Pharmacology Update

Imatinib (Gleevec) for Treatment of CML

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

Imatinib (gleevec) was recently approved for the treatment of chronic myeloid leukemia (CML). The drug is considered a major breakthrough in oncologic therapy and its approval was heralded with much fanfare, which included a cover story in Time magazine. The drug is revolutionary because it targets the molecular understructure of cancer cells, leaving healthy cells alone. Because of this and intense public pressure, the drug was approved by the FDA less than 3 months following application.

Indications

Imatinib is indicated for the treatment of patients with CML in blast crisis, accelerated phase, or in chronic phase after failure with interferon therapy.1

Dosage

The recommended dose of imatinib is 400 mg daily for patients in chronic phase CML and 600 mg daily for patients with accelerated phase or blast crisis. The dose may be increased if there is disease progression, inadequate hematologic response after 3 months of therapy, or the loss of a previously achieved response. For patients with chronic phase CML, the dose may be increased from 400 mg daily to 600 mg daily if tolerated (ie, absence of severe adverse hematologic or nonhematologic reactions). For patients with accelerated phase or blast crisis the dose may be increased from 600 mg to 800 mg (400 mg twice daily).1 The drug should be taken with a meal and with a large glass of water to reduce gastrointestinal irritation. The drug should be continued as long as it remains effective.

The dose should be adjusted or withheld if severe nonhematologic adverse reactions (hepatotoxicity or fluid retention) or severe hematologic adverse reactions (neutropenia or thrombocytopenia) occur. Complete blood counts should be performed weekly for the first month and biweekly for the second month of therapy, and every 2-3 months thereafter.1

Imatinib is supplied as 100 mg capsules.

Potential Advantages

Imatinib appears to have significant advantages over current therapies for CML such as interferon alpha. Imatinib appears to have a better and more rapid response, fewer adverse effects, and can be given orally.2,4 It also appears to be effective in patients who have failed interferon therapy.3

Potential Disadvantages

The most frequent side effects are nausea (55-68%), vomiting (28-54%), fluid retention (52-58%), diarrhea (33-49%), and muscle cramps (25-46%). Severe fluid retention (eg, pleural effusion, pericardial effusion, pulmonary edema, ascites) has been reported in 1-2% of patients and increases with higher imatinib dose and age older than 65 years. Severe superficial edema has been reported in 1-3% of patients. Cytopenias are more frequent with patients with accelerated CML or blast crisis than with chronic phase CML. The frequencies of cytopenias range from 16-30% for grade 3 and 8-46% for grade 4. The frequency of anemia was 4-40% and less than 1-10%, respectively. Severe elevation of transaminases or bilirubin can also occur and the patients should be monitored at baseline and monthly or as clinically indicated.1 Due to the expedited FDA approval and limited follow-up time, toxicities as a result of long-term use are not known.1

Imatinib is metabolized primarily by cytochrome P450 3A4, and as such, pharmacokinetics of the drug can be affected by substances which inhibit, induce, or are substrates of this isoenzyme. Imatinib is also a inhibitor of CYP3A4 and CYP2D6.1

Comments

Imatinib is an inhibitor of BCR-ABL tyrosine kinase. This deregulated kinase is produced by the BCR-ABL fusion gene and appears to have a pathogenic role in CML. BCR-ABL oncoprotein, found on the Philadelphia chromosomes, is a result of the reciprocal translocation of 2 normal genes, BCR and ABL. Tyrosine kinase activity is apparently required for the oncogenic activity.5 Imatinib has produced significant responses in patients with CML. A total of 1027 patients were studied in the clinical trials: 532 with chronic phase CML and prior interferon treatment, 235 with accelerated phase disease, and 260 with myeloid blast crisis.1 Response was most impressive in chronic phase interferon patients with 88% showing a hematologic response, 88% complete response, and 49% showing a major cytogenetic response and 30% showing a complete response. Responses in accelerated phase and myeloid blast crisis were 63%, 28%, 21%, and 14% and 26%, 4%, 13.5%, and 5%, respectively.1 The median time to hematologic response was 1 month. Hematologic response was defined as a 50% reduction in white cell count from baseline maintained for 2 weeks. Complete response was defined as a reduction in white-cell count to less than 10,000 mm3 and platelet counts to less than 450,000 mm3 maintained for at least 4 weeks.3 Cytogenetic response was defined as 35% or less of cells in the metaphase that were positive for the Philadelphia chromosome in the bone marrow.3 Complete response is 0%. Increased survival or improved disease-related symptoms have not been demonstrated in a controlled trial.

The drug is extremely expensive. Monthly cost is about $2400 and annual cost is about $30,000. Novartis will provide the drug free to uninsured patients with an annual income of under $43,000 and a sliding scale for those from households with an annual income of $43,000-$100,000.6

Clinical Implications

CML is a clonal disorder characterized by leukocytosis and the presence of immature white blood cells in the peripheral blood and hypercellular marrow with myeloid hyperplasia in the bone marrow. It is estimated that there are about 25,000 people in the United States with the disease. CML generally progresses through a chronic phase, accelerated phase, and blast crisis (acute leukemia), with median survival about 6 years. Current therapies—all with limitations—include allogeneic bone marrow transplantation, chemotherapy (eg, hydroxyurea), and interferon-alfa with or without cytarabine. Imatinib provides a breakthrough treatment for CML compared to interferon. Although the drug is directed at the abnormal "target" in CML, it is not a cure, is not completely effective, and does have side effects. Also, the long-term effects are not known due to inadequate follow-up of study patients. Whether imatinib is only specific to CML or can be effective in other types of cancers (eg, gastrointestinal stromal tumor) is yet to be determined.

References

1. Gleevec Product Information. Novartis Pharmaceutical Corporation. May 2001.

2. Goldman JM, JV Melo. N Engl J Med. 2001;344: 1084-1086.

3. Druker BJ, et al. N Engl J Med. 2001;344:1031-1037.

4. Druker BJ, et al. N Engl J Med. 2001;344:1038-1042.

5. Lugo TG, et al. Science. 1990;247:1079-1082.

6. FDC Report. The Pink Sheet 2001;63:3-4.