36 Chronic Myeloid Leukemia
- BCR-ABL1 fusion (t(9;22)) defines CML; TKI 1st-line therapy
- CP: <10% blasts → 5-yr+ median OS w/ TKI
- AP: 10–19% blasts or ≥20% basophils → intensify therapy
- BP: ≥20% blasts → 12–18 mo OS w/o optimal TKI
- Milestones: BCR-ABL1 ≤10% @ 3mo, ≤0.1% @ 12mo (optimal)
- Deep molecular response (DMR) enables TKI dose ↓
- 2G TKIs (dasatinib, nilotinib, bosutinib) for imatinib failure/intolerance
- Allo-SCT for AP/BP or TKI-resistant disease
- Pregnancy: imatinib acceptable 2nd/3rd trimester; don’t abruptly D/C
36.1 Pathogenesis & Molecular Biology
Philadelphia chromosome (Ph+) - t(9;22) → BCR-ABL1 fusion → constitutive TK activity - JAK/STAT ↑, apoptosis ↓, DNA repair impaired - Detection: cytogenetics, FISH, RT-PCR - Ph+ in 95–98% @ dx; rare Ph− CML = poor prognosis
WHO phase classification
| Phase | Blasts (%) | Basophils (%) | Features |
|---|---|---|---|
| Chronic (CP) | <10 | <20 | WBC ↑, splenomegaly, rare constitutional sx |
| Accelerated (AP) | 10–19 | 20–30 | Cytopenias, new karyotype, TKI ± resistance |
| Blast (BP) | ≥20 | ≥20 | AML-like, extramedullary disease, OS 12–18mo |
AP features: ≥30% blasts, new karyotype (trisomy 8/19), basophils/eos ≥20%, WBC >100×10^9 therapy-resistant, plt <100×10^9 w/ new aberrations
36.2 Diagnosis & Initial Assessment
Presentation - 40–50% incidental Dx on labs - Splenomegaly (50%), hepatomegaly (20%), abdominal pain - Complications: hyperleukostasis, leukostasis, thrombosis
| Finding | CP | AP | BP |
|---|---|---|---|
| WBC | ↑↑ (>100×10^9) | ↑ w/ cytopenia | Variable |
| Blasts (PB) | <5% | 10–19% | ≥20% |
| Basophils/eos | ↑ | ↑↑ | ↑↑ |
| Hgb | Normal/↓ | ↓ | ↓↓ |
| Plts | Normal/↑ or ↓ | ↓↓ | ↓↓ |
| BM | Hypercellular, myeloid | ↑ blasts | AML-like |
Confirmation - BCR-ABL1 qPCR (baseline for monitoring) - FISH or cytogenetics (Ph+ in ≥10 metaphases) - Sokal score (age, spleen size, plt, blasts) → prognostic in CP
Prognosis (CP) - Median OS >5y on TKI - 30% survive >10y w/o allo-SCT - Worse: high Sokal, >30% blasts
36.3 Chronic-Phase CML Treatment
1st-line TKI selection
Low-risk (Sokal) - Imatinib 400 mg QD - ↓ cost, longest safety record - Best for: elderly, comorbidities, pregnancy - Switch to 2G if: high Sokal, T315I, intolerance, suboptimal response
Intermediate/high-risk or imatinib intolerant - Dasatinib 100 mg QD - 300–500× potency vs imatinib - Faster response (3–6mo) - Pleural effusion (20–30%), cytopenias - Partial T315I activity - Nilotinib 300–400 mg BID - 30× potency vs imatinib - ↑ CCyR/MMR @ 12mo - QTc ↑, need baseline ECG - Monitor lipids - Bosutinib 400 mg QD - 4G TKI, comparable to 2G - Diarrhea (74–90% mild, 30% grade ≥3) - Renal toxicity; avoid renal impairment
Molecular monitoring (BCR-ABL1 IS, qPCR)
| Timepoint | Optimal | Warning | Failure |
|---|---|---|---|
| 3mo | ≤10% | >10% | — |
| 6mo | ≤1% | 1–10% | >10% |
| 12mo | ≤0.1% | 0.1–1% | ≥1% |
| 18mo | ≤0.1% | — | >0.1% rising |
