Gleevec Linked to Heart Failure in Some CML Patients

PHILADELPHIA, July 24 -- Gleevec (imatinib), the most prominent symbol of the age of targeted anti-cancer drugs, can on occasion cause serious cardiotoxicity with congestive heart failure, according to researchers.

The finding, based on human, animal and laboratory studies, raises the possibility that similar drugs -- the tyrosine kinase inhibitors -- could also have deleterious effects on heart muscle, according to researchers led by Thomas Force, M.D., of Thomas Jefferson University here.

Gleevec, a successful therapy for chronic myelogenous leukemia (CML), targets the kinase activity of a fusion protein, Bcr-Abl, which causes the disease. In patients with chronic-phase CML, more than 70% of those treated with Gleevec achieve complete cytogenic remission. Gleevec is also indicated for gastrointestinal stromal tumors (GIST).

But, Dr. Force and colleagues reported today in the online issue of Nature Medicine, 10 CML patients treated with Gleevec at the M.D. Anderson Cancer Center in Houston developed congestive heart failure, although they had normal heart function when they began taking the drug. Studies in mice and in culture showed that the Abl tyrosine kinase protects cardiac cells from damage; when it is inhibited, heart cells die.

Dr. Force and colleagues called cardiotoxicity "an unanticipated side effect" of Gleevec. However, they provided no indication of what they suspected the rate of congestive heart failure might be.

"Clinical trials of the agent, however, have reported a relatively high incidence of peripheral edema (63% to 66%), some of which has been classified as severe (4% to 5%)," they wrote. "In addition, dyspnea has been reported in 12% to 16% of treated individuals and has been classified as severe in 4% to 5%."

"Although these symptoms and signs are difficult to evaluate in individuals with CML, it has become apparent to us in clinical practice that many individuals, including those reported herein, have developed left ventricular dysfunction and even frank congestive heart failure without a prior history of heart disease."

They characterized Gleevec as a "wonderful drug and patients with these diseases need to be on it." Nevertheless, "we're trying to call attention to the fact that Gleevec and other similar drugs coming along could have significant side effects on the heart and clinicians need to be aware of this."

The researchers recommended that patients taking Gleevec should be followed closely for signs of heart failure.

An official of Novartis, which makes the drug, said the research is "very interesting and definitely something that needs to be looked into."

But Diane Young, M.D., the company's vice-president for clinical development in oncology, said in an interview that it's important "that patients not panic and change their therapy because it's obviously a life-saving medication."

She said the possibility of cardiac failure is mentioned as an infrequent adverse effect in the drug's labeling. The company's data indicate that between 0.1% and 1.0% of patients may be affected.

"Because it's uncommon," she said, "it's not clear that routine screening of these patients is going to beneficial in the long run."

The 10 patients, Dr. Force and colleagues reported, had normal heart function when they started taking Gleevec: their left ventricular ejection fraction was 56% (plus or minus 7%). However, between one and 14 months after starting the drug, they had symptoms corresponding to New York Heart Association (NYHA) class 3 or 4 heart failure.

Specifically, their left ventricular ejection fraction was 25% (plus or minus 8%), which was significantly lower than the pre-treatment LVEF, at P