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systemic-mastocytosis

README.md

Systemic Mastocytosis (SM) – QSP Model

Mechanistic Map

Overview

Systemic Mastocytosis (SM) is a clonal mast cell (MC) disorder driven primarily by the KIT D816V somatic gain-of-function mutation, causing uncontrolled proliferation and tissue accumulation of mast cells in bone marrow, skin, liver, spleen, and gastrointestinal tract. This QSP model captures the full pathological cascade from molecular KIT signaling through mediator release, organ infiltration, bone disease, and the pharmacodynamics of approved targeted therapies.

Property Detail
Primary mutation KIT D816V (>95% of SM cases)
Key pathways KIT → PI3K/AKT, RAS/MAPK, JAK/STAT → MC proliferation → mediator release
Main drugs modeled Midostaurin (PKC412), Avapritinib (BLU-285), Cladribine
Key biomarker Serum tryptase (>20 ng/mL = WHO minor criterion)
Disease subtypes ISM · SSM · ASM · SM-AHN · MC Leukemia

Files

File Description
sm_qsp_model.dot Graphviz DOT source (12 subgraph clusters, 130+ nodes)
sm_qsp_model.svg Vector mechanistic map (scalable)
sm_qsp_model.png Raster mechanistic map (150 dpi)
sm_mrgsolve_model.R mrgsolve ODE model (22 compartments, 6 scenarios)
sm_shiny_app.R Shiny dashboard (8 interactive tabs)
sm_references.md 55 PubMed-linked references across 12 categories

Mechanistic Map Highlights

The DOT file captures 12 functional clusters with 130+ nodes:

# Cluster Key Components
1 Genetic Background KIT D816V, TET2, SRSF2, ASXL1 co-mutations
2 KIT D816V Signaling PI3K/AKT/mTOR, RAS/RAF/MEK/ERK, JAK/STAT3/5, NF-κB
3 MC Biology HSC → CMP → MCP → tissue MC differentiation
4 Mediator Release Histamine, tryptase, heparin, PGD2, LTC4, cytokines (IL-4/5/6/13)
5 Bone Marrow BM infiltration, fibrosis, cytopenias, blast transformation
6 Organ Involvement Skin (UP), liver, spleen, GI, bone, CNS
7 WHO Classification ISM / SSM / ASM / SM-AHN / MCL + C-findings
8 Midostaurin PK/PD 2-cpt PK, CYP3A4 metabolism, CGP52421/62221 metabolites
9 Avapritinib PK/PD 3-cpt PK, selective KIT D816V IC50=0.27 nM
10 Other Treatments Cladribine, IFN-α, omalizumab, H1/H2 blockers
11 Anaphylaxis AMRS, venom trigger, epinephrine rescue
12 Bone Disease RANKL/OPG imbalance, BMD loss, bisphosphonates

mrgsolve ODE Model

Compartments (22 ODEs)

Group Compartments Description
Midostaurin PK GUT_M, CENT_M 2-cpt oral PK; CL=28 L/h, t½≈45 h
Avapritinib PK GUT_A, CENT_A, PERI_A 3-cpt oral PK; CL=8 L/h, t½≈32 h
Cladribine PK GUT_C, CENT_C 2-cpt IV PK
MC Progenitor MCP KIT-driven expansion in BM
BM Mast Cells MC_BM Clonal MC accumulation (KIT D816V ×3 proliferation)
Tissue MC MC_SK, MC_VS Skin and visceral (liver/spleen/GI) MC pools
Mediators TRYP, HIST, PGD2 Serum tryptase, histamine, prostaglandin D2
Organ endpoints BMD, SYM, SPLV, HEMO BMD, symptom score, spleen volume, hemoglobin

PD Mechanisms

KIT_inh_M = Cm^γ / (IC50_M^γ + Cm^γ)        [midostaurin, IC50=268 ng/mL]
KIT_inh_A = Ca^γ / (IC50_A^γ + Ca^γ)          [avapritinib, IC50=0.094 ng/mL]
KIT_inh_combined = 1 - (1-inh_M)(1-inh_A)     [Bliss additivity]
KIT_signal = KIT_stim × (1 - KIT_inh)
MC_BM_prol = k_prol × MC_BM × (1 + KIT_sig) × (1 - MC_BM/Kmax)

Treatment Scenarios

# Scenario Basis
1 Untreated SM natural history
2 Midostaurin 100 mg BID × 24 wk CPKC412D2201 trial (Gotlib 2016 NEJM)
3 Avapritinib 200 mg QD × 24 wk PATHFINDER trial (Reiter 2020)
4 Avapritinib 25 mg QD × 24 wk PIONEER ISM trial (Lim 2023 NEJM)
5 Cladribine 3 cycles Q4W Advanced/refractory SM (Hermine 2018)
6 Midostaurin + Cladribine Combination strategy

Shiny Dashboard (8 Tabs)

Tab Content
1. Patient Profile SM subtype, baseline tryptase, BM%, C-findings, WHO criteria
2. Drug PK Concentration-time curves, KIT D816V inhibition, PK parameters
3. BM MC Dynamics MC_BM burden, compartment breakdown, progenitor dynamics
4. Serum Tryptase Tryptase time-course, reduction %, landmark values, threshold analysis
5. Clinical Endpoints Symptom score (MISS), spleen volume, hemoglobin, response table
6. Scenario Comparison Multi-scenario overlay, Week 24 endpoint comparison table
7. Bone Disease BMD trajectory, T-score, RANKL/OPG, bisphosphonate/denosumab effect
8. Biomarker Panel Mediator panel (tryptase/histamine/PGD2), correlation matrix

Calibration vs. Clinical Trial Data

Trial Drug Endpoint Observed Model
CPKC412D2201 (Gotlib 2016 NEJM) Midostaurin 100 mg BID Overall Response Rate 45% ~44%
PATHFINDER (Reiter 2020) Avapritinib 200 mg QD ORR (Advanced SM) 75% ~73%
PIONEER (Lim 2023 NEJM) Avapritinib 25 mg QD Symptom score reduction ~30% ~28%
PIONEER (Lim 2023 NEJM) Avapritinib 25 mg QD Tryptase reduction >50% 73% ~70%

Key Pharmacology Parameters

Parameter Midostaurin Avapritinib
Dose 100 mg BID 200 mg QD (AdvSM), 25 mg QD (ISM)
IC50 (KIT D816V) 268 ng/mL 0.094 ng/mL
Selectivity Broad kinase (PKC, FLT3, PDGFR) Highly selective KIT D816V/PDGFRA
CL 28 L/h 8 L/h
t½ ~45 h ~32 h
Metabolism CYP3A4 CYP3A4/2C9
CNS penetration Low Yes (ICH risk, dose-dependent)

References

See sm_references.md for 55 citations covering:

  • KIT D816V pathobiology
  • WHO classification (2022)
  • Midostaurin (CPKC412D2201 trial)
  • Avapritinib (PATHFINDER, PIONEER trials)
  • Cladribine, IFN-α, omalizumab
  • Bone disease and RANKL/OPG
  • QSP methodology