Gleevec: Questions and Answers
- What is Gleevec? Gleevec, also known as STI571, is a new drug that was approved by the the Food and Drug Administration for the treatment of chronic myeloid leukemia (CML), a cancer of white blood cells and for the treatment of a rare form of stomach cancer called gastrointestinal stromal tumor (GIST). (Question 1)
- Why is Gleevec different from most chemotherapy drugs? Gleevec represents a new class of cancer drugs and a new way of thinking about cancer. These molecularly targeted drugs are different because they target abnormal proteins that are fundamental to the cancer itself. (Question 2)
- What were the results of the previous clinical trials with Gleevec? In June 1998, the first clinical trial of Gleevec was launched. This small, initial study sought primarily to determine whether Gleevec is safe in people, not its effectiveness as a cancer drug. However, as the doctors gradually increased the dose of the drug, they noticed dramatic responses in their patients, all of whom were no longer benefitting from previous therapy. (Question 3)
- What is chronic myelogenous leukemia, or CML? CML affects the blasts that develop into multiple cell types in the bone marrow, including the white blood cells (granulocytes). The white blood cells do not mature normally and become too numerous. Immature white blood cells are then found in the blood and the bone marrow. (Question 4)
- What is GIST? A Gastrointestinal stromal tumor (GIST) is a type of tumor that usually begins in cells in the wall of the gastrointestinal tract. It can be benign or malignant.
1. What is Gleevec?
Gleevec, also known as STI571, is a new drug that was approved by the Food and Drug Administration in 2001 for the treatment of chronic myeloid leukemia (CML), a cancer of white blood cells, and for the treatment of a rare form of stomach cancer called gastrointestinal stromal tumor (GIST) in 2002. It was designed in the laboratory to target an abnormal version of a normal cellular protein, present in nearly all CML patients. The abnormal protein is much more active than the normal version and is probably the cause of the disease. By blocking the abnormal protein, called BCR-ABL, Gleevec kills the leukemia cells.
2. Why is Gleevec different from most chemotherapy drugs?
Gleevec represents a new class of cancer drugs and a new way of thinking about cancer. These molecularly targeted drugs are different because they target abnormal proteins that are fundamental to the cancer itself. Most current cancer therapies lack specificity, killing both cancer and normal cells. This is one reason why many people who undergo chemotherapy experience unwanted side effects from their medications. But Gleevec and other drugs in development are designed to zero in on specific cancer-causing molecules, eliminating cancer cells while avoiding serious damage to other, non-cancerous cells. In the case of Gleevec, the drug is targeted at the bcr-abl protein in CML cells. (Gleevec also affects other messenger systems in a cell which may contribute to its toxicity.)
3. What were the results of the previous clinical trials with Gleevec?
In June 1998, the first clinical trial of Gleevec was launched. This small, initial study sought primarily to determine whether Gleevec is safe in people, not its effectiveness as a cancer drug. However, as the doctors gradually increased the dose of the drug, they noticed dramatic responses in their patients, all of whom were no longer benefitting from previous therapy.
In December 1999, Brian Druker, M.D., and his collaborators reported the preliminary results of this early study. Their data showed that once patients reached an effective daily dose of 300 mg or more, 31 out of 31 patients had their blood counts return to normal, a sign that a treatment is working. In nine of the 20 patients who were treated for five months or longer, no leukemia cells could be found, which showed that the drug was eliminating the source of the cancer. They also noted that side effects were minimal in these patients. Such dramatic results are rarely seen in such an early clinical study.
In April 2001, Druker and colleagues reported the results of a larger follow-up study of Gleevec in the New England Journal of Medicine. They reported that Gleevec restored normal blood counts in 53 out of 54 chemotherapy-resistant CML patients, a response rate rarely seen in cancer with a single agent. Fifty-one of these patients were still doing well after a year on the medicine, and most reported few side effects.
4. What is chronic myelogenous leukemia, or CML?
CML is a disease in which too many white blood cells are made in the bone marrow. The bone marrow is the spongy tissue inside the large bones in the body. The bone marrow makes red blood cells (which carry oxygen and other materials to all tissues of the body), white blood cells (which fight infection), and platelets (which make the blood clot).
