Since its introduction a few years ago, the cancer drug imatinib has given patients with chronic myelogenous leukemia an unprecedented chance at long-term survival. But studies of the drug in people and mice reveal an unexpected risk of heart failure lurking beneath imatinib’s benefits.
A research team led by Thomas Force of Jefferson Medical College in Philadelphia evaluated 10 patients who suffered moderate-to-severe heart failure while taking imatinib, which is marketed as Gleevec by the drug company Novartis. In all 10 patients, none of whom had had previous heart problems, their heart’s blood-pumping efficiency decreased after 1 to 14 months on the drug. When the researchers examined heart tissue from two of the patients, they found cell abnormalities characteristic of heart damage.
In a second study, Force’s team gave imatinib to healthy mice. After 3 weeks, those mice showed a deterioration in heart contractions, the researchers report in the August Nature Medicine. The mice received drug doses similar—adjusted for size—to those prescribed for people.
“I don’t think anyone would have expected this drug to have any cardiotoxicity,” says Force.
About 90 percent of chronic myelogenous leukemia patients treated with imatinib survive for 5 years or longer. Before the drug was approved in 2001, average survival was less than 5 years.
Imatinib also treats a rare stomach cancer called gastrointestinal stromal tumor.
The drug stops the leukemia by inhibiting a cancer-causing two-protein combination called Bcr-Abl. The new study pinpoints Abl inhibition as the factor that leads to the heart failure. Although the protein’s role remains unclear, Abl may be essential in maintaining cardiac health, says Force.
Only 1 to 5 percent of patients taking imatinib will develop heart failure, Force estimates, but he adds that long-term data are needed to establish a more precise figure.
One reason that earlier studies of imatinib didn’t reveal the cardiac risk might be that instead of attributing heart problems to the drug, physicians assigned them to hypertension, diabetes, or other ailments common in the leukemia patients, Force says.
Heart problems may not have shown up in early mouse studies because rodents metabolize imatinib quickly, he says.
Despite imatinib’s success against chronic myelogenous leukemia, recent studies have found that the drug loses its effectiveness in about one-fifth of patients