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The drug imatinib mesylate, also known as STI571 or Gleevec™, offers much promise for treatment of chronic myeloid leukemia (CML) and may soon surpass interferon alpha as the standard treatment for the disease, according to two reports published April 5, 2001, in the New England Journal of Medicine.

The positive results of the new studies have put imatinib mesylate on track for marketing approval, which is expected soon from the U.S. Food and Drug Administration, according to the journal. (Note: On May 10, 2001, the FDA approved Gleevec as a treatment for CML.) Imatinib mesylate is one the first molecularly targeted drugs to emerge from the ongoing genetic revolution, which has enabled scientists to design drugs based on the changes that cancer causes in cells. In CML, the imatinib mesylate is targeted at a specific genetic abnormality found in cells of patients with this disease.

Brian J. Druker, M.D., from the Oregon Health Sciences University, has been a driving force in the clinical studies of imatinib mesylate and is the lead author on both reports. In the first report (see the journal abstract), he and his colleagues at four other institutions enrolled patients with early (chronic phase) CML for whom standard therapy with interferon alpha was no longer effective. Participants received the drug in the form of a pill and in doses ranging from 25 mg to1000 mg per day.

The drug quickly corrected the blood cell abnormalities caused by the leukemia in a majority of patients. All doses were found to be safe and to have generally mild side effects, which included nausea, muscle pain, tissue swelling, and diarrhea. Several patients developed more serious side effects, including abnormal liver function and low blood counts; although in a few cases these effects were life-threatening, there were no deaths due to imatinib mesylate.

When the researchers looked at the patients receiving daily doses of 300 mg or more of imatinib mesylate, they found exciting results: 98 percent (53 out of 54 patients) experienced a complete disappearance of the leukemic blood cells and the return of normal blood cells. Usually this occurred within a month of starting the drug, a sign that the CML might be in remission.

Also striking in this group of patients was the decrease in the number of bone marrow cells carrying the characteristic genetic abnormality: some decrease was seen in more than half of the group and seven patients had a complete disappearance of the abnormal cells. This so-called "complete cytogenetic response" is better than that seen for interferon. (Note: Five-year follow-up data from this trial were subsequently published in the Dec. 7, 2006, New England Journal of Medicine; see the journal abstract.)

The striking results spurred the investigators to swiftly examine if imatinib mesylate would work in the late, or blast crisis, stage of CML, when people often die in a matter of months. In the second report (see the journal abstract), Druker and his team described their investigation of whether the drug was safe and could be tolerated in patients with two forms of late-stage CML, known as either "myeloid blast crisis" or "lymphoid blast crisis." The investigators also included in this effort 10 patients who had a certain form of acute lymphoblastic leukemia (ALL) characterized by the same genetic bone marrow cell defect seen in people with CML.

Dosages used in this case ranged from 300 mg to 1000 mg per day. Again, the scientists saw that not only was the drug well tolerated, it was effective: within one week of starting treatment, many patients experienced a drop in their leukemic blood cell counts.

More than 50 percent of patients with myeloid blast crisis -- 21 patients out of 38 -- had a response to imatinib mesylate, as measured by a decrease in the abnormal leukemic blood cells. And in four of these 38 patients the blood counts completely returned to normal. In addition, three patients, or eight percent, had a complete cytogenetic response. Seven patients with myeloid blast crisis continue to receive imatinib mesylate and were still in remission more than 100 days after beginning the drug.

For patients with lymphoid blast crisis, about 20 percent (four patients out of 20) had normal blood cell counts after taking imatinib mesylate. A complete cytogenetic response was seen in two of these patients. All but one of the patients with lymphoid blast crisis has relapsed. Similar side effects were reported in this part of the study, and again, no deaths from the drug itself were observed.

Studies of imatinib mesylate in CML continue, including one trial comparing the drug to a combination of interferon and cytarabine. This study is no longer enrolling patients; results are being collected and will be published later. In addition, the drug appears to have some effect on other cancers including certain brain tumors and a very rare type of stomach cancer called gastrointestinal stromal tumor, or GIST. Studies in both of these types of cancers are ongoing.

In the United States, more than 4,500 people were diagnosed with CML in the year 2000. While treatments are available, the only known curative treatment is bone marrow transplantation. Besides the studies involving imatinib mesylate, there are many other ongoing clinical trials for CML. The link below will generate a list of clinical trials for CML that are currently open in NCI's clinical trials database.

• Clinical Trials for Patients with CML
• Non-Transplant Clinical Trials for Patients with CML

Imatinib mesylate "is charting new territory in the treatment of CML -- and maybe of other cancers," said Anthony Murgo, M.D., of the National Cancer Institute (NCI). NCI, along with the drug company Novartis, funded the study. "Although the number of patients affected by CML is small compared to other cancers, the remarkable properties of the drug seen in these preliminary studies have the whole cancer field excited -- giving hope that other molecularly targeted drugs now in development for other cancers will produce similar results."

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