Normally, bone marrow cells called blasts mature into several different types of blood cells that have specific jobs in the body. CML affects the blasts that develop into multiple cell types in the bone marrow, including the white blood cells (granulocytes). The white blood cells do not mature normally and become too numerous. Immature white blood cells are then found in the blood and the bone marrow. Most people with CML have an abnormal chromosome, known as the Philadelphia chromosome, in which segments of chromosomes 9 and 22 are fused together to create the abnormal protein at the root of CML.
CML is diagnosed in about 4,500 Americans each year, usually people who are middle-aged or older, although the cancer also can occur in children. In the first stages of CML, most people don't have symptoms and the disease progresses slowly.
Treatment with interferon alfa may produce partial or complete remissions in chronic phase CML, restoring normal blood counts in up to 70 percent of patients. Complete cytogenetic responses (disappearance of cancer cells) have been reported in up to 20 percent of patients with a delay of disease progression and prolongation of survival. Bone marrow transplantation in the chronic phase is the only treatment known to cure CML. However, many patients are not young or healthy enough to tolerate a transplantation or don't have a suitable marrow donor, and the procedure can cause serious side effects or death.
5. Is it possible to target abnormal proteins in other tumors with molecular-targeting drugs?
Yes, provided that the target is correctly chosen. It is important to note that Gleevec builds on an observation that was first made in 1960. Scientists then had just learned how to isolate and study human chromosomes, and they noticed that CML patients often had an unusually small chromosome that is not found in other people. They named it the Philadelphia chromosome, after the city in which the research was conducted. This set in motion decades of work to determine its cause, which was eventually found to be a genetic mistake in which segments of chromosomes 9 and 22 stick together to form the Philadelphia chromosome. The bcr-abl gene is located at the place where chromosome 9 and 22 are fused together.
With the emergence of gene cloning technologies in the late 1980s, scientists later isolated the bcr-abl gene and characterized its aberrant, cancer-causing protein. By the early 1990s, scientists at CIBA-Geigy, later Novartis Pharmaceuticals, were able to use this well-defined target to create Gleevec, designing it to shut off the BCR-ABL protein in people with CML.
Given the success of Gleevec and the recent explosion of powerful molecular technology now available in cancer research, scientists are searching intensively to discover the correct targets in other cancers. At NCI, for example, several initiatives are under way to accelerate the discovery process. These include: Cancer Genome Anatomy Project; Director's Challenge: Toward a Molecular Classification of Cancer; the Molecular Targets Initiative; and Molecular Target Laboratories.
6. Does the approval of Gleevec mean that scientists now will stop studying the drug after only a few clinical trials?
No. Though the results of the first clinical trials have been dramatic, many research questions remain to be answered. These include:
- How long does Gleevec control CML?
- Does Gleevec actually cure patients of CML? Or, does the drug delay the onset of more advanced forms of the cancer? If so, how long does Gleevec keep CML in check?
- Can the effectiveness of Gleevec be enhanced in combination with other drugs?
- Why does Gleevec not help all people with CML?
Because Gleevec is a molecularly targeted drug, it will only be effective in cancers in which a target protein is present and involved in causing the tumor. In addition to BCR-ABL, Gleevec may also target the cellular proteins c-kit and platelet-derived growth factor receptor (PDGFR). Several clinical trials with Gleevec are already under way to find other tumors that might respond to Gleevec. Currently, these tumors are: gastrointestinal stromal tumor (GIST), glioma, and soft tissue sarcoma.
7. Where can I find out more about clinical trials with Gleevec?
There are several options. By telephone, contact the NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237); deaf and hard of hearing callers with TTY equipment may call 1-800-332-8615. Or, on the Internet, visit the Clinical Trials section of the NCI's Web site. It provides a comprehensive list of clinical trials now under way to study Gleevec. The Web site address is: http://www.cancer.gov/clinicaltrials/search. The site also contains helpful background information on Gleevec.
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