Chronic myeloid leukaemia
Description
- MPN driven by a single lesion: t(9;22)(q34;q11) -> BCR::ABL1
- Triphasic if untreated: chronic -> accelerated -> blast phase
- >90% present in chronic phase, often incidentally on FBE
- Marrow is hypercellular but not failing - Hb and platelets preserved or high
- Cytopenias at diagnosis should prompt a search for another cause or advanced phase
- The proof-of-concept disease for targeted therapy - near-normal life expectancy on TKI
Epidemiology
- ~15% of adult leukaemias; incidence ~1-1.5/100,000/yr (~350 new cases/yr Australia)
- Median age ~60-65; M>F ~1.4:1
- Prevalence rising steeply - incidence flat, mortality collapsed
- Only established risk factor: ionising radiation. Not inherited, no familial clustering
Aetiopathogenesis
- Reciprocal translocation ABL1 (9q34) -> BCR (22q11) = Philadelphia chromosome
- Constitutively active cytoplasmic tyrosine kinase
- -> RAS/MAPK, JAK-STAT, PI3K activation
- -> proliferation, dec apoptosis, dec stromal adhesion (premature marrow release)
| Transcript | Protein | Disease |
|---|---|---|
| e13a2 / e14a2 (b2a2/b3a2) | p210 | CML (>95%) |
| e1a2 | p190 | Ph+ ALL; rare CML with monocytosis |
| e19a2 | p230 | Neutrophilic CML, thrombocytosis |
- Transcript type matters practically: standardised IS quantitation only exists for p210 - atypical transcripts need a lab-specific assay
- Progression to blast phase = acquisition of additional lesions
- ACAs (+8, +Ph, i(17q), +19), TP53 (myeloid blast crisis), IKZF1/CDKN2A (lymphoid)
- BCR::ABL1 alone is necessary and sufficient for chronic phase, not for transformation
Diagnosis
FBE + film
- Leucocytosis with the full myeloid series - myelocyte peak ("myelocyte bulge"), left shift without a leukaemic gap
- Basophilia - near universal, the single most useful film clue
- Eosinophilia; platelets normal or high; anaemia mild
- Low LAP/NAP score - historic, no longer performed
Marrow
- Hypercellular, M:E ratio >10:1, small hypolobated ("dwarf") megakaryocytes
- Pseudo-Gaucher cells, sea-blue histiocytes
- Reticulin fibrosis grade = independent adverse prognostic marker
- Needed at diagnosis for karyotype, blast %, phase - not for the diagnosis itself
Confirming the lesion
- RT-qPCR for BCR::ABL1 on peripheral blood, reported on the International Scale (%IS) - baseline and all monitoring
- Karyotype (20 metaphases) - detects ACAs and variant/masked Ph
- FISH if karyotype fails
Phase
| Blasts (blood or marrow) | |
|---|---|
| Chronic | <10% |
| Accelerated | 10-19% (+ basophils >=20%, ACAs, resistant thrombocytosis/cytopenia) |
| Blast phase | >=20%, or extramedullary blastic proliferation |
- *WHO 5th edition and ICC 2022 both de-emphasise accelerated phase* - the meaningful division in the TKI era is chronic vs blast
- Blast phase: ~70% myeloid, ~30% lymphoid (lymphoid responds better, treat as Ph+ ALL)
Risk score
- ELTS (EUTOS Long-Term Survival) has replaced Sokal - age, spleen, platelets, blasts
- Predicts CML-related death; guides frontline TKI potency
Management
A. Frontline TKI - choose by ELTS risk and comorbidity
All achieve similar overall survival. Second-generation and asciminib achieve deeper responses faster -> more patients reach TFR.
