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Targeted Therapy for Leukemia May Prove a Breakthrough

Medically Reviewed by Charlotte E. Grayson Mathis, MD
From the WebMD Archives

April 4, 2001 -- Cindy Littrell of Salem, Ore., has leukemia -- chronic myeloid leukemia, or CML, to be exact. Diagnosed in February 1993 at age 45 by a blood test taken during a routine physical exam, she later endured a bone marrow transplant in an attempt to rid her body of the disease.

After the bone marrow transplant, she was hospitalized and treated with full-body radiation and chemotherapy.

"I was in a 'bubble room,'" she tells WebMD. "I could not have anyone come in the room unless they were totally sanitized and properly attired. I was alone. It was a very lonely feeling. I was in there for 30 days. You're exhausted from the chemotherapy and radiation. [The treatment] destroys your taste buds for a while, and you don't feel like eating, although they want you to eat. You're fed protein and that sort of thing intravenously. You try and exercise and move to build your strength up."

Littrell was back at work in a record six months, but five years later the leukemia was back, discovered again through a routine blood test. Standard treatments either didn't work or made her too sick. Her doctors considered giving her a second bone marrow transplant, even though they knew it would be even harder on her this time and less likely to work. While making plans for a second transplant, they found that Littrell had moved from the early or chronic stage of the disease to the more aggressive, accelerated phase called the blastic phase.

Until recently, a diagnosis of accelerated or acute CML was practically a death sentence, but for Littrell this was good news. It meant she was eligible to participate in a clinical trial of an experimental drug being conducted by Brian Druker, MD, a professor of medicine at Oregon Health Sciences University in Portland. Druker helped develop the drug called STI571.

STI571 represents the latest phase in cancer research and therapy where drugs are designed to target the specific molecular abnormalities that cause disease, and it is being hailed as a breakthrough for CML.

CML, a cancer of the blood cells, accounts for 15-20% of all leukemia cases. An estimated 5,000 new cases of CML are diagnosed in the U.S. every year. The disease is usually first detected in individuals aged 50-60 and is relatively mild in its early stages. Late-stage CML, however, is deadly.

Current treatments of CML are not adequate. Bone marrow transplantation, the most effective therapy, is feasible in only about one-third of patients and is so toxic that some people die from the procedure itself. Other drugs for CML include interferon and hydroxyurea, both of which make patients very ill and are not very effective in all cases.

Based on earlier research, Druker and his team knew that the molecular pathway that leads to CML is based on an enzyme called BCR-ABL found in cancer cells. They tested several potential blockers of this enzyme and found the most promising is STI571, which will be called Glivec if it is approved by the FDA and marketed later this year by Novartis.

Just over two years ago, Druker and his team started testing this new drug on CML patients who had not responded to other therapy.

The results so far have been dramatic. Not only is the drug safe (side effects include only mild cases of nausea, muscle cramps, and eye puffiness), but it is also extremely effective, especially when first given during the early stage of the disease.

So far, relapse rates have only been high in those starting the drug later in the disease process, but there is some hope that combining STI571 with other therapies will control these relapses. Druker presented his award-winning findings last week in New Orleans at the annual meeting of the American Association for Cancer Research.

"For CML, this is a major breakthrough, and it validates the paradigm in cancer research of targeting the specific abnormalities that drive the course of cancer instead of [using] chemotherapy, which kills normal cells as well as the [cancer] cells," Druker tells WebMD. "Therapies coming in the future are just going to attack the cancer cells."

STI571 also blocks molecular pathways known to be involved in other cancers, and other research teams are currently testing its effectiveness in these other cancers. Druker has tried the drug in another form of leukemia that typically affects children and adolescents, called acute lymphoblastic leukemia, or ALL, with good results.

A team of Finnish researchers led by Heikki Joensuu, MD, PhD, a specialist in oncology and head of the department of oncology at Helsinki University Central Hospital in Finland, has shown the drug is effective in a woman with a gastrointestinal tumor that had started to spread to the liver. STI571 shrank the tumors even though this patient had not responded to any other therapy. Studies on STI571 for CML, ALL, and stomach cancer are published in the April 5 issue of The New England Journal of Medicine.

John M. Goldman, MD, co-wrote an editorial that accompanied these studies. He considers STI571 a real breakthrough in the treatment of CML because it is far more effective than currently available therapy and has far fewer side effects, at least in the short term.

Because the drug has only been used for a couple of years, however, there is no proof that its positive effects are long lasting or that it really lengthens people's lives. Researchers, therefore, must continue to compare STI571 to available therapies for CML, says Goldman. And, he notes, younger, healthier patients might do best with a more radical therapy, like bone marrow transplantation, that is more dangerous but is also known to cure CML when it is successful. Goldman is from the Imperial College School of Medicine in London.

According to Goldman, STI571 is now being tested for patients with lung, prostate, and brain tumors.

And how is Littrell doing? "I got on the [STI571] pills in December [1999]," she says. "I didn't have to have the [second] transplant. I didn't miss any work -- I continued my life in normal fashion. We go snowmobiling in the winter and boating in the summer. ... This drug has just been a miracle. ... It's literally given me a future. My prognosis with a second transplant was 20% chance of survival in the first year." Currently, her long-term prognosis is unclear, but Littrell and her doctor are very optimistic.

Novartis, maker of STI571, requested approval of the drug in February. The FDA put the drug on priority review, a status reserved for treatments that promise to offer a significant improvement over currently available treatments. If STI571 is approved, it will be sold as Glivec later this year.