New Mutations Found in CML Patients Treated with Gleevec

December 12, 2002

Dec.12, 2002 (Philadelphia) — German researchers have found new mutations in cells from eight of 48 chronic myeloid leukemia (CML) patients who had been successfully treated with imatinib mesylate (Gleevec).

None of the patients showed any sign of the Philadelphia chromosome, the abnormality that is the main marker for CML. Instead, six new and different mutations were identified.

Two of the patients also had signs of myelodysplastic syndrome, and several others were reported to have experienced prolonged cytopenias while they were receiving imatinib.

All of the genetic changes had occurred after therapy with the new drug, according to Michael W.N. Deininger, MD, PhD, who presented the finding here at the American Society of Hematology (ASH) annual meeting.

"There is no reason to panic now, but there is reason to have concern that this is [just] the tip of the iceberg," he said at an ASH press conference.

Since the pilot study was conducted at the University of Leipzig, Dr. Deininger has joined the faculty of Oregon Health Services University (OHSU) in Portland. He said he hopes to start a registry of imatinib patients there to see whether the observed changes were an isolated phenomenon or somehow associated with the drug.

"We have approached Novartis [the drug's manufacturer], and I think they are interested," he told Medscape.

The medical community has not had an opportunity to observe the long-term effects of imatinib. Because the drug was lifesaving, the U.S. Food and Drug Administration (FDA) last year expedited approvals for Philadelphia chromosome-positive CML patients in blast crisis, accelerated phase, or in chronic phase after the failure of interferon-alpha therapy.

Novartis applied to the FDA for approval as a first-line treatment for newly diagnosed CML in June and received priority review status. The FDA action date on the application is Dec. 28.

Dr. Deininger warned against rushing to conclusions based on the German study, which involved a small number of patients at a single institution. He said the mutations might be the result of chemotherapy given to individual patients prior to their being treated with imatinib. If that is the case, he suggested future patients could be placed directly on imatinib after diagnosis.

Other possibilities, according to the abstract, are that imatinib favors the outgrowth of clones with previously acquired lesions or somehow induces cytogenetic abnormalities in some patients. Several of the abnormalities — t(3;21), t(20;21), del (20q), trisomy 8, monosomy 7 and –Y — are associated with poor cancer prognosis, Dr. Deininger said.

"As of now there is no indication that Gleevec itself would induce these lesions," he said, "but it is not possible to exclude the possibility."

Dr. Deininger recommended that patients receiving imatinib be screened every six months, and that oncologists do a cytogenetic assay if hemoglobin or white blood cells become low.

More than 1,000 CML patients in the International Randomized Study of Interferon vs. STI571 (IRIS) trial comparing imatinib to interferon are being screened every six months, according to Jerry Raditch, MD, of the Fred Hutchinson Cancer Center in Seattle, Washington. He was not sure whether all the centers are up to date on providing this information, but he said, "I suspect there's going to be a big push to do that."

Dr. Raditch and Tim Hughes, MD, of the Institute of Medical and Veterinary Studies in Adelaide, Australia, are performing polymerase chain reaction analysis of the samples. Also at ASH, they reported finding molecular traces of CML in cells that had been cleared cytogenetically.

"There appears to be a plateau. It doesn't get to zero," Dr. Raditch said, raising the question of whether people can live with the low levels of the drug being found.

"The bottom line," concluded Nancy Berliner, MD, of Yale Medical School, "is that [imatinib] is an incredibly effective drug. A lot is going to have to be worked out."

ASH 44th Annual Meeting: Abstracts 345, 613. Presented Dec. 9, 2002.

Reviewed by Gary D. Vogin, MD

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