Gleevec Outperforms Interferon Therapy for Newly Diagnosed CML

December 09, 2002

Jane Salodof MacNeil

Dec. 9, 2002 (Philadelphia) -- Investigators have recommended that imatinib mesylate (Gleevec) replace interferon alpha and ara-C therapy as the standard treatment for newly diagnosed chronic myeloid leukemia (CML).

The pronouncement came after imatinib significantly outperformed interferon and ara-C at every measure in 18-month data from the International Randomized Study of Interferon vs. STI571 (IRIS). The most striking result from the study presented here at the American Society of Hematology's annual meeting was a complete cytogenetic response rate of 76% at 18 months for patients who received imatinib, which was originally called STI571.

Only 7.4% of patients receiving standard treatment did as well. More than half (58%) of the patients originally assigned to the interferon arm of the trial have switched to imatinib.

Either they could not tolerate interferon, did not respond, or had stopped responding to the standard treatment, principal investigator Richard Larson, MD, of the University of Chicago in Illinois, said at a press conference. Only 11% were still receiving interferon.

Despite these overwhelming results in the largest imatinib trial to date, Dr. Larson stopped short of calling the new oral therapy a cure for CML. "Even though the response is remarkably high, we are still unsure what the ultimate outcome will be. Hopefully, the disease will not progress in patients who have responded to imatinib," he said, noting that it was first used on any patient in June 1998.

Stephen MacKinnon, MD, head of Bone Marrow Transplantation at University College Hospital in London, said during a plenary session lecture that the study shows imatinib is clearly superior to interferon but raises difficult questions about bone marrow transplants -- which remain the only known cure for CML. "Many physicians think STI stands for Stop Transplants Now," Dr. MacKinnon said.

Bone marrow transplants have a high mortality rate, he said: 20% of transplant patients die in the first year if the donor is related and 35% to 40% if unrelated. Transplants are more likely to be successful if done soon after diagnosis, however. Consequently, physicians and patients must decide whether prolonged imatinib treatment will make transplantation more risky if it becomes necessary later on.

For the time being, Dr. Larson said the investigators are recommending that patients continue to take imatinib as long as it helps them. In the United States, he said, many physicians and patients have already made that decision as advance word of the trial's positive outcomes became known.

Imatinib has been available for off-label use since the U.S. Food and Drug Administration approved it for CML patients with the Philadelphia chromosome, those who have gone into blast crisis, or those who are in chronic phase after failing interferon therapy. All patients in the IRIS trial had the chromosome defect.

European physicians have not been able to prescribe imatinib as a first-line therapy, according to Dr. Larson. He said Switzerland has already moved to approve it based on the new results and he predicted that other countries will soon follow.

The IRIS trial enrolled 1,106 newly diagnosed patients with CML in 16 countries between June 2000 and January 2001. Of 553 patients initially assigned to imatinib, 86% are still receiving the agent, which inhibits the BCR-ABL tyrosine kinase. "Importantly, patients have continued to show an increasing response rate," Dr. Larson said at the press conference, updating the results from the 12-month data he had planned to present to ever better 18-month numbers.

Progression-free survival was 92.3% for the imatinib arm compared with 73.6% for the patients who received the standard combination of interferon-alpha plus ara-C. Moreover, 97% of patients receiving imatinib had no progression of disease.

"Even 66% of patients with high-risk disease have had complete cytogenetic response," he said.

Adverse effects have been minimal, according to Dr. Larson. Less than 2% of patients receiving imatinib had non-hematological grade 3-4 toxicities compared with 31% of patients receiving interferon therapy. Nearly one in four interferon patients could not tolerate their initial treatments compared with 2% of imatinib patients. The most common adverse effects of imatinib were mild edema, skin rashes, and muscle cramps,

Ultimately, researchers are waiting to see whether imatinib can eradicate all traces of the disease. Cellular response is not the same as molecular response, Dr. Larson cautioned. "Only 5% on the imatinib arm have had complete disappearance of [polymerase chain reaction]-detectible disease," he said.

ASH 44th Annual Meeting: Abstract 2. Presented Dec. 8, 2002.

Reviewed by Gary D. Vogin, MD

Jane Salodof MacNeil is a freelance writer for Medscape.

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