By Christine Haran
Two years ago, when US Food and Drug Administration approved GleevecTM (imatinib mesylate) for the treatment of chronic myeloid leukemia (CML), an uncommon but life-threatening blood cancer, the drug was hailed as a breakthrough. Unlike many other drugs celebrated as breakthroughs, Gleevec has largely fulfilled its promise. Since its approval for CML, Gleevec has been shown to be effective in three other cancers. Most recently, a small study published in the March 27th issue of The New England Journal of Medicine (NEJM) indicated that Gleevec was effective in patients with hypereosinophilic syndrome (HES), another blood cancer.
Unlike other chemotherapy drugs, which attack good and bad cells alike, Gleevec is a targeted therapy. In CML, for example, Gleevec inhibits a protein called BCR-ABL, which is a member of a class of proteins called tyrosine kinases. This protein is responsible for the overgrowth of mature and immature white blood cells in the bone marrow and blood of people with CML.
Cancers are caused by genetic mistakes that lead to the production of dysfunctional proteins. Because proteins carry out the instructions held in a cell's DNA, dysfunctional proteins deliver the wrong message to cells. When these proteins, which are sometimes also called enzymes, are inhibited, the progression of the cancer is likewise inhibited. Hopefully, researchers will uncover many other cancers in which tyrosine kinases are active, so that Gleevec, or drugs with a similar method of attack, could potentially block these proteins.
Below, Dr. Marshall Lichtman, executive vice president of research and medical programs at the Leukemia and Lymphoma Society, which funded the NEJM study, talks about the significance of Gleevec.
How does Gleevec work?
Gleevec inhibits the action of an enzyme that is part of a class of proteins called tyrosine kinases, which play a role in some forms of cancer. In normal cells, tyrosine kinase transmits outside signals to the cell so that the cell does the things that it's supposed to do. But when this enzyme is abnormal, it sends signals that lead to uncontrolled growth of certain cells and results in cancer.
Gleevec was first studied in chronic myelogenous leukemia (CML), a form of leukemia that 4,500 Americans are diagnosed with every year. CML is caused by a genetic change in the cells, which results from a translocation, or an exchange of parts of two chromosomes. This exchange results in a mutant tyrosine kinase. It's felt that this is the principal abnormality that leads the cells to become leukemic.
Why is Gleevec more targeted than other kinds of cancer treatments?
With most chemotherapeutic agents, the drug indiscriminately attacks dividing cells, including those of skin, hair follicles, gastrointestinal tract lining and bone marrow. In addition, some drugs may inadvertently injure organs, such as the lung, kidney or heart.
Gleevec targets the specific leukemia-causing protein encoded by the genetic abnormality that is specific to the cancer. Although this drug also has toxicity, such as nausea, skin rashes, fluid accumulation, these effects are more restricted and usually less severe than those of other forms of chemotherapy.
What did clinical trials of Gleevec in CML demonstrate?
The trials demonstrated that the drug was better than any other form of therapy for patients with CML. Nearly all patients had marked improvement in their blood counts, and it markedly reduced the leukemic cells in more patients than the prior therapy had. Gleevec also worked in most persons who had became intolerant or unresponsive to the prior therapy, which was injections of interferon-alpha. In addition, side effects were less frequent and less severe. Older patients, who could not tolerate interferon, could tolerate Gleevec. And because it is given as a pill, the need for several injections per week was avoided, making self-administration universal.
What other cancers is Gleevec effective in treating?
Gleevec has been studied in many different diseases, especially those where there might be abnormal tyrosine kinases at work in the disease. Abnormal tyrosine kinases sensitive to Gleevec are known to play a role in at least three other conditions. One is a condition called gastrointestinal stromal tumor (GIST), which is a stomach tumor that was previously extremely difficult to treat. The abnormal tyrosine kinase that contributes to this cancer is in a slightly different family than the CML tyrosine kinase, but Gleevec still inhibited it. Currently, about 60 percent of patients with this tumor have very good effects from the drug. It's still a little early to know how long some of these effects will last.
There are two other blood diseases that Gleevec has been found to be useful in, both of them quite uncommon. One is chronic myelomonocytic leukemia, which is another type of chronic myelogenous leukemia. And this new study shows that Gleevec is effective in what has been called hypereosinophilic syndrome (HES).
What is hypereosinophilic syndrome (HES)?
The hypereosinophilic syndrome results in a large accumulation of eosinophils, which is a type of white blood cell. In large numbers, eosinophils have toxic properties. When they die, they release their contents and these contents can be toxic to certain tissues, especially the nervous system and the heart. We know that there are probably several different causes of this syndrome. But the type of HES that was the subject of the article in The New England Journal of Medicine is really a type of chronic eosinophilic leukemia. In these patients, Gleevec substantially improves the patient's condition.
Why is Gleevec superior to other therapies?
For GIST, chronic myelomonocytic leukemia and eosinophilic leukemia, there were not very effective previous therapies, so this is a dramatic improvement for them. In the case of CML, there have been therapies over the decades, including bone marrow transplant, which is curative but only available to a minority of patients. Yet Gleevec is more effective and less toxic than any of the therapies other than transplant, and it can be taken orally. So it's really a very significant advance. It is hoped that other drugs will be found that inhibit other types of mutant tyrosine kinases, and a few are already being studied in other diseases.
Does this drug represent sort of a shift in cancer therapy?
It isn't a shift because we don't have molecular targeted drugs for the bulk of cancers, so most patients with cancer are getting the drugs that we have used previously. But what I would say is that this probably has stimulated the search for more specific therapy. Over time, as we learn more about genetic abnormalities, it's likely that there will be similar improvements for other cancers.
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