Response definitions - CHR: WBC <10×10^9, plt <450×10^9, blasts <5%, no EMD - CCyR: 0% Ph+ metaphases - MCyR: 0–35% Ph+ metaphases - MMR: BCR-ABL1 ≤0.1% → ↑ OS - DMR: BCR-ABL1 <0.0032% (MR4.5) → enables TKI dose ↓
Imatinib (pioneering TKI, FDA 2001) - CHR 95% @ 12mo - CCyR 85% @ 12mo, 91% @ 18mo - MMR 87% @ 10y (progression-free 99%) - OS 91.1% @ 10y (vs 83.3% w/ ACA) - AE: myelosuppression, fluid retention, cramps, rash, diarrhea - Rare: hepatotox, thrombocytopenia, cardiomyopathy - Monitor CBC q mo ×3, then q3mo; LFTs baseline
| Trial (N) | TKI | CCyR@12mo | MMR@12mo | OS@5y |
|---|---|---|---|---|
| DASISION (519) | Imatinib | 73% | 40% | 90% |
| Dasatinib | 67% | 28% | 33% | |
| ENESTND (846) | Nilotinib 300 BID | 80% | 55% | 54% |
| Imatinib | 65% | 37% | 38% | |
| BFORE (536) | Bosutinib | 77.2% | 47.2% | 57.4% |
| Imatinib | 66.4% | 36.9% | 36.6% |
Key findings - 2G TKIs → deeper/faster MMR vs imatinib @ 12mo - OS similar both groups; BCR-ABL1 >1% @ baseline → ↑ AP/BP risk - ↑ grade ≥3 cytopenia w/ 2G vs imatinib - Imatinib OK for low Sokal, elderly, comorbidities
2nd-line TKI options
Dasatinib (imatinib failure/intolerance) - START-R: CCyR 62%, MMR 44% @ 24mo - Pleural effusions (20–30% cumulative 5y) - Myelosuppression, cytopenias common
Nilotinib (imatinib failure/intolerance) - Phase 2 (N=137): 77% MCyR, 56% CCyR @ 2y - 59% MMR; OS 78% - MI/SCD risk; baseline ECG, lipid panel required
Bosutinib (imatinib failure/intolerance) - CCyR 33%, MMR 28.4% @ 12mo - Diarrhea (leading DC reason) → improves w/ dose ↓ - Efficacy comparable to 2G in advanced disease
Ponatinib (3G TKI; T315I only TKI-sensitive) - FDA: T315I+ CML or AP/BP refractory to ≥2 TKIs - PACE trial: 55% MCyR, 45% CCyR @ 24mo resistant/intolerant - CCyR 42% imatinib-resistant - Vascular toxicity: ATE 2%, VTE 2%, PAD 0.8%, MI 0.4%, stroke 0.8% - Mandatory CV risk assessment; avoid high-risk pts
TKI dose reduction & DMR
Rationale - Long-term TKI → cumulative cardiotox, metabolic dysfunction, 2° malignancies - Phase II/III: optimal biologic dose < phase 1 dose - After DMR/MMR ≥2y: consider dose ↓
TKI discontinuation (TFR) - STIM trial: 55% imatinib-free @ 12mo, 38% @ 60mo - Molecular relapse (BCR-ABL1 ↑ ≥1log) common → TKI re-start responsive - EURO-SKI (N=large): 61% sustained TFR @ 12mo; relapse 39% median 3y F/U - Success factors: durable DMR >2y, slow BCR-ABL1 kinetics, adherence
36.4 TKI Resistance & Intolerance
Resistance mechanisms - KD mutations (50–60%): T315I (↓binding), M244V, G250E (2G-resistant) - ABL amplification (10–20%) - BCR-ABL overexpression (splicing, transcriptional ↑) - Clonal evolution: new karyotype (tri8, tri19, i(17q)) - Pharmacokinetics: absorption ↓, CYP3A4 interactions
Management - Mutational analysis before TKI switch - T315I → ponatinib only - Other mutations → try different 2G/3G (dasatinib fail → nilotinib; nilotinib fail → dasatinib/ponatinib) - BM biopsy: phase, karyotype, evolution - ≥2 TKI failures + good PS → consider allo-SCT (AP/BP preferred)
