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acute-lymphoblastic-leukemia

README.md

Acute Lymphoblastic Leukemia (ALL) — QSP Model

Comprehensive Quantitative Systems Pharmacology (QSP) library entry for precursor B-/T-cell acute lymphoblastic leukemia — covering cytogenetic leukemogenesis (BCR-ABL1, ETV6-RUNX1, KMT2A-r, hyperdiploidy, Ph-like, NOTCH1), bone-marrow niche adhesion, glucocorticoid apoptosis signaling, and nine therapeutic agents spanning conventional chemotherapy, tyrosine-kinase inhibition (Ph+ ALL), CD19×CD3 bispecific T-cell engagement (blinatumomab), anti-CD22 antibody-drug conjugate (inotuzumab ozogamicin), and CD19 CAR-T cell therapy (tisagenlecleucel).

Files

File Purpose
all_qsp_model.dot Mechanistic map source (137 nodes, 15 clusters)
all_qsp_model.svg Vector render
all_qsp_model.png 150-dpi PNG render
all_mrgsolve_model.R 27-compartment mrgsolve ODE model + 10 scenarios
all_shiny_app.R 8-tab Shiny dashboard
all_references.md 40+ PubMed-linked references

Mechanistic map (15 clusters)

  1. Lymphoid progenitor biology & leukemogenic drivers — BCR-ABL1, ETV6-RUNX1, KMT2A-r, hyperdiploidy/hypodiploidy, Ph-like, TCF3-PBX1, NOTCH1/TLX1/TLX3 (T-ALL)
  2. Bone-marrow microenvironment & niche adhesion — CXCL12/CXCR4, VCAM-1/VLA-4, hypoxia, niche-mediated chemoresistance
  3. Survival signal transduction — PI3K/AKT/mTOR, JAK/STAT5, RAS/MAPK
  4. Apoptosis resistance & glucocorticoid (NR3C1) signaling — BCL-2/MCL-1, BIM/NUR77, steroid resistance
  5. Surface immunophenotype — CD19, CD20, CD22, CD3 anchor, antigen-loss/ lineage-switch immune escape
  6. Vincristine — microtubule inhibitor PK/PD, peripheral neuropathy
  7. Dexamethasone/prednisone — glucocorticoid PK/PD, hyperglycemia, osteonecrosis
  8. PEG-asparaginase — enzymatic asparagine depletion, ASNS resistance, pancreatitis/thrombosis/hepatotoxicity
  9. Methotrexate (HD-MTX + IT) — antifolate PK/PD, CSF penetration, leucovorin rescue, CNS sanctuary
  10. 6-Mercaptopurine (maintenance) — TPMT/NUDT15 pharmacogenomic TGN formation
  11. TKI (dasatinib/ponatinib) — BCR-ABL1 inhibition, T315I resistance, Ph+ ALL
  12. Blinatumomab — CD19×CD3 BiTE immunologic synapse, polyclonal T-cell activation
  13. Inotuzumab ozogamicin & CD19 CAR-T — ADC payload release, antigen- driven CAR-T expansion/contraction/persistence
  14. CRS & ICANS — IL-6/IFN-γ cytokine release, BBB permeability, tocilizumab/steroid rescue
  15. Myelosuppression & clinical endpoints — Friberg ANC/platelet chain, MRD, CR, relapse, EFS/OS

mrgsolve model — 27 ODE compartments

  • PK chains: vincristine (2-cmt), dexamethasone (1-cmt oral), PEG- asparaginase (enzyme-activity depot), methotrexate (3-cmt incl. CSF), 6-MP → TGN (pharmacogenomic-scaled), dasatinib/ponatinib (1-cmt oral), inotuzumab ozogamicin (1-cmt), blinatumomab (1-cmt continuous infusion)
  • CD19 CAR-T cell kinetics: antigen-driven expansion/contraction (blood + marrow/tissue trafficking), IL-6 cytokine-release coupling
  • Leukemic blast burden: logistic growth minus combined multi-agent log-kill (Hill/Emax per agent); CNS sanctuary-site compartment killed only by CSF-penetrant MTX (± partial dasatinib)
  • MRD (log10 scale), CR/MRD-negativity flags
  • Friberg semi-mechanistic myelosuppression: 4-compartment ANC transit chain + simplified platelet compartment

Pre-built scenarios

ID Regimen Source
1 Untreated (natural history) —
2 Pediatric SR B-ALL induction (VCR+DEX+PEG-ASP+IT-MTX) COG/DFCI-style
3 Pediatric HR B-ALL + HD-MTX consolidation COG-style
4 Adult Ph-negative B-ALL (hyper-CVAD-like) Larson CALGB 8811-style
5 Ph+ ALL + Dasatinib + steroid GIMEMA LAL1509-style
6 Ph+ ALL (T315I) + Ponatinib hyper-CVAD+ponatinib-style
7 R/R B-ALL + Blinatumomab TOWER
8 R/R B-ALL + Inotuzumab ozogamicin INO-VATE
9 R/R B-ALL + CD19 CAR-T ELIANA (tisagenlecleucel)
10 Maintenance 6-MP, TPMT poor- vs normal-metabolizer CPIC-style

Shiny dashboard — 8 tabs

  1. Patient / disease profile
  2. Drug PK (cytotoxic/targeted + immunotherapy exposure)
  3. Disease biology (BM blast %, MRD, CNS sanctuary burden)
  4. Hematologic toxicity (Friberg ANC, platelets)
  5. Immunotherapy & CRS (IL-6, CD19 CAR-T cell kinetics)
  6. Clinical endpoints (CR, MRD-negativity, relapse risk)
  7. Scenario comparison (10 regimens)
  8. Biomarkers / safety (plasma asparagine, TGN)

How to render

dot -Tsvg all_qsp_model.dot -o all_qsp_model.svg
dot -Tpng -Gdpi=150 all_qsp_model.dot -o all_qsp_model.png
source("all_mrgsolve_model.R")
shiny::runApp("all_shiny_app.R")

Notes

  • Time unit throughout is days; clinical PK parameters typically reported in L/h were converted to L/day so CL/V ratios stay dimensionally consistent with the day-based dosing/leukemic-kinetics axis.
  • CAR-T cell kinetics follow the antigen-driven expansion/contraction structure described by Stein AM et al. (CPT:PSP 2019) for tisagenlecleucel; CRS (IL-6) is coupled to both CAR-T tissue activation and blinatumomab-driven T-cell engagement.
  • Growth-rate (k_grow) and baseline blast burden (BM_blast_init) are exposed as parameters so relapsed/refractory or MRD-level (low-burden) starting conditions can be explored without editing compartment code.
  • This is an illustrative, mechanism-forward teaching/exploration model, not a clinically validated dosing tool.