Gleevec still beneficial, despite evidence of heart disease

By Jerry Call

On July 23, 2006, the medical journal Nature Medicine published an article about heart damage caused by Gleevec. Many news agencies have picked up this story. This story is very new and further information may become available over time.

Norman Scherzer, Executive Director of The Life Raft Group and Jerry Call, LRG Science Coordinator, attended a Novartis briefing.

Novartis shared some of the following information:

Ten Gleevec patients from M.D. Anderson experienced some degree of heart failure or heart dysfunction. Three of these patients had previous heart disease and some of the others had risk factors such as high blood pressure and diabetes. Several details were not reported. These include the number of total patients examined for heart problems as well as the number of patients that could be expected to have these type problems in a normal population. Without such a comparison, we cannot determine whether the Gleevec patients are at higher risk than a normal population. Novartis reports that they have not seen any significant trend of heart problems in their large database of Gleevec patients.

In addition to the report of 10 patients with heart dysfunction, the Nature Medicine article reported on mice studies that showed some heart damage from Gleevec. Some caution should probably be used in applying these findings to humans. For instance, liver toxicity occurred in dogs in preclinical testing of Gleevec, but it turned out that the liver toxicity in humans was lower than would have been predicted from the dog studies.

The authors of the article performed experiments that suggest the probable cause of the heart damage in mice to be inhibition of the c-abl protein. Gleevec inhibits c-abl (and other forms of abl such as bcr/abl), KIT and PDGFR. They speculate that other drugs that inhibit cabl (such as dasatinib and AMN107) might also cause heart damage.

Apparently, the authors of the mouse study have recommended routine heart screening for patients taking Gleevec. According to Novartis, they have backed off of this recommendation in communications to Novartis. Novartis recommends screening only for patients who are having symptoms of heart dysfunction.

We should note that a decrease in left ventricular ejection fraction (LVEF) has also been reported for Sutent as well, but only 1 percent of patients had reductions below 40 percent (grade 3 reductions). Because of this, the Sutent.com website says “. . . baseline and periodic evaluations of LVEF should be considered.”

Gleevec is intended to treat very serious diseases. We know that without Gleevec (or a similar drug), metastatic GIST will progress, ending in death. All medicines balance risk versus benefit. We know that for most patients with metastatic GIST, Gleevec provides great benefit. At this time these benefits seem to far outweigh the risks for the great majority of patients. We will continue to monitor this situation and report on new developments. We also welcome comments from experts in the field.