Gleevec Combined with Interferon, Cytabarine for CML

December 13, 2002

Jane Salodof MacNeil

Dec. 13, 2002 (Philadelphia) - Preliminary results from two European trials raise the possibility that combining imatinib mesylate (Gleevec) with pegylated interferon alpha 2b (Peg IFN alpha/PegIntron) or cytabarine (Ara-C) might be effective in Philadelphia chromosome-positive chronic myeloid leukemia (CML) patients who do not have a complete response to imatinib alone.

The Italian Cooperative Study Group on CML reported that 93% of the first 57 early chronic phase patients evaluated in an ongoing phase II trial of imatinib and pegylated interferon had a complete hematolgical response within 12 weeks. The proportion of these patients having an early cytogenetic response was also encouraging - 60% in three months.

The CML French Group reported all 30 early chronic phase patients in a study combining imatinib and cytabarine had a complete hematological response in a median time of three weeks. At nine months, 57% had a complete cytogenetic response and 80% had a major cytogenetic response to the combination, which is to be tested in a phase III randomized trial.

Data from both studies were presented here at the American Society of Hematology annual meeting. In another major presentation, the International Randomized Study of Interferon vs. STI571 (IRIS) reported imatinib to be superior to a combination of interferon and cytabarine as a front-line therapy for newly diagnosed cases.

Michele Baccarani, MD, of the Institute of Hematogy Seragnoli in St. Orsola, Italy, cautioned that more data is needed before any comparison of imatinib and interferon to imatinib alone can be made.

He reported the early results do suggest, however, that the patient's risk profile at diagnosis could affect all nontransplant therapies for CML, including imatinib. At six months, 74% of low-risk patients and 70% of intermediate risk patients, but only 15% of high-risk patients had a major cytogenetic response.

All patients in the Italian trial received 400 mg of imatinib daily. They were broken into three cohorts that received pegylated interferon subcutaneously at 50 mg, 100 mg, or 150 mg weekly.

"Safety was not a problem, not at all," Dr. Baccarani said. "Compliance was a problem. More than half the patients discontinued the PegIFN because of toxicity."

Half the patients in the cytabarine trial had grades 3 or 4 hematologic toxicities, and a third had to stop cytabarine, according to Martine Gardembas, MD, of hematology and internal medicine at CHU Angers in France. Nonetheless, the investigators concluded that the imatinib-cytabarine combination could be given safely.

"Toxicity was quite acceptable for the physicians and the patients," Dr. Gardembas said. "Ara-C can be stopped for one or two months and resumed."

The French patients received the standard 400-mg daily dose of imatinib. Cytabarine was injected subcutaneously at an initial dose of 20 mg/m 2 per day.

Dr. Gardenas said the assumption behind using the combination was that by reducing the number of cell mutations, the French group hopes to achieve a sustained response.

"Sustained response is crucial with CML," she said. "We know from the past that patients would achieve transient response, but not improved survival."

Dr. Baccarani predicted that many drugs will be tested in combination with imatinib. "They will come, but they will come step by step," he said.

Commenting on these early reports, Nancy Berliner, MD, of Yale University Medical School noted that despite the high response rates, some patients were not helped even with the imatinib combinations. "Clearly, there are going to be some patients who are going to need other therapies," she said.

ASH 44th Annual Meeting: Abstracts 348, 351. Presented Dec. 9, 2002.

Reviewed by Gary D. Vogin, MD

JaneSalodof MacNeil is a freelance writer for Medscape.


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