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6/25/2001

New Drug Targets Genetic Malfunction in Chronic Myeloid Leukemia

Cheryl A. Thompson

Two and a half months after Novartis submitted a new drug application for imatinib mesylate (Gleevec [PDF]), FDA approved the marketing of the tyrosine kinase inhibitor for the treatment of patients with chronic myeloid leukemia (CML). The drug has been described by government officials as the first one available designed by molecular targeting—that is, identifying a disease's genetic malfunction and attacking it.

Most patients with CML have the Philadelphia chromosome, formed by the translocation of segments of chromosomes 9 and 22. The abnormal gene sequence on chromosome 22 encodes a protein, BCR-ABL, that causes white blood cells (WBCs) to rapidly increase in number. By inhibiting BCR-ABL's tyrosine kinase activity, imatinib stops the protein’s oncogenic activity.

The rapid decision by FDA was made under the regulations governing the accelerated approval of drugs for serious or life-threatening diseases. Three multicenter, open-label, noncomparative studies indicated that imatinib mesylate produced hematologic and cytogenetic responses in adults with Philadelphia chromosome-positive CML in the chronic phase after inadequate response to interferon alfa therapy; the accelerated phase; or myeloid blast crisis. Novartis must report the results of four other studies, including one that compares imatinib mesylate with interferon alfa and cytarabine in patients with newly diagnosed, previously untreated Philadelphia chromosome-positive CML in the chronic phase.

The three noncomparative studies of imatinib's efficacy involved 1027 patients, more than half of whom were in the chronic phase of CML and had received interferon alfa therapy. Patients received 400 or 600 mg/day of imatinib, depending on the stage of their disease. A hematologic response was reported for 88% of the patients in the chronic phase, 63% of those in the accelerated phase, and 26% in myeloid blast crisis.

A major cytogenetic response, meaning that <35% of Philadelphia chromosome-positive WBCs were in metaphase, was reported for 49% of patients in the chronic phase, 21% of those in the accelerated phase, and 13.5% in myeloid blast crisis. The duration of either response, hematologic or cytogenetic, was not reported in the labeling because the follow-up on most patients was fairly short. As yet, there are no controlled clinical studies showing that the drug increases patients' survival or decreases their disease-related symptoms.

The major adverse effects of imatinib therapy are fluid retention, edema, GI irritation, neutropenia, thrombocytopenia, and hepatotoxicity. Clinicians should regularly weigh patients and monitor them for signs and symptoms of fluid retention. Severe fluid retention has occurred in up to 2% of patients during therapy. Clinicians should monitor patients' complete blood count weekly for the first month, every other week for the second month, and then periodically. The should also monitor patients’ liver function before the start of treatment and then monthly or as clinically indicated. Long-term use of the drug may reveal other notable adverse effects.

After oral administration, imatinib is almost completely absorbed. About 75% of a dose is metabolized, primarily by cytochrome P-450 (CYP) isoenzyme 3A4, which produces the major active metabolite, but also by isoenzymes 1A2, 2D6, 2C9, and 2C19. Ketoconazole, a CYP 3A4 inhibitor, increases the plasma concentration of imatinib. The labeling advises that clinicians prescribe low-molecular-weight or unfractionated heparin to patients requiring anticoagulation and imatinib therapy because warfarin is metabolized by CYP 2C9. Also, clinicians should exercise caution when prescribing imatinib to patients taking CYP 3A4 substrates that have a narrow therapeutic range.

Drug clearance varies among patients by as much as 40%, which, according to the labeling, does not warrant adjusting the initial dosage but does indicate the need for clinicians to closely monitor patients for drug-related toxicity. The clinical studies conducted to date did not include patients with impaired hepatic function or a serum creatinine concentration of more than two times the upper limit of the normal range.

The recommended dosage of imatinib is 400 mg/day for patients in chronic phase CML; 600 mg/day for patients in the accelerated phase or blast crisis. Therapy should continue for as long as the patient benefits. Each dose should be taken orally once daily with a meal and a large glass of water. The dosage may be increased by, at most, 200 mg/day, to achieve a dosage of 600 or 800 mg/day, if the patient does not respond adequately to treatment and does not have a severe adverse drug reaction or severe neutropenia or thrombocytopenia unrelated to leukemia. If severe neutropenia or thrombocytopenia develops, the dosage of imatinib should be reduced or therapy should be stopped. The package insert includes instructions on adjusting the dosage and restarting therapy.

Gleevec is available as 100-mg capsules in bottles of 120.

Less than two weeks before FDA approved the marketing of imatinib mesylate, Novartis changed the brand name from Glivec to Gleevec at the agency's request. An FDA official said the agency discussed the name Glivec with inhouse physicians and focus groups and concluded that it could be confused with Glynase (Pharmacia’s glyburide product) and Glyset (Bayer’s miglitol). Glivec remains imatinib's brand name in countries other than the United States and appears in the medical literature.