On May 20, 2003, the FDA granted accelerated approval of imatinib mesylate tablets (Gleevec™, a trademark of Novartis Pharmaceuticals) for treatment of pediatric patients with chronic phase Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) whose disease has recurred after stem cell transplant or become resistant to the drug interferon alpha. (Leukemic cells of more than 95 percent of patients with CML have a distinctive cytogenetic – chromosomal – abnormality, the Philadelphia or “Ph” chromosome.)

Approval is based on extrapolation of results from adults with CML and additional information from studies in children. Supportive pediatric information included complete cytogenetic responses, pharmacokinetic (drug activity in the body) information, and a safe pediatric dose. Approval is enabled by the separate approval of the scored 100 milligram (mg) tablet on April 18, 2003, for dosing in children. Novartis plans to make the tablets commercially available in July 2003.

Two phase 1 studies evaluated a total of 17 children who had experienced a recurrence of CML after they’d undergone stem cell transplant or become resistant to alpha interferon therapy. Patients were treated at doses of 260 mg/m2/day to 570 mg/m2/day. Dose limiting toxicity was not seen.

In 16 patients with chronic phase CML for whom cytogenetic data are available for these two studies, nine had a complete cytogenetic response (56 percent). Cytogenetic response rate appeared similar at all dose levels.

The recommended dose is 260 mg/m2/day. A dose increase to 340 mg/m2/day may be considered in the absence of severe adverse drug reaction and severe non-leukemia-related neutropenia (an abnormal decrease in the number of neutrophils, a type of white blood cell ) or thrombocytopenia (a decrease in the number of platelets in the blood) in the following circumstances: disease progression (at any time); failure to achieve a satisfactory hematologic response after at least three months of treatment; failure to achieve a cytogenetic response after 6-12 months of treatment; or loss of a previously achieved hematologic or cytogenetic response. There is no experience with imatinib treatment in children under three years of age.

Accelerated approval was granted based on evidence from surrogate endpoints. There are no controlled trials in children demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival. As a condition of approval, Novartis has agreed to provide data from an ongoing NCI-sponsored phase 2 study in children with chronic phase Ph+ CML.

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.

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