The BCR-ABL protein
Chronic myeloid leukaemia (CML) is caused by a chromosomal translocation known as the Philadelphia chromosome. This creates an abnormal fusion gene, BCR-ABL, which produces a constitutively active tyrosine kinase — a protein that permanently signals cells to divide. Imatinib fits precisely into the ATP-binding site of BCR-ABL and blocks this signal.
Mechanism of action
Imatinib is a tyrosine kinase inhibitor (TKI). By occupying the kinase domain, it prevents the phosphorylation cascade that drives uncontrolled cell proliferation. It also inhibits KIT (relevant in gastrointestinal stromal tumours, GIST) and PDGFR.
How it is taken
Standard CML dosing is 400 mg once daily taken with a meal and a large glass of water to reduce nausea. GIST treatment uses 400 mg or 600 mg daily. Food significantly reduces peak plasma concentration but not overall absorption — taking it with food primarily reduces gastric side effects.
Common side effects
Nausea (most common, usually mild and time-limited), periorbital oedema (puffiness around the eyes), muscle cramps, fatigue, and skin rash. Serious but rare: hepatotoxicity, fluid retention, and cardiac events — patients have liver function monitored regularly.
Resistance
About 20–25% of patients develop resistance over time, usually through point mutations in the BCR-ABL kinase domain. Second-generation TKIs (dasatinib, nilotinib) or third-generation (ponatinib, asciminib) are used for resistant or intolerant patients.