Gleevec - Drug Monograph

Introduction

Gleevec (imatinib mesylate) is a revolutionary targeted therapy that represents a paradigm shift in cancer treatment. Developed by Novartis, this tyrosine kinase inhibitor was first approved by the FDA in 2001 and has transformed the management of several hematologic malignancies and solid tumors. Gleevec specifically targets abnormal proteins that drive cancer cell proliferation, offering a more selective approach compared to traditional chemotherapy.

Mechanism of Action

Gleevec works as a selective inhibitor of multiple tyrosine kinases, including:

• BCR-ABL tyrosine kinase (the pathogenic fusion protein in chronic myeloid leukemia)
• c-KIT (CD117) receptor tyrosine kinase
• Platelet-derived growth factor receptors (PDGFR-α and PDGFR-β)

The drug competitively inhibits the ATP-binding site of these kinases, preventing phosphorylation of downstream substrates and interrupting signal transduction pathways that promote cellular proliferation and inhibit apoptosis. This targeted approach specifically affects cancer cells expressing these abnormal kinases while sparing normal cells.

Indications

FDA-approved indications include:

• Chronic myeloid leukemia (CML) in chronic phase, accelerated phase, or blast crisis
• Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL)
• Myelodysplastic/myeloproliferative diseases (MDS/MPD) with PDGFR gene rearrangements
• Aggressive systemic mastocytosis (ASM) without the D816V c-KIT mutation or with unknown c-KIT status
• Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL)
• Dermatofibrosarcoma protuberans (DFSP)
• Gastrointestinal stromal tumors (GIST) that are c-KIT positive

Dosage and Administration

• CML chronic phase: 400 mg orally once daily
• CML accelerated phase/blast crisis: 600 mg orally once daily
• Ph+ ALL: 600 mg orally once daily
• GIST: 400 mg orally once daily
• DFSP: 800 mg daily (400 mg twice daily)

• Take with a meal and large glass of water to minimize gastrointestinal irritation
• Tablets should be swallowed whole
• For patients unable to swallow tablets, tablets may be dispersed in water or apple juice

• Hepatic impairment: Reduce dose by 25%
• Renal impairment (CrCl <30 mL/min): Reduce dose by 50%
• Elderly: No specific dose adjustment required
• Pediatrics: Safety established for children ≥2 years

Pharmacokinetics

Contraindications

• Hypersensitivity to imatinib or any component of the formulation
• Pregnancy (unless potential benefit justifies potential risk to fetus)

Warnings and Precautions

• Congestive heart failure and left ventricular dysfunction
• Severe fluid retention (pleural effusion, pericardial effusion, pulmonary edema, ascites)

• Hematologic toxicity: Severe neutropenia, thrombocytopenia, and anemia
• Hepatotoxicity: Monitor liver function tests regularly
• Severe dermatologic reactions including Stevens-Johnson syndrome
• Hypothyroidism in patients undergoing thyroidectomy
• Growth retardation in children and adolescents
• Tumor lysis syndrome (particularly in patients with high tumor burden)
• GI perforation (rare)

Drug Interactions

• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin): ↑ imatinib levels
• Strong CYP3A4 inducers (rifampin, phenytoin, carbamazepine): ↓ imatinib levels
• Warfarin: Use alternative anticoagulants due to CYP2C9 inhibition

• Simvastatin: Increased risk of myopathy
• Cyclosporine, pimozide: Increased concentrations of these drugs

Adverse Effects

• Fluid retention (periorbital edema, peripheral edema)
• Nausea, vomiting, diarrhea
• Muscle cramps, musculoskeletal pain
• Fatigue, headache
• Rash
• Neutropenia, thrombocytopenia

• Severe fluid retention (pleural effusion, ascites)
• Hepatotoxicity
• Severe neutropenia/thrombocytopenia
• Hemorrhage
• Congestive heart failure

• Stevens-Johnson syndrome
• GI perforation
• Tumor lysis syndrome
• Growth retardation in children

Monitoring Parameters

• Complete blood count with differential
• Comprehensive metabolic panel (including liver function tests)
• Cardiac assessment (ECHO or MUGA scan if indicated)
• Pregnancy test in women of childbearing potential

• CBC weekly for first month, then monthly
• LFTs monthly
• Weight regularly to monitor for fluid retention
• Clinical assessment for edema and respiratory symptoms
• Response monitoring: Cytogenetic analysis, FISH, or PCR for BCR-ABL in CML

• Annual cardiac assessment in high-risk patients
• Bone density monitoring in children
• Thyroid function in patients with thyroidectomy
• Growth parameters in pediatric patients

Patient Education

• Take with food and large glass of water to reduce GI upset
• Do not crush or break tablets
• Report immediately: Unexplained weight gain, swelling, shortness of breath, unusual bleeding or bruising, yellowing of skin/eyes, severe rash
• Use effective contraception during treatment and for at least 3 months after discontinuation
• Regular follow-up appointments are essential
• Inform all healthcare providers about Gleevec therapy
• Many drug interactions possible - discuss all medications (including OTC and herbal) with healthcare provider
• Adherence is critical for optimal response - do not miss doses

References

1. FDA Prescribing Information: Gleevec (imatinib mesylate) tablets 2. Druker BJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344(14):1031-1037. 3. Kantarjian H, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346(9):645-652. 4. Demetri GD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347(7):472-480. 5. NCCN Clinical Practice Guidelines in Oncology: Chronic Myeloid Leukemia (2023) 6. Hochhaus A, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376(10):917-927. 7. Larson RA, et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood. 2008;111(8):4022-4028.