WASHINGTON —The Food and Drug Administration, acting with dispatch, has approved the marketing of Gleevec (imatinib mesylate, Novartis) for the treatment of chronic myeloid leukemia (CML). The agency granted the drug priority review and orphan drug status, and approved it under the FDA’s "accelerated approval" regulations less than 3 months after the sponsor submitted its marketing request.
The FDA approved Gleevec, an oral agent also known as STI-571, for use in patients with CML myeloid blast crisis, accelerated phase, or chronic phase after failure of interferon treatment. It acted on the basis of three separate single-arm, phase II studies that included more than 1,000 patients. All three trials showed a cytogenetic response, either a disappearance or a reduction of cells positive for the Philadelphia chromosome.
"Although the long-term benefits of the drug are not yet known, early studies have shown that Gleevec will offer a significant improvement for many patients," said Bernard A. Schwetz, DVM, PhD, the FDA acting commissioner.
Results of the clinical trials showed that patients with chronic phase CML after failure of interferon therapy achieved an 88% hematologic response and 49% overall major cytogenetic response, both primary endpoints in the studies. Among patients in more advanced stages of the disease, the cytogenetic response was 21% for those with accelerated phase and 14% for those in myeloid blast crisis.
CML results from a reciprocal translocation between chromosomes 9 and 12, which produces the "Philadelphia chromosome," which has been used for years as a marker for the disease. The translocation causes production of an abnormal protein designated Bcr-Abl, which, in turn, leads to an uncontrolled proliferation of white blood cells.
According to Novartis, Gleevec, which blocks Bcr-Abl from functioning, is the first oncology drug developed based on a rational design strategy.
In addition to blocking Bcr-Abl, Gleevec also inhibits two other proteins. One is the c-kit receptor, which is active in several cancers, including gastrointestinal stromal tumors (GIST) and small-cell lung cancers. The other protein is the PDG-F receptor, which is active in gliomas, prostate cancer, and soft tissue sarcoma. Trials of Gleevec are currently in progress for GIST and glioblastoma.
Adverse Events
The majority of patients treated in the three Gleevec studies experienced adverse events, mostly of mild to moderate grade. Discontinuation of the drug because of side effects occurred in 1% of the patients with chronic phase CML, 2% with the accelerated phase, and 5% in myeloid blast crisis.
Moderate and mild side effects observed in the three studies (regardless of relationship to the study drug) and their ranges were: nausea (55% to 68%), fluid retention (52% to 68%), muscle cramps (25% to 46%), diarrhea (33% to 49%), vomiting (28% to 54%), hemorrhage (13% to 48%), musculoskeletal pain (27% to 39%), skin rash (32% to 39%), headache (24% to 28%), and fatigue (24% to 33%). Severe side effects included severe superficial edema (1% to 5%), elevated liver enzymes (1.1% to 3.5%), and hemorrhage (0.4% to 16%).
Under the FDA’s accelerated approval program, Novartis is required to conduct a phase IV postmarketing study to provide further evidence of Gleevec’s safety and efficacy. "Further studies are needed to evaluate whether Gleevec provides an actual clinical benefit, such as improved survival, and to examine its effect in early-stage disease," Dr. Schwetz said.
