What is the role of Imatinib (Gleevec) in the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GISTs)?

From the Guidelines

Imatinib (Gleevec) is a first-line treatment for both chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GISTs), with a standard dosage of 400 mg daily for CML and 400 mg daily for GISTs, which may be increased to 800 mg daily in certain cases with specific mutations.

Key Points

• Imatinib works by specifically inhibiting the BCR-ABL tyrosine kinase enzyme produced by the Philadelphia chromosome abnormality in CML, and the KIT (CD117) protein or PDGFRA mutations that drive tumor growth in GISTs 1.
• The treatment is typically continued indefinitely as long as the patient responds and tolerates the medication, with regular monitoring of blood counts and liver function essential during treatment 1.
• Common side effects include edema, muscle cramps, nausea, diarrhea, and fatigue, with a dose reduction considered in patients who achieved a major molecular response (MMR) 1.
• Imatinib has revolutionized treatment for these conditions, transforming CML from a fatal disease to a manageable chronic condition and significantly improving survival rates for GIST patients, demonstrating the power of targeted molecular therapy in cancer treatment 1.

Dosage and Administration

• The standard dose of imatinib is 400 mg once daily for CML, with a lower dose of 300 mg used if 400 mg is not tolerated and the response is optimal 1.
• For GISTs, the standard dose is 400 mg daily, which may be increased to 800 mg daily in certain cases with specific mutations, such as KIT exon 9 mutations 1.

Efficacy and Safety

• Imatinib has shown high efficacy in treating CML and GISTs, with early molecular response rates at 3 and 6 months ranging between 60 and 80%, and 5-year probability of achieving a deep molecular response (DMR) ranging between 35 and 68% 1.
• The most frequent causes of poor tolerance are early fluid retention, gastrointestinal symptoms, muscle cramps, joint pain, skin rash, and fatigue, with many of these adverse events resolving over time or after a brief drug holiday 1.

From the FDA Drug Label

Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events In vitro,imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-Kit mutation.

The role of Imatinib (Gleevec) in the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GISTs) is to inhibit the proliferation of cancer cells and induce apoptosis.

• Key mechanism of action: Inhibition of the BCR-ABL tyrosine kinase and the receptor tyrosine kinases for PDGF and SCF, c-Kit.
• Effect on CML cells: Inhibition of proliferation and induction of apoptosis in BCR-ABL positive cell lines.
• Effect on GIST cells: Inhibition of proliferation and induction of apoptosis in GIST cells with an activating c-Kit mutation 2.

From the Research

Imatinib in Chronic Myeloid Leukemia (CML) and Gastrointestinal Stromal Tumors (GISTs)

• Imatinib, also known as Gleevec, is a tyrosine kinase inhibitor that targets constitutively activated tyrosine kinases, such as BCR-ABL in CML and c-KIT in GISTs 3.
• The introduction of imatinib has substantially changed the clinical management of both diseases, improving prognosis and being surprisingly well tolerated 3.
• Imatinib induces high rates of cytogenetic and molecular responses in all phases of CML and has substantial activity in GIST patients 3.

Mechanism of Action and Efficacy

• Imatinib prevents the BCR-ABL protein from exerting its role in the oncogenic pathway in CML by directly inhibiting the constitutive tyrosine kinase activity 4.
• Imatinib binds to the BCR-ABL kinase domain, preventing the transfer of a phosphate group to tyrosine on the protein substrate, and subsequently blocking the transmission of proliferative signals to the nucleus and inducing leukemic cell apoptosis 4.
• The FDA has approved imatinib as first-line treatment for newly diagnosed CML, and it has shown outstanding effectiveness and superiority with respect to rates of complete hematological response, major and complete cytogenetic response, and overall survival 4, 5.

Safety Profile and Long-term Considerations

• Treatment with imatinib is generally well tolerated, with a low risk of severe adverse effects, which are more likely to occur during the early phase of treatment and correlate with imatinib dose, phase of disease, and patient characteristics 3, 6.
• Prolonged treatment with imatinib in both CML and GIST demonstrates excellent tolerability, with few significant concerns, such as cardiotoxicity, which have been found to be exaggerated 6.
• Therapeutic drug monitoring (TDM) for imatinib has been suggested to improve efficacy, assess compliance, and evaluate drug-drug interactions, particularly in patients with suboptimal response to treatment, treatment failure, rare adverse events, or suspected nonadherence 7.