Chronic Myeloid Leukaemia (CML)

See Leukaemias — Overview for the cross-subtype comparison table, and Myeloproliferative Disorders for CML’s place in that broader classification.

Clonal myeloproliferation from a transformed pluripotent stem cell, producing a striking overproduction of mature and immature granulocytes. Granulocytes predominate, but the neoplastic clone also includes red cells, megakaryocytes and monocytes.

Demographics: average age 66. Lifetime risk about 1 in 500.

Philadelphia chromosome

The Philadelphia chromosome is present in 90–95% of cases — a reciprocal translocation t(9;22) fusing ABL to BCR. The resulting BCR::ABL1 oncoprotein is a constitutively active tyrosine kinase that drives proliferation, reduces adhesion to marrow stroma, and blocks apoptosis. It is the drug target and the monitoring marker.

Three phases

• Chronic — indolent, may last 5–6 years. <10% blasts. About 85–95% of patients are diagnosed here.
• Accelerated — treatment failure, worsening anaemia, thrombocytopenia or thrombocytosis, persistent splenomegaly, rising basophils, 10–19% blasts, new clonal cytogenetic abnormalities.
• Blast — ≥20% blasts in blood or marrow, or extramedullary blast proliferation (bone, CNS, lymph nodes, skin). Behaves like acute leukaemia. Some patients jump straight here from chronic phase.

Presentation

Often asymptomatic and picked up on an incidental FBC or during work-up of splenomegaly. When symptoms occur they are insidious:

• Fatigue, weakness, anorexia, weight loss, night sweats.
• Left upper quadrant fullness or early satiety from splenomegaly.
• Gouty arthritis.
• Leukostasis — tinnitus, stupor, urticaria.

Examination: moderate or extreme splenomegaly in 60–70%. Pallor, bleeding, easy bruising and lymphadenopathy are unusual early. Fever, marked lymphadenopathy and maculopapular skin involvement are ominous.

Investigations

FBC and film

• Granulocytes usually <50 × 10⁹/L in asymptomatic patients, and 200–1000 × 10⁹/L when symptomatic.
• Left-shifted neutrophilia with myelocytes and metamyelocytes, plus basophilia and eosinophilia — this combination is what distinguishes CML from reactive leucocytosis.
• Platelets normal or raised; thrombocytosis is occasionally the presenting finding.
• Haemoglobin usually >100 g/L at diagnosis.

Confirming the diagnosis

• RT-PCR for BCR::ABL1 on peripheral blood is the most sensitive test, and the same assay is used to quantify residual disease.
• FISH or cytogenetics if RT-PCR unavailable — the classic Philadelphia karyotype is absent in about 5% of cases despite BCR::ABL1 being present.
• Baseline bone marrow aspirate and biopsy with cytogenetics, to assess phase, cellularity and myelofibrosis.
• Sokal or Hasford risk score in chronic phase, before choosing first-line therapy.

Treatment

Tyrosine kinase inhibitors are the mainstay and are started at diagnosis. First-line options in Australia are imatinib (first generation) and dasatinib or nilotinib (second generation). Bosutinib is also used. Progression is slightly more likely on imatinib, but it is less likely to cause life-threatening adverse events; dasatinib and nilotinib induce faster responses.

• Ponatinib — third generation, reserved for resistance to other TKIs and for the T315I mutation. Higher rate of vascular toxicity: myocardial infarction, stroke, peripheral vascular disease.
• Asciminib — binds an alternative allosteric site on BCR::ABL1; used after two or more prior TKIs, and in chronic phase with the T315I mutation.
• Allogeneic stem cell transplant — reserved for accelerated or blast phase, or TKI-resistant disease. Potentially curative.
• Hydroxyurea, busulfan and interferon are now only palliative (mainly to reduce splenomegaly and tumour burden); none prolongs survival.

TKI dosing and practical points

Drug	Dose	Practical points
Imatinib	400–600 mg daily	Take with food. More nausea, vomiting, diarrhoea and fluid retention (peripheral, eyelid and periorbital oedema) than other TKIs.
Dasatinib	100 mg daily	With or without food. Prolongs QT. Antacids within 2 hours, H2 blockers and PPIs reduce absorption — combined use not recommended. Pleural and pericardial effusions. Rare fatal pulmonary hypertension — investigate unexplained dyspnoea.
Nilotinib	300 mg twice daily	Empty stomach — 2 hours before or 1 hour after food. Prolongs QT. Vaso-occlusive events, raised lipids and glucose, pancreatitis.
Bosutinib	500 mg daily	Second-generation alternative.
Ponatinib	45 mg daily	Third line / T315I. High vascular toxicity.

All are major CYP3A4 substrates — check for interacting inhibitors and inducers at every prescription.

Monitoring

• Quantitative RT-PCR for BCR::ABL1 at 3, 6 and 12 months, then every 3–6 months once a major molecular response is achieved.
• BCR::ABL1 is set at 100% at diagnosis on the international scale; major molecular response is <0.1%.
• Optimal ELN response targets: ≤10% at 3 months, <1% at 6 months, ≤0.1% at 12 months. Failing these prompts a check of adherence, then a change of TKI.
• Treatment-free remission is possible for selected patients with a deep, durable response — roughly 40–60% of low-to-intermediate-risk patients. Criteria are strict. Most relapses occur in the first 6 months, so monitoring is monthly for the first year.

GP role

• Adherence is the single biggest modifiable factor. Patients on imatinib with adherence below 85% are over 17 times more likely to lose disease control.
• Cardiovascular risk. Dasatinib and nilotinib raise the risk of ischaemic heart and cerebrovascular disease — actively manage smoking, blood pressure, lipids and weight.
• Vaccination. Influenza and pneumococcal vaccines should be considered; live attenuated vaccines are advised against in patients taking TKIs.
• Hepatitis B. Reactivation is the one recognised infection risk in CML — check serology and consider antiviral prophylaxis if positive.
• Pregnancy. All TKIs are category C or D. Refer to the haematologist before conception; effective contraception otherwise.

Prognosis

Over 90% five-year survival on TKIs, up from 33% before imatinib, and 10-year survival around 84%. Annual CML mortality has fallen to under 2% per year, and most patients diagnosed in chronic phase reach near-normal life expectancy. Most patients need lifelong therapy.