Chronic Myeloid Leukaemia
Myeloproliferative neoplasm characterised by the Philadelphia chromosome t(9;22) BCR-ABL1 fusion gene. Tyrosine kinase inhibitors (imatinib) have transformed CML from a fatal disease to one with near-normal life expectancy.
Key Facts
Philadelphia chromosome t(9;22): BCR-ABL1 fusion gene present in ~95% — constitutively active tyrosine kinase driving proliferation Three phases: chronic (>90% at diagnosis; manageable), accelerated, and blast crisis (resembles acute leukaemia) Imatinib 400mg OD: first-line TKI; transformed CML survival to near-normal life expectancy; ~95% achieve complete haematological response Massive splenomegaly: characteristic at presentation; leucocytosis with full range of myeloid maturation on film Leucocytosis: often very high (50–400 × 10⁹/L); basophilia is a characteristic finding NICE TA251: imatinib first-line; second-generation TKIs (dasatinib, nilotinib, bosutinib) for resistance/intolerance Treatment-free remission: ~50% of patients with deep molecular response can successfully stop TKI (STIM/EURO-SKI trials) Gout risk: high cell turnover → hyperuricaemia
Overview
Key Facts
Chronic myeloid leukaemia (CML) is a myeloproliferative neoplasm characterised by the Philadelphia chromosome and its BCR-ABL1 fusion gene. TKI therapy has revolutionised outcomes.
Epidemiology
- Incidence: ~1 per 100,000 per year; ~700 new cases/year in UK
- Median age at diagnosis: 55–60 years; all ages affected
- Slight male predominance
Aetiology
- Philadelphia chromosome t(9;22)(q34;q11): reciprocal translocation creating BCR-ABL1 fusion gene
- BCR-ABL1 encodes constitutively active tyrosine kinase
- Risk factor: ionising radiation (only established)
Pathophysiology
- BCR-ABL1 tyrosine kinase → uncontrolled myeloid proliferation, reduced apoptosis, impaired adhesion
- Clonal expansion of myeloid cells at all stages of maturation
- Three phases:
- Chronic phase (~90% at diagnosis): controlled proliferation
- Accelerated phase: increasing blasts (10–19%), basophilia, additional cytogenetic changes
- Blast crisis: ≥20% blasts (myeloid ~60%, lymphoid ~30%) — resembles acute leukaemia
Clinical Presentation
Chronic Phase (Most Common Presentation)
- Often incidental: raised WCC on routine blood test (~50%)
- Symptomatic: fatigue, weight loss, sweating, abdominal fullness
- Massive splenomegaly: may extend to pelvis
- Leucocytosis: WCC 50–400+ × 10⁹/L
- Gout: hyperuricaemia from high cell turnover
Accelerated/Blast Crisis
- Worsening symptoms, increasing spleen, fever
- Bleeding, infections
- Bone pain, lymphadenopathy
- Blast crisis: behaves like acute leukaemia
Red Flags
- Leucostasis (WCC >300): respiratory distress, altered consciousness, visual changes
- Blast crisis features
- Splenic infarction (acute left upper quadrant pain)
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| Leukaemoid reaction | Infection/inflammation, no Ph chromosome, LAP score high | BCR-ABL1, clinical context |
| Other MPNs (PV, ET, PMF) | Specific features for each, no Ph chromosome | JAK2, CALR, BCR-ABL1 |
| CLL | Lymphocytosis, mature lymphocytes, CD5/19/23+ | Flow cytometry |
| AML | >20% blasts, no Ph (unless CML blast crisis) | Bone marrow |
Diagnosis / Investigation
Bloods
- FBC: leucocytosis (often 50–400+); full range of myeloid maturation — myelocytes, metamyelocytes, neutrophils, basophilia, eosinophilia
- Blood film: leucocytosis with orderly left shift; basophilia; no maturation gap (unlike AML)
- LDH, urate: raised
Definitive
- BCR-ABL1 by RT-PCR (peripheral blood): most sensitive; quantitative monitoring
- Cytogenetics (bone marrow): Philadelphia chromosome t(9;22)
- FISH: BCR-ABL1 fusion
Bone Marrow
- Hypercellular with granulocytic hyperplasia
- Cytogenetics: for additional chromosomal abnormalities
Monitoring on TKI
- BCR-ABL1 RT-qPCR: every 3 months
- Major molecular response (MMR): BCR-ABL1 ≤0.1% IS
- Deep molecular response (MR4/MR4.5): ≤0.01%/0.0032%
- Treatment milestones: BCR-ABL1 ≤10% at 3 months, ≤1% at 6 months, ≤0.1% at 12 months
Management
Pharmacological
First-line (chronic phase):
- Imatinib 400mg OD: first-generation TKI (NICE TA251)
- ~95% complete haematological response
- ~85% complete cytogenetic response at 5 years
Second-generation TKIs (faster/deeper responses):
- Dasatinib 100mg OD (NICE TA426)
- Nilotinib 300mg BD (NICE TA251)
- Bosutinib: for resistance/intolerance
Resistance/intolerance:
- Switch to alternative TKI
- Ponatinib: for T315I 'gatekeeper' mutation (resistant to all other TKIs)
- Asciminib: novel allosteric BCR-ABL1 inhibitor (NICE TA969)
Blast crisis:
- TKI + acute leukaemia-type chemotherapy; allogeneic SCT if possible
Treatment-Free Remission (TFR)
- Patients with sustained deep molecular response (MR4/MR4.5 for ≥2 years) may attempt TKI discontinuation
- ~50% maintain TFR; ~50% lose MMR and need to restart (virtually all re-respond)
- STIM and EURO-SKI trials
Supportive
- Allopurinol: prevent gout/TLS at diagnosis
- Monitoring: FBC, LFTs, lipase (TKI side effects)
Referral Criteria
- Haematology: all confirmed/suspected CML
- Specialist CML centre for treatment decisions
Prognosis
- Pre-imatinib era: median survival ~3–5 years
- Imatinib era: 10-year survival ~85–90%; near-normal life expectancy for most chronic phase patients
- Chronic phase responding to TKI: life expectancy approaches general population
- Accelerated phase: reduced survival (~2–3 years historically; improved with TKIs)
- Blast crisis: median survival ~6–12 months
- T315I mutation: poor (addressed by ponatinib/asciminib)
- TFR achievable in ~50% of eligible patients
Other Relevant Information
CML Phase Criteria
| Phase | Blasts | Other Features |
|---|---|---|
| Chronic | <10% | Controlled; most patients at diagnosis |
| Accelerated | 10–19% | Basophilia >20%, persistent thrombocytopenia, additional cytogenetics |
| Blast crisis | ≥20% | Resembles acute leukaemia |
TKI Treatment Milestones
| Time | Optimal Response |
|---|---|
| 3 months | BCR-ABL1 ≤10% IS |
| 6 months | BCR-ABL1 ≤1% IS |
| 12 months | BCR-ABL1 ≤0.1% IS (MMR) |