New England Journal of Medicine Highlights Success of Leukemia Pill in Clinical Trials

04/04/01    Portland, Ore.

Pill also fights form of intestinal cancer; placed on FDA priority review list

A compound developed to fight one form of leukemia at the molecular level also is working to combat a rare gastrointestinal cancer, say researchers in the April 5 issue of the New England Journal of Medicine. The compound, Glivec, was developed by Oregon Health Sciences University researcher Brian Druker, M.D., in collaboration with Novartis Pharmaceuticals, and now is in Phase III clinical trials.

Glivec, formerly known as STI571, was formulated to inhibit the activity of the protein bcr-abl, which is produced by the mutant Philadelphia chromosome. The protein is responsible for the overproduction of white blood cells that is a hallmark of chronic myeloid leukemia (CML), which affects about 5,000 Americans each year.

Two studies reported in the journal looked at treatment of CML patients in chronic phase and in blast-phase, which is the stage at which the disease rapidly shuts down the body's immune system. Of 54 chronic-phase patients at optimum dosage, 53 saw their white blood cell counts return to normal within four weeks, and more than half the patients (29) saw a disappearance of the Philadelphia chromosome.

In blast-phase CML patients and patients with acute lymphoblastic leukemia (ALL), the majority responded positively to Glivec, however, relapses have been common. About 20 percent of ALL patients have the Philadelphia chromosome.

"What we see in these studies is that Glivec is well tolerated in nearly all patients we've tested and it is especially effective for patients in the early stage of the disease," said Druker, director of the OHSU Leukemia Program and lead author on the studies. "Continuing studies have verified these results in larger groups of patients and we are now trying combination therapies of Glivec and other treatments for those advanced stage patients who relapsed when treated with Glivec alone."

Unlike chemotherapy, which kills both normal and abnormal cells in an attempt to eradicate the cancer, Glivec targets the abnormal bcr-abl protein and causes only the leukemic cells to die. Side effects have been minimal, including nausea, swelling and diarrhea. "The paradigm of understanding the critical differences between cancer cells and normal cells, then targeting those differences with more effective and less toxic treatments has been validated by these clinical trials," said Druker.

In looking at other potential targets for Glivec, in 1993, Druker found that the compound also inhibited kit, an enzyme related to bcr-abl that subsequently was shown to be involved in the growth of gastrointestinal stromal tumors (GIST).

In a third study reported in this week's journal, researchers from Finland and the Dana Farber Cancer Institute report on the first case of a patient with GIST being treated with Glivec. This case study demonstrates for the first time that the strategy of tumor-specific targeting also could be useful in solid tumors. Clinical trials using Glivec to treat GIST patients began last year and will be reported on at the American Society of Clinical Oncology meeting in San Francisco on May 13.

"While it's too early to comment on the success of Glivec on GIST patients, we are optimistic that the scientific studies will carry over to this clinical application," said Charles Blanke, M.D., co-investigator of the GIST clinical trials and associate professor at OHSU.

"It's wonderful to report that people with CML are feeling better than they have in years on this treatment," said Druker. "If this treatment can do the same for people with any other cancers, it will be a dream come true."

In February, Novartis submitted Glivec to the Food and Drug Adminstration for approval. The FDA has put the drug on priority review, which is reserved for products that may offer a significant improvement compared to currently available products. If Glivec is approved, it is expected to be on the market later this year.

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