Imatinib

• Chronic Myeloid Leukemia (CML)
• Gastrointestinal Stromal Tumor (GIST)
• Philadelphia Chromosome-Positive Leukemia
• Targeted Cancer Therapy

Imatinib is a tyrosine kinase inhibitor (TKI) that revolutionized the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). This targeted therapy was one of the first molecularly targeted cancer treatments and transformed CML from a fatal disease to a manageable chronic condition.

Mechanism of Action

Imatinib is a small molecule that selectively inhibits the BCR-ABL tyrosine kinase, the constitutively active kinase created by the Philadelphia chromosome translocation in CML. Imatinib binds to the ATP-binding site of BCR-ABL, blocking its kinase activity and the downstream signaling that drives leukemic cell proliferation and survival. Imatinib also inhibits other tyrosine kinases including the stem cell factor receptor (KIT) and platelet-derived growth factor receptors (PDGFR). The inhibition of KIT is particularly important for the treatment of GIST, where activating KIT mutations drive tumor growth.

Available Formulations

Imatinib mesylate is available as film-coated tablets in 100 mg and 400 mg strengths. The tablets should be taken with a meal and a large glass of water to minimize gastrointestinal irritation. For patients unable to swallow tablets, they can be dispersed in water or apple juice. Generic formulations are available.

Medical Uses

Imatinib is FDA-approved for newly diagnosed adult and pediatric patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase; patients with Ph+ CML in blast crisis, accelerated phase, or chronic phase after failure of interferon-alpha therapy; adults with relapsed or refractory Ph+ acute lymphoblastic leukemia (ALL); adults with myelodysplastic/myeloproliferative diseases with PDGFR gene rearrangements; adults with aggressive systemic mastocytosis; adults with KIT+ unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST); and adjuvant treatment of adults with KIT+ GIST after resection.

Dosing Guidelines

For CML chronic phase, the dose is 400 mg once daily (adults) or 340 mg/m²/day (pediatrics, max 600 mg). For CML accelerated phase or blast crisis, 600 mg daily is used. For GIST, 400 mg daily is standard; 800 mg daily (400 mg twice daily) may be used after disease progression. Doses may be increased if response is inadequate and no severe adverse reactions occur. Dose reductions are available for toxicity management.

Important Safety Information

Imatinib can cause severe fluid retention, including pleural effusion, pericardial effusion, pulmonary edema, and ascites. Cytopenias (neutropenia, thrombocytopenia, anemia) are common, especially in advanced CML; complete blood counts should be monitored regularly. Severe hepatotoxicity, including fatal liver failure, has been reported; liver function should be monitored. Cardiac toxicity including left ventricular dysfunction and congestive heart failure has occurred. The medication may cause fetal harm.

Drug Interactions

CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, grapefruit juice) increase imatinib levels. CYP3A4 inducers (rifampin, phenytoin, carbamazepine, St. John's Wort) decrease imatinib levels; avoid concurrent use or increase imatinib dose with careful monitoring. Imatinib inhibits CYP3A4 and CYP2D6; caution with substrates of these enzymes. Warfarin effect may be altered; use low molecular weight heparin instead.

Special Populations

Imatinib may cause fetal harm. Women should avoid becoming pregnant during treatment. Females and males of reproductive potential should use effective contraception during and after treatment. Imatinib is excreted in breast milk; breastfeeding should be discontinued. Safety and efficacy have been established in pediatric patients with Ph+ CML. Elderly patients do not require dose adjustment but may experience more edema. Patients with mild to moderate renal impairment may have increased exposure; doses greater than 600 mg are not recommended. Hepatic impairment requires dose reduction; 25% reduction for mild, 50% for moderate/severe impairment.