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This is a clinician-written, evidence-based summary aligned to the 2026 MLA Content Map. It is intended for medical students and junior doctors preparing for the UKMLA. Always cross-reference with NICE guidance, local protocols, and clinical judgement.
Key points
- Defined by the Philadelphia chromosome: t(9;22) producing BCR-ABL1 fusion gene — a constitutively active tyrosine kinase
- Presentation: insidious with fatigue, weight loss, massive splenomegaly, raised WCC with left-shifted differential (all stages of granulocyte maturation on film)
- Three phases: chronic (most patients at diagnosis) → accelerated → blast crisis (behaves like acute leukaemia)
- Treatment: imatinib (first-generation TKI) is first-line — transforms CML from fatal disease to chronic manageable condition. Near-normal life expectancy if good response
- Monitor response with BCR-ABL1 transcript levels (quantitative PCR). Treatment-free remission possible in some patients after deep molecular response
Overview
Chronic myeloid leukaemia (CML) is a myeloproliferative neoplasm characterised by the Philadelphia chromosome — a reciprocal translocation t(9;22)(q34;q11) creating the BCR-ABL1 fusion gene. The resulting BCR-ABL1 protein is a constitutively active tyrosine kinase that drives uncontrolled proliferation of myeloid cells. CML progresses through three phases: chronic phase (90% at diagnosis), accelerated phase, and blast crisis (transformation to acute leukaemia). The development of imatinib (the first tyrosine kinase inhibitor) in 2001 revolutionised treatment, converting CML from a uniformly fatal disease to one with near-normal life expectancy.
Epidemiology
CML accounts for approximately 15% of adult leukaemias, with around 700 new cases per year in the UK. The median age at diagnosis is 55-60 years, with a slight male predominance. CML is rare in children. The incidence has remained stable, but prevalence is rising due to the dramatically improved survival with TKI therapy — patients now live near-normal lifespans. The only established risk factor is prior radiation exposure.
Clinical Features
Symptoms
Often insidious onset or incidental finding on routine FBC
Fatigue and malaise
Weight loss, night sweats
Left upper quadrant discomfort or early satiety (massive splenomegaly)
Bruising or bleeding (if thrombocytopenia — more common in accelerated/blast phase)
Gout (hyperuricaemia from high cell turnover)
Signs
MASSIVE SPLENOMEGALY — the hallmark physical finding. May extend to the right iliac fossa
Hepatomegaly
Sternal tenderness (marrow expansion)
Pallor (if anaemic)
Lymphadenopathy is uncommon (unlike CLL)
Investigations
First-line
FBCMarkedly raised WCC (often 50-500 × 10⁹/L) with left-shifted differential: neutrophils, myelocytes, metamyelocytes, promyelocytes, and basophils at every stage of maturation
Blood filmFull spectrum of granulocyte maturation (unlike AML where there is a "hiatus" between blasts and mature cells). Basophilia is characteristic. Low/absent leucocyte alkaline phosphatase (LAP)
Cytogenetics / FISHPhiladelphia chromosome t(9;22) — DIAGNOSTIC. Must be confirmed in all cases
Second-line
BCR-ABL1 quantitative PCRBaseline and ongoing monitoring — the key treatment response marker. Reported on International Scale (IS) as log reduction from baseline
Bone marrow aspirate and trephineConfirms chronic phase (blasts <10%). Required at diagnosis for baseline and if disease progression suspected
Urate, LDH, K+Hyperuricaemia common from high cell turnover
Specialist
BCR-ABL1 mutation analysisIf TKI resistance suspected — identifies mutations (e.g. T315I "gatekeeper" mutation resistant to first/second-gen TKIs, requires ponatinib)
1
Chronic phase — first-line TKI
- Imatinib 400 mg once daily — first-generation TKI, well-tolerated, excellent long-term outcomes
- Alternative first-line: dasatinib or nilotinib (second-generation TKIs) — faster and deeper responses but more side effects
- Monitor BCR-ABL1 PCR at 3, 6, 12 months and then 3-6 monthly
- Milestones: BCR-ABL1 ≤10% at 3 months, ≤1% at 6 months, ≤0.1% (major molecular response) at 12 months
2
Treatment failure or intolerance
- Switch to alternative TKI: dasatinib, nilotinib, bosutinib
- T315I mutation: ponatinib (third-generation TKI) or asciminib (STAMP inhibitor)
- Allogeneic stem cell transplant: reserved for blast crisis or multi-TKI failure
3
Blast crisis
- Behaves like acute leukaemia (lymphoid or myeloid blast crisis)
- TKI + induction chemotherapy. Consider allogeneic transplant if returns to chronic phase
- Prognosis poor — median survival 6-12 months if blast crisis
4
Treatment-free remission (TFR)
- Selected patients with deep molecular response (MR4.5 for ≥2 years) may attempt TKI discontinuation
- Approximately 50% maintain remission after stopping TKI
- Close molecular monitoring essential — restart TKI if molecular relapse detected
Complications
- Blast crisis: Transformation to acute leukaemia — the major cause of CML-related death. 70% myeloid, 30% lymphoid
- TKI side effects: Imatinib: fluid retention, nausea, muscle cramps, rash. Dasatinib: pleural effusions, pulmonary hypertension. Nilotinib: QT prolongation, vascular events
- Leukostasis: Very high WCC can cause pulmonary and cerebral symptoms — hydroxycarbamide for rapid cytoreduction
- Hyperuricaemia and gout: From massive cell turnover
UKMLA Exam Tips
- 1Philadelphia chromosome t(9;22) BCR-ABL1 = CML. This is THE defining feature — no Philadelphia = not CML
- 2Massive splenomegaly + very high WCC + basophilia + full spectrum of granulocyte maturation on film = CML
- 3Imatinib transformed CML from fatal disease to near-normal life expectancy — the paradigm for targeted cancer therapy
- 4CML vs leukaemoid reaction: CML has LOW leucocyte alkaline phosphatase (LAP) and Philadelphia chromosome. Reactive leucocytosis has HIGH LAP and no Philadelphia
- 5Blast crisis = CML transforming to acute leukaemia. Very poor prognosis
- 6T315I gatekeeper mutation = resistant to imatinib, dasatinib, nilotinib — requires ponatinib or asciminib
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