Intolerance - Dose hold, dose ↓, or switch TKI
Adherence - Imatinib adherence ~85% - ADAGIO: 57% adherence → improves molecular response - Barriers: pill burden, cost, diet (nilotinib), AE, GI upset
36.5 Accelerated-Phase CML
Features: 10–19% blasts, ≥20% basophils/eos, new karyotype (tri8/19, i17q), WBC >100×10^9 therapy-resistant, plt <100×10^9
De novo AP (ELN 2020): Ph+ @ dx w/ BCR-ABL1 >1% → high-risk, intensified early tx
Treatment - 2G TKI preferred over imatinib (faster response, deeper suppression) - Allo-SCT evaluation (preferred); median RFS 50–70% myelo/RIC - If allo-SCT contraindicated: intensify TKI; OS 2–3y - Imatinib-resistant: ponatinib or dasatinib + imatinib
36.6 Blast-Phase CML
Definition: ≥20% blasts in blood/marrow
Features - 5–10% new CML, common endpoint w/o effective TKI - Median time to transformation: 5–7y untreated CP - LyBC 70% (Ph+ ALL), myeloid 30%, mixed rare - CNS <10%; EMD common (spleen, nodes, soft tissue) - Karyotype: tri8/19, i(17q), complex, extra Ph, dbl Ph
Prognosis: myeloid worse, ECOG PS, cytopenia severity
Management 1. Confirm BP (≥20% blasts) + mutational analysis 2. Imatinib-resistant/intolerant - Ponatinib/dasatinib/nilotinib ± chemo 3. Myeloid BP: low-dose ara-C, hydroxyurea, TKI intensification 4. Lymphoid BP: HyperCVAD, FLAG-IDA, inotuzumab (CD22 mAb) 5. Allo-SCT (medically fit, chemosensitive): RFS 20–40% long-term; ↑ if 2nd remission pre-SCT 6. OS: 12–18mo TKI alone; 3–5y w/ allo-SCT + chemo
TKI dose escalation: imatinib 800 mg, dasatinib 200 mg, nilotinib 600 mg → limited efficacy, need chemo; response 3–12mo
36.7 Management in Pregnancy
Teratogenicity - Imatinib: Cat D (2nd/3rd trim); fetal loss risk if post-implantation - 2G TKIs: limited data; avoid if possible
Approach - D/C TKI @ pregnancy Dx; monthly BCR-ABL1 qPCR - Re-start if BCR-ABL1 ↑ >1log or AP develops - IFN-α bridge if TKI D/C not tolerated - Leukoreduction if WBC >100×10^9 (hyperleukostasis risk) - Resume TKI immediately post-delivery - Imatinib safe in breast milk - 2G TKI safety unknown
36.8 Stem Cell Transplantation
Modern era: <5% CML → allo-SCT (historically AP/BP/TKI-resistant)
Outcomes - CP: 60–80% long-term RFS - AP: 40–60% long-term RFS - BP: 10–40% RFS (↑ if AML phenotype & chemosensitive) - TRM: 20–40% (age, PS, donor, stem cell source) - GVL: primary benefit mechanism; durable remissions possible even AP/BP
Indications 1. AP CML (if good PS + matched donor) 2. BP CML w/ chemosensitive, medically fit 3. Imatinib-resistant AP/BP post-TKI escalation 4. T315I mutation + ponatinib contraindication 5. ≥2 TKI failures
36.9 Clinical Pearls
- BCR-ABL1 KD mutations → TKI resistance; mutational analysis @ dx & resistance signs; T315I mandates ponatinib
- Molecular depth (MMR @ 12mo) → ↑ PFS/OS; DMR → safe dose ↓ & potential D/C
- Pregnancy: Imatinib safe 2nd/3rd trim; never abruptly D/C w/o BCR-ABL1 monitoring; resume immediately post-delivery