	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RUNX1	Orphanet:102724	Acute myeloid leukemia with t(8;21)(q22;q22) translocation
RUNX1	Orphanet:521	Chronic myeloid leukemia
RUNX1	Orphanet:71290	Familial platelet disorder with associated myeloid malignancy
RUNX1	Orphanet:98850	Aggressive systemic mastocytosis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RUNX1	HGNC:10471	ENSG00000159216	Q01196	Runt-related transcription factor 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RUNX1	Runt-related transcription factor 1	Forms the heterodimeric complex core-binding factor (CBF) with CBFB.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RUNX1	Transcription factor	no		AML1_Runt, p53-like_TF_DNA-bd_sf, p53/RUNT-type_TF_DNA-bd_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
epithelium of bronchus	1
mucosa of paranasal sinus	1
olfactory segment of nasal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RUNX1	253	ubiquitous	marker	olfactory segment of nasal mucosa, epithelium of bronchus, mucosa of paranasal sinus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RUNX1	4,994

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RUNX1	Q01196	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 43. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RUNX3 regulates RUNX1-mediated transcription	1	3806.7×	0.003	RUNX1
RUNX1 regulates expression of components of tight junctions	1	2284.0×	0.003	RUNX1
RUNX1 regulates transcription of genes involved in interleukin signaling	1	2284.0×	0.003	RUNX1
RUNX2 regulates genes involved in differentiation of myeloid cells	1	2284.0×	0.003	RUNX1
RUNX1 regulates estrogen receptor mediated transcription	1	1903.3×	0.003	RUNX1
RUNX1 regulates transcription of genes involved in BCR signaling	1	1903.3×	0.003	RUNX1
RUNX1 regulates transcription of genes involved in WNT signaling	1	1903.3×	0.003	RUNX1
RUNX1 regulates transcription of genes involved in differentiation of myeloid cells	1	1427.5×	0.003	RUNX1
RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)	1	1142.0×	0.003	RUNX1
RUNX1 regulates transcription of genes involved in differentiation of keratinocytes	1	1142.0×	0.003	RUNX1
RUNX3 regulates p14-ARF	1	1142.0×	0.003	RUNX1
Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)	1	878.5×	0.004	RUNX1
SLC-mediated transport of organic cations	1	761.3×	0.004	RUNX1
R-HSA-549132	1	761.3×	0.004	RUNX1
Regulation of RUNX1 Expression and Activity	1	671.8×	0.004	RUNX1
Pre-NOTCH Expression and Processing	1	368.4×	0.007	RUNX1
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	1	300.5×	0.008	RUNX1
Transcriptional regulation by RUNX3	1	271.9×	0.008	RUNX1
SARS-CoV-1 activates/modulates innate immune responses	1	271.9×	0.008	RUNX1
Transcriptional regulation by RUNX2	1	253.8×	0.008	RUNX1
R-HSA-425366	1	181.3×	0.011	RUNX1
Signaling by NOTCH	1	175.7×	0.011	RUNX1
SARS-CoV-1-host interactions	1	175.7×	0.011	RUNX1
Transcriptional regulation by RUNX1	1	146.4×	0.012	RUNX1
SARS-CoV-1 Infection	1	142.8×	0.012	RUNX1
ESR-mediated signaling	1	128.3×	0.012	RUNX1
Transcriptional regulation of granulopoiesis	1	125.5×	0.012	RUNX1
Pre-NOTCH Transcription and Translation	1	122.8×	0.012	RUNX1
RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function	1	120.2×	0.012	RUNX1
Signaling by Nuclear Receptors	1	102.0×	0.014	RUNX1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of connective tissue replacement	1	16852.0×	9e-04	RUNX1
myeloid leukocyte differentiation	1	5617.3×	9e-04	RUNX1
regulation of plasminogen activation	1	5617.3×	9e-04	RUNX1
negative regulation of CD4-positive, alpha-beta T cell differentiation	1	4213.0×	9e-04	RUNX1
cardiac muscle tissue regeneration	1	4213.0×	9e-04	RUNX1
positive regulation of extracellular matrix organization	1	4213.0×	9e-04	RUNX1
positive regulation of CD8-positive, alpha-beta T cell differentiation	1	3370.4×	9e-04	RUNX1
regulation of cardiac muscle cell proliferation	1	3370.4×	9e-04	RUNX1
positive regulation of granulocyte differentiation	1	2808.7×	1e-03	RUNX1
negative regulation of granulocyte differentiation	1	2106.5×	0.001	RUNX1
peripheral nervous system neuron development	1	1532.0×	0.001	RUNX1
myeloid cell differentiation	1	648.1×	0.003	RUNX1
positive regulation of collagen biosynthetic process	1	648.1×	0.003	RUNX1
hematopoietic stem cell proliferation	1	648.1×	0.003	RUNX1
positive regulation of interleukin-2 production	1	468.1×	0.004	RUNX1
regulation of cell differentiation	1	432.1×	0.004	RUNX1
chondrocyte differentiation	1	300.9×	0.005	RUNX1
hemopoiesis	1	267.5×	0.005	RUNX1
ossification	1	227.7×	0.006	RUNX1
positive regulation of angiogenesis	1	115.4×	0.011	RUNX1
neuron differentiation	1	100.3×	0.012	RUNX1
positive regulation of DNA-templated transcription	1	27.9×	0.041	RUNX1
negative regulation of transcription by RNA polymerase II	1	17.7×	0.061	RUNX1
positive regulation of transcription by RNA polymerase II	1	14.9×	0.070	RUNX1
regulation of transcription by RNA polymerase II	1	11.7×	0.086	RUNX1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
RUNX1	APOMORPHINE HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RUNX1	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
APOMORPHINE HYDROCHLORIDE	4	RUNX1
MOLIBRESIB	2	RUNX1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
RUNX1	20	Binding:17, Functional:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
APOMORPHINE HYDROCHLORIDE	4	RUNX1
MOLIBRESIB	2	RUNX1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RUNX1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 8.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	4
Not specified	3
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04996875	PHASE2	RECRUITING	(Apex) Bezuclastinib in Patients With Advanced Systemic Mastocytosis
NCT01807598	PHASE2	COMPLETED	Brentuximab Vedotin in Treating Patients With Advanced Systemic Mastocytosis or Mast Cell Leukemia
NCT02415608	PHASE2	TERMINATED	Ibrutinib in Treating Patients With Advanced Systemic Mastocytosis
NCT03580655	PHASE2	COMPLETED	(PATHFINDER) Study to Evaluate Efficacy and Safety of Avapritinib (BLU-285), A Selective KIT Mutation-targeted Tyrosine Kinase Inhibitor, in Patients With Advanced Systemic Mastocytosis
NCT02561988	PHASE1	COMPLETED	(EXPLORER) Study of BLU-285 in Patients With Advanced Systemic Mastocytosis (AdvSM) and Relapsed or Refractory Myeloid Malignancies
NCT02380222	Not specified	COMPLETED	Patient-Reported Outcome Questionnaire for Systemic Mastocytosis
NCT04695431	Not specified	COMPLETED	Retrospective Study Assessing the Effect of Avapritinib Versus Best Available Therapy in Patients With AdvSM
NCT05219266	Not specified	NO_LONGER_AVAILABLE	Managed Access Programs for PKC412, Midostaurin

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
AVAPRITINIB	4	2
BRENTUXIMAB VEDOTIN	4	1
IBRUTINIB	4	1
MIDOSTAURIN	4	1
BEZUCLASTINIB	3	1
CHEMBL3647964	0	1
CHEMBL4466205	0	1
CHEMBL4790597	0	1
CHEMBL5199540	0	1