Chronic myeloid leukaemia — clinical features and management

Definition and cytogenetics. A myeloproliferative neoplasm defined by the Philadelphia chromosome — t(9;22) (q34;q11) — producing the BCR::ABL1 fusion gene, which encodes a constitutively active tyrosine kinase. Median age at diagnosis is about 65 years.

Clinical features. Up to 50% are asymptomatic and detected on a routine blood count. Otherwise: fatigue, weight loss, night sweats, low-grade fever, massive splenomegaly with early satiety, left hypochondrial dragging pain and splenic infarction, bone tenderness over the sternum, gout from hyperuricaemia, and rarely leucostasis (priapism, visual disturbance, confusion) when the white count exceeds 300 × 109/L.

Phases. Chronic phase — blasts <10%, over 90% present here, indolent. Accelerated phase — blasts 10–19%, basophils ≥20%, persistent thrombocytopenia or thrombocytosis, clonal evolution. Blast crisis — blasts ≥20% in blood or marrow, or an extramedullary blast proliferation; two-thirds are myeloid and one-third lymphoid, and prognosis is poor.

Laboratory diagnosis. Marked leucocytosis (often >100 × 109/L) with the full spectrum of immature granulocytes ("left shift"), a myelocyte bulge, and characteristic basophilia and eosinophilia; thrombocytosis is common; the leucocyte alkaline phosphatase score is characteristically low (distinguishing it from a leukaemoid reaction). Confirm with cytogenetics for the Philadelphia chromosome, FISH, and quantitative RT-PCR for BCR::ABL1 transcripts (which is also used for monitoring). Marrow shows granulocytic hyperplasia with a raised myeloid:erythroid ratio.

Treatment. Tyrosine kinase inhibitors are the treatment of choice and have converted CML into a chronic disease with near-normal life expectancy. First-line: imatinib 400 mg daily, or a second-generation agent (dasatinib, nilotinib, bosutinib) for higher-risk disease or faster response. Hydroxyurea is used briefly for cytoreduction and leukapheresis for leucostasis. Allopurinol and hydration prevent tumour lysis. Allogeneic transplantation is now reserved for blast crisis or multiple TKI failure. For T315I mutation, use ponatinib or asciminib.

Monitoring, toxicity and treatment-free remission. Monitor BCR::ABL1 by RT-PCR on the International Scale every 3 months. Milestones: ≤10% at 3 months, ≤1% at 6 months, and ≤0.1% (major molecular response, MMR or MR3) at 12 months. In the elderly, watch TKI toxicity — imatinib: oedema, cramps, cytopenias; dasatinib: pleural effusion; nilotinib: QT prolongation, hyperglycaemia and arterial occlusive events; ponatinib: arterial thrombosis — and check drug interactions (CYP3A4). Treatment-free remission may be attempted after at least 3 years of therapy with a sustained deep molecular response (MR4.5) for 2 years, with monthly monitoring; about half remain in remission.

Asciminib — ASC4FIRST trial (NEJM 2024;391:885; FDA accelerated approval October 2024, NCCN category 1). Asciminib is the first allosteric BCR::ABL1 inhibitor, which binds the ABL myristoyl pocket (a "STAMP" inhibitor) rather than the ATP site. In newly diagnosed chronic-phase CML it produced a major molecular response at 48 weeks in 68% versus 49% with investigator-selected TKIs, with markedly fewer dose reductions and discontinuations for toxicity — a particular advantage in older patients with comorbidity. It is also effective against the T315I mutation.