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Expanded Role Seen for Breakthrough Leukemia Drug

By Diane West


NEW YORK—The chronic myeloid leukemia (CML) drug that startled doctors last year after sending all of its first takers into speedy remission and continues to show promise as its use is expanded to treating other stages and forms of leukemia, and possibly to other types of cancer.

“There are no other stories like this, but you will see this story again and again as research into the molecular behavior of cancer continues,” said David Parkinson, M.D., vice president of clinical research at Novartis Oncology, the new oncology division of the company that makes Glivec, the new brand name for STI571.

Leukemia is a cancer of the blood, bone marrow, liver and in which white blood cells reproduce at an abnormally high rate. Scientists believe this is caused by a chromosomal rearrangement dubbed the “Philadelphia chromosome,” which produces an abnormal enzyme called bcr-abl that in turn triggers out-of-control growth. STI571 interrupts this process – often compared to a stuck throttle in a car – by, in effect, cutting off the “gas” – the abnormal enzyme.

Parkinson and colleagues David Epstein, president of Novartis Oncology, and Stephen D. Nimer, M.D., head of the division of hematologic oncology at Memorial Sloan-Kettering Cancer Center in New York, spoke at a special press briefing here Nov. 30 before the American Society of Hematology (ASH) annual meeting now being held in San Francisco. More than 50 reports on STI571, which is still in clinical trials, are being presented at the meeting.

There are currently over 2,800 leukemia patients with a variety of stages and forms of the disease now taking the once-daily oral drug at 490 centers worldwide. “We expect to file a New Drug Application request with the Food and Drug Administration for Glivec in the first quarter of 2001,” Epstein said. “We have every confidence that it will be in the public’s hands by the end of 2001.”

Epstein said it was a challenge to expedite approval and production of the drug after initial patient responses in early clinical trials, reported last year, were 100 percent positive in 31 CML patients—29 of whom remain in remission. “We had to scale production up from kilos to tons,” he said, “like cooking for a family to cooking for a stadium.”

The so-called Phase I trials grew to include patients with late and resistant or relapsed leukemia. Results were not as dramatic in these patients as they were in the chronic-phase CML patients, and all but one with the lymphocytic form of the disease relapsed within a few months of initially responding. However, some patients in the critical blast stage maintained their remissions with a daily dose of STI571 for up to one year.


Researchers recently zeroed in on possible causes of this resistance and are working on ways to overcome it.

With the results of several Phase II trials in, researchers predict the drug will continue to affect the way leukemia, as well as other cancers, are treated. One trial (scheduled to be presented at ASH), which studied 234 people with CML in accelerated phase, showed signs of working in 78 percent of patients within four weeks, with 22 patients (about 10 percent) achieving. Another Phase II trial, which studied STI571 in 532 patients who had tried and failed to respond to typical interferon therapy, worked in 37 percent of them after three months and 56 percent after six months.

However, one person with accelerated CML died from liver failure, possibly due to the drug, and there is evidence that taking the drug with acetaminophen, a common over-the-counter pain reliever, may prove fatal, according to the study.

“It still works best in the chronic leukemia phase,” acknowledged Brian Druker, M.D., one of the “founding fathers” of the drug at Oregon Health Sciences University. “If you look at any cancer, it becomes more complicated as it progresses. The transition of CML is no different as it becomes more complicated and abnormal than just a matter of targeting the bcr/abl enzyme alone.”

Therefore, Druker said, researchers are now turning their attention to trying STI571 in combination with other agents, including low doses of interferon. Druker said he and research teams are also enrolling patients in a trial that will match STI571 head to head against interferon; that trial is scheduled to begin sometime next year.

Plans are under way to study STI571 in a host of solid tumors, including soft-tumor cancers, brain tumors called gliomas, rare stomach tumors, small-cell lung cancer, and breast and prostate cancers. Researchers believe the drug may inhibit other cell growth regulators in the same general family as bcr/abl.

“The data are a little less convincing for breast and prostate cancer,” Druker said, “but there is some suggestion that Glivec could play a role in treating them.