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Key Words: chronic myelogenous leukemia, imatinib mesylate (Gleevec™). (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)

The molecularly targeted drug Gleevec delayed progression of disease for longer, produced milder side effects, and resulted in a significantly better response than conventional therapy in patients with previously untreated chronic myelogenous leukemia (CML), researchers report in the March 13, 2003, issue of the New England Journal of Medicine (see the journal abstract).

At 18 months of follow-up, however, the researchers found no evidence that treatment with Gleevec lengthens patients lives: 97 percent of patients treated with Gleevec (imatinib, formerly known as STI571) survived, compared with 95 percent of those who got conventional therapy.

Early results of this study were considered so significant that they were released ahead of schedule at the American Society of Clinical Oncology annual meeting in May 2002. At that time, patients had been followed for an average of six to eight months.

Randomized study

The study--known as the International Randomized Study of Interferon and STI571--involved 1,106 patients in 16 countries. Patients were randomly assigned to receive either Gleevec or conventional therapy with interferon and low-dose cytarabine. The research team was led by Stephen G. O'Brien, M.D., of the University of Newcastle in the United Kingdom.

At 18 months of follow-up, 92 percent of patients on Gleevec had no progression of disease, compared with 73.5 percent of patients on conventional therapy. Eighty-five percent of patients on Gleevec had a major cytogenetic response (a significant reduction in the number of cancerous cells), compared with 22 percent of patients on conventional therapy.

"Crossover" permitted

Patients were permitted to "cross over" to the other treatment group if they stopped responding to therapy or had intolerable side effects. Seventy-nine patients (14 percent) in the Gleevec group either stopped treatment or crossed over, whereas 493 patients (89 percent) on conventional therapy did so.

The high rate of crossover to Gleevec from conventional therapy made it impossible to detect whether Gleevec had a beneficial effect on patients' survival, say the authors. The study will continue for at least five years. Longer-term results may provide a clearer picture of Gleevec's impact on survival.

Transplant: curative but risky

Some CML patients may continue to opt for the only treatment known to cure the disease -- a bone marrow transplant. However, the risk of death or serious side effects from transplantation increases with age. Many patients are not young or healthy enough to tolerate transplantation or do not have a suitable marrow donor. An editorial accompanying the study report says Gleevec "now seems to be the initial treatment of choice for patients with CML who do not have a suitable bone marrow donor or who are not candidates for transplantation."

Gleevec was approved by the U.S. Food and Drug Administration in May 2001 to treat CML in patients for whom interferon had failed.

Gleevec turns off protein signal

The drug targets an abnormal version of a normal cellular protein that is present in nearly all CML patients. The abnormal protein called BCR-ABL, is much more active than the normal version and is probably the cause of the disease. By blocking the abnormal protein, Gleevec kills the leukemic cells. It is the first approved drug that directly turns off the signal of a protein known to cause a cancer. Unlike other drugs used in cancer treatment, Gleevec does not kill normal cells in addition to cancer cells.

CML is a disease in which too many white blood cells are made in the bone marrow, the spongy tissue inside large bones. Most of the 4,500 Americans diagnosed with CML each year are middle-aged or older, although the cancer can occur in children. In the first stages of CML, most people do not have any symptoms of cancer, and the disease progresses slowly.

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