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chronic-myeloid-leukemia

README.md

Chronic Myeloid Leukemia (CML) — QSP Model

First Oncology Model in the QSP Disease Library — 2026-06-20

CML QSP Model Map

Disease Overview

Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative neoplasm defined by the Philadelphia chromosome — a t(9;22)(q34;q11) translocation generating the BCR-ABL1 fusion oncogene. The resulting p210 BCR-ABL oncoprotein is a constitutively active tyrosine kinase that drives uncontrolled proliferation and survival of myeloid progenitors.

Epidemiology

Parameter Value
Incidence ~1-2 per 100,000 / year
Prevalence ~70,000 in US (rising due to TKI success)
Median age at diagnosis 57 years
Male:Female ratio 1.4:1
10-year OS (imatinib era) ~85%
Phase distribution CP 90% · AP 5% · BC 5%

CML Phase Criteria (EWI 2022)

Phase Blast % Key Features
Chronic (CP) <10% Splenomegaly, WBC ↑, Ph+
Accelerated (AP) 10–19% Basophils ≥20%, Plt <100×10⁹/L
Blast Crisis (BC) ≥20% Lymphoid (30%) or Myeloid (70%)

Pathophysiology

t(9;22) Translocation
    ↓
BCR-ABL1 Fusion Gene → p210 Protein (tyrosine kinase)
    ↓
Constitutive Signaling: RAS-MAPK · PI3K-AKT-mTOR · JAK-STAT · MYC
    ↓
Leukemic Stem Cell (LSC) Self-Renewal ↑ · Apoptosis ↓ · Quiescence ↑
    ↓
Clonal Expansion: LSC → LPC → Leukemic Blasts → WBC ↑↑
    ↓
Clinical Manifestations: Splenomegaly · Fatigue · Elevated WBC

Key Signaling Pathways

Pathway Effectors Oncogenic Effect
RAS-MAPK GRB2 → SOS1 → RAS → RAF → MEK → ERK Proliferation, MYC activation
PI3K-AKT-mTOR PI3K → PIP3 → AKT → mTORC1/2 Survival, protein synthesis
JAK-STAT JAK2 → STAT5 BCL-2/BCL-xL anti-apoptosis
MYC/Cyclin MYC → CDK4/6 → Cyclin D1 Cell cycle G1/S progression

Leukemic Hierarchy (Michor 2005 Framework)

Quiescent LSC (x0q) ←→ Cycling LSC (x0p)
                              ↓ differentiation
                    Leukemic Progenitor 1 (x1)
                              ↓
                    Leukemic Progenitor 2 (x2)
                              ↓
                    Leukemic WBC/Blasts (x3)   ← BCR-ABL IS% numerator

TKI sensitivity by compartment:

  • x0q (quiescent LSC): TKI-REFRACTORY (primary resistance mechanism)
  • x0p (cycling LSC): TKI-sensitive
  • x1, x2 (LPC): partially sensitive
  • x3 (WBC): highly sensitive → rapid clearance

TKI Drug Parameters

TKI Generation Standard Dose IC50 (BCR-ABL) Bioavailability t½ T315I
Imatinib 1st 400 mg/day 0.25 µM 98% 18h Resistant
Dasatinib 2nd 100 mg/day 0.025 µM 14-34% 5-6h Resistant
Nilotinib 2nd 300 mg BID 0.020 µM 30-40% 17h Resistant
Bosutinib 2nd 400 mg/day 0.10 µM ~34% 22-27h Resistant
Ponatinib 3rd 15-45 mg/day 0.37 nM ~54% 24h Sensitive
Asciminib 3rd STAMP 40 mg BID 0.5 nM ~72% 8.7h 200mg BID

OCT1 pharmacology (imatinib-specific):

  • OCT1 (SLC22A1) mediates ~80% of intracellular imatinib uptake
  • Low OCT1 activity → reduced IC → inferior response
  • Dasatinib, nilotinib: OCT1-independent (passive diffusion)

Clinical Response Milestones (ELN 2020)

Timepoint Optimal Response Warning Failure
3 months BCR-ABL ≤10% BCR-ABL >10% BCR-ABL >10% + Ph >95%
6 months BCR-ABL ≤10% — BCR-ABL >10%, Ph >35%
12 months BCR-ABL ≤1% (CCyR) BCR-ABL 1-10% BCR-ABL >1%, Ph >0%
Any time MMR (≤0.1%) — Loss of CCyR/CHR

Molecular Response Definitions

  • CHR: Complete Hematologic Response — WBC <10×10⁹/L, no immature cells
  • CCyR: Complete Cytogenetic Response — 0% Ph+ metaphases
  • MMR/MR3: BCR-ABL IS ≤0.1%
  • MR4: BCR-ABL IS ≤0.01%
  • MR4.5: BCR-ABL IS ≤0.0032% (TFR prerequisite)

Treatment-Free Remission (TFR)

Prerequisites (ELN 2020):

