Higher doses of cancer drug imatinib proven effective and safe

04/01/04

(WASHINGTON, April 1, 2004) The cancer drug imatinib mesylate, also known as Gleevec, has proven to be increasingly effective at higher doses, according to a new study published in the April 15, 2004, issue of Blood, the official journal of the American Society of Hematology.

Researchers from The University of Texas M. D. Anderson Cancer Center in Houston examined 114 patients recently diagnosed with chronic myelogenous leukemia (CML), a cancer that is diagnosed in about 4,600 people in the U.S. every year. CML is classified into three stages: chronic, accelerated, and blastic. Study participants were all in chronic phase, the least severe of the three. The current dosage recommended by the Food and Drug Administration for chronic phase CML patients is 400 mg of imatinib daily, with higher doses of 600 to 800 mg recommended only for patients in the later stages of CML. The researchers, hypothesizing that higher dosages given in the earlier chronic stage could be more effective than the standard treatment, provided patients with 800 mg of imatinib daily (administered in two 400 mg oral doses).

All of the patients in this study also had a genetic abnormality called Philadelphia translocation (common to 95 percent of CML patients) in which some of the DNA on chromosomes 9 and 22 are switched. A result of the switch is the development of a hybrid gene called BCR-ABL, which codes for an enzyme that causes the overproduction of white blood cells in the bone marrow, crowding out normal blood cells and platelets. Therefore, the primary goal of CML treatment is complete cytogenetic response (CCR), the elimination of cells with this genetic defect. Ninety percent of the patients in this study experienced CCR, a significantly greater result than seen in patients in a prior study who were taking the standard dosage of imatinib. Those patients had a CCR rate of 60 to 75 percent.

The high percentage of CCR among these patients is of significant importance as previous studies of another cancer drug (interferon alpha) have shown that CCR is associated with a 70 to 80 percent chance of 10-year survival, a positive prospect as the survival time for newly diagnosed CML patients is typically about five years.

Another measure of successful treatment is the number of patients with complete molecular response, occurring when the levels of BCR-ABL are so low that they are undetectable using a highly sensitive method called polymerase chain reaction. In past studies, patients who had undetectable levels of BCR-ABL after treatment have not relapsed after long-term follow up. In high-dose therapy patients, the incidence of complete molecular response was 28 percent compared to only seven percent of patients taking the standard dosage of imatinib.

"The high rates of complete cytogenetic and molecular response that we've seen in this study are unprecedented. If such responses have similar long-term significance as seen in previous studies, this translates into a major improvement in the prognosis of patients with CML," states Hagop Kantarjian, M.D., chairman of the Department of Leukemia at M. D. Anderson Cancer Center and the lead author of the study.

Researchers found that the high dosage of imatinib was generally well tolerated, with a similar rate of side effects as standard dose imatinib. To reduce more severe side effects, the dosage of imatinib was lowered to 600 mg or 400 mg daily for some patients, though a majority remained at the target dosage.

The disease did not transform beyond the chronic phrase in any of the study patients, and 98 percent had a complete hematologic response, meaning the number of white blood cells was no longer out of control and the signs and symptoms of leukemia were gone.

The results of the study indicate that patients in the early stage of this cancer may benefit from higher doses of the drug imatinib in their initial treatment to safely and effectively improve their condition and improve their chance at long-term survival. According to hematologist George Daley, M.D., Ph.D., of Children's Hospital and Harvard Medical School, "This is a remarkable study. It shows that because highly targeted therapy incurs fewer side effects, dosages can be increased to achieve truly astounding rates of remission."

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