| Agent | Dose | Positioning |
|---|---|---|
| Imatinib | 400 mg daily | Low ELTS, older, vascular comorbidity. Cheapest, best long-term safety |
| Nilotinib | 300 mg bd, fasting | Deep responses; worst vascular signal |
| Dasatinib | 100 mg daily | Deep responses; pleural effusion |
| Bosutinib | 400 mg daily | Diarrhoea, transaminitis |
| Asciminib | 80 mg daily | STAMP/allosteric myristoyl-pocket inhibitor. ASC4FIRST: superior MMR at 48 wk vs all comparators with fewer discontinuations; now a frontline option |
- High ELTS, young, TFR intent -> 2nd-generation or asciminib
- Vascular disease, diabetes, older -> imatinib
B. Monitoring - BCR::ABL1 %IS, 3-monthly
| Timepoint | Optimal | Failure |
|---|---|---|
| 3 mo | <=10% | >10% (confirmed) |
| 6 mo | <=1% | >10% |
| 12 mo | <=0.1% (MMR) | >1% |
| Any later | <=0.1% | >1%, loss of MMR, resistance mutation, ACA |
- MR4.0 = <=0.01%; MR4.5 = <=0.0032% - the depth needed for TFR
- *ELN 2025: do not switch at 3 months on molecular grounds alone* - check adherence, interactions and transcript type first
C. Treatment failure
- *Non-adherence is the commonest cause of failure* - and drives resistance mutation acquisition (incl. T315I). Ask before changing drug
- Then: drug interactions (PPIs with nilotinib/bosutinib; CYP3A4), dose intensity
- Kinase domain mutation analysis on confirmed failure or loss of response
| Mutation | Action |
|---|---|
| T315I | Ponatinib, asciminib 200 mg bd, or olverembatinib. No other TKI works |
| V299L, F317L | Avoid dasatinib -> nilotinib |
| Y253H, E255K/V, F359V | Avoid nilotinib -> dasatinib |
| Myristoyl-pocket (A337T, P465S) | Asciminib resistance |
D. TKI toxicity
- Class effects (all): myelosuppression, transaminitis, electrolyte disturbance, rash
- Imatinib - periorbital/facial oedema, muscle cramps, nausea/diarrhoea
- Dasatinib - pleural effusion (~30% cumulative), pulmonary hypertension, platelet dysfunction/bleeding, moderate vascular risk
- Nilotinib - arterial occlusive events, QT prolongation, hyperglycaemia, dyslipidaemia, pancreatitis, transaminitis. Fasting dosing, ECG monitoring
- Bosutinib - early diarrhoea (usually self-limiting), transaminitis
- Ponatinib - highest vascular risk (arterial occlusion ~25%), pancreatitis, hypertension. Response-adjusted dose reduction 45 -> 15 mg mitigates
- Asciminib - best-tolerated; pancreatic enzyme rise, hypertension, low-grade vascular events
- Baseline and ongoing cardiovascular risk assessment for every patient on a 2nd/3rd-generation TKI
E. Treatment-free remission
- ~50% of eligible patients stay in remission off drug
- Attempt only if:
- Chronic phase only, typical transcript, >=5 yr TKI (>=3 yr 2G)
- >=2 yr of sustained MR4.0 or deeper
- Access to monthly PCR for 6 months, then 2-monthly
- Restart TKI on loss of MMR - essentially all regain response
- TKI withdrawal syndrome - musculoskeletal pain in ~30%
F. Advanced phase
- Blast phase: TKI (ponatinib/asciminib guided by mutation) + phase-appropriate induction, then allogeneic SCT in remission
- Allo-SCT otherwise reserved for TKI-refractory or T315I with ponatinib failure
G. Other
- Hydroxyurea for cytoreduction pre-TKI; leukapheresis for symptomatic hyperleucostasis or in pregnancy
- Allopurinol + hydration at induction
- Interferon-alfa remains the option in pregnancy - TKIs are teratogenic in the first trimester
Associations
- Ph+ ALL - same lesion, usually p190
- Chronic neutrophilic-appearing CML with p230
- Prior ionising radiation exposure
- Pseudohyperkalaemia and spurious hypoglycaemia from extreme leucocytosis
- Gout / urate nephropathy from high cell turnover
- Splenic infarction; priapism with hyperleucostasis
Natural history & complications
- On TKI with an optimal response: survival approaches that of the age-matched population
- Most deaths now non-CML
- Untreated: chronic phase 3-5 yr -> blast phase -> median survival 6-12 months
- Annual risk of progression on TKI <1%/yr, and concentrated in the first 2-3 years
Adverse markers
- High ELTS, ACAs at diagnosis, marrow fibrosis, failure to reach <=10% at 3 months
- T315I
What to monitor
- BCR::ABL1 %IS 3-monthly until stable MR4, then 3-6 monthly indefinitely
- Confirmed rising transcript -> adherence check, then mutation analysis
- Cardiovascular risk factors, lipids, HbA1c on 2G/3G TKI
- Echo/CXR if dyspnoea on dasatinib
- Second cancers - no consistent excess attributable to TKI
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