  • CP CML, no history of AP/BC
  • Frontline TKI treatment ≥ 5 years
  • Sustained MR4.5 for ≥ 2 years (or MR4 ≥ 3 years)
  • BCR-ABL IS quantifiable assay (sensitivity ≥MR4.5)

TFR Success Rates (Clinical Trials):

Trial TKI TFR Rate @ 12mo
STIM1 (Mahon 2010) Imatinib 38%
EURO-SKI (Saussele 2018) Mixed 43%
ENESTfreedom (Hochhaus 2017) Nilotinib 51%
DADI (Imagawa 2015) Dasatinib 49%

Molecular relapse after TFR: ~50-60%; >90% respond to TKI re-initiation

Resistance Mechanisms

Mechanism Frequency Implications
BCR-ABL kinase domain mutations ~50% T315I (gatekeeper): all 1st/2nd-gen TKIs
T315I ~15% of mutations Ponatinib or asciminib 200mg BID
BCR-ABL amplification/overexpression ~10% Dose escalation, switch TKI
LSC quiescence (primary resistance) All patients Combination strategies
OCT1 downregulation Variable (imatinib) Switch to dasatinib/nilotinib
ABCB1/MDR1 overexpression ~10% Switch TKI
Bypass pathways (LYN, FGF2) Rare Src inhibitor (dasatinib)

Model Files

File Description
cml_qsp_model.dot Graphviz mechanistic map (100+ nodes, 12 clusters)
cml_qsp_model.svg SVG vector graphic (interactive)
cml_qsp_model.png PNG thumbnail (150 dpi)
cml_mrgsolve_model.R mrgsolve ODE model (22 compartments, 7 scenarios)
cml_shiny_app.R Shiny interactive dashboard (6 tabs)
cml_references.md 60 PubMed-linked references

ODE Model Structure (mrgsolve)

22 Compartments:

Compartment Symbol Description
y0 HSC Normal hematopoietic stem cells
y1 CMP Common myeloid progenitor
y2 GMP Granulocyte-macrophage progenitor
y3 Neutrophil Mature normal WBC
x0q LSC_q Quiescent CML stem cells (TKI-refractory)
x0p LSC_p Cycling CML stem cells (TKI-sensitive)
x1 LPC1 Leukemic progenitor committed
x2 LPC2 Leukemic progenitor differentiated
x3 WBC_leuk Mature leukemic cells/blasts
xs LSC_sens TKI-sensitive LSC clone (BCR-ABL WT)
xsp LPC_sens Sensitive progenitors
xr LSC_res T315I-resistant LSC clone
xrp LPC_res Resistant progenitors
Gut_imt — Imatinib GI absorption
Cp_imt — Imatinib plasma (µM)
Cic_imt — Imatinib intracellular (OCT1-dependent, µM)
Cp_das — Dasatinib plasma (µM)
Cic_das — Dasatinib intracellular (µM)
Gut_nil — Nilotinib GI absorption
Cp_nil — Nilotinib plasma (µM)
Cic_nil — Nilotinib intracellular (µM)
Cp_asc — Asciminib plasma (µM)

Clinical Trial Calibration

Trial TKI Key Endpoint Observed Model (12mo)
IRIS Imatinib 400mg MMR @ 12mo 28% ~25-32%
IRIS Imatinib 400mg MMR @ 18mo 39% ~35-42%
ENESTnd Nilotinib 300mg BID MMR @ 12mo 44% ~40-48%
DASISION Dasatinib 100mg MMR @ 12mo 46% ~42-50%
ASCEMBL Asciminib 40mg BID MMR @ 24mo 25% ~22-28%

Shiny App Features

Tab Contents
환자 프로파일 Sokal/EUTOS score calculator, ELN treatment recommendation
약동학 (PK) Plasma & intracellular TKI concentration profiles
분자반응 BCR-ABL IS% trajectory, ELN milestone checker
세포역학 Normal vs leukemic cell population dynamics
시나리오 비교 Head-to-head TKI comparison (MMR/MR4/MR4.5 rates)
내성/TFR 평가 T315I clone kinetics, TFR simulation, mutation table

Key References

  1. Michor F, et al. (2005). Dynamics of chronic myeloid leukaemia. Nature 435:1267. [PMID: 15988530]
  2. O'Brien SG, et al. (2003). IRIS trial. NEJM 348:994. [PMID: 12637609]
  3. Saglio G, et al. (2010). ENESTnd trial. NEJM 362:2251. [PMID: 20525993]
  4. Kantarjian H, et al. (2010). DASISION trial. NEJM 362:2260. [PMID: 20525994]
  5. Réa D, et al. (2021). ASCEMBL trial. Blood 138:2031. [PMID: 34407542]
  6. Wylie AA, et al. (2017). Asciminib mechanism. Nature 543:733. [PMID: 28329763]
  7. Mahon FX, et al. (2010). STIM trial (TFR). Lancet Oncol 11:1029. [PMID: 20965785]
  8. Hochhaus A, et al. (2020). ELN 2020 Guidelines. Leukemia 34:966. [PMID: 32127639]

See cml_references.md for complete 60-reference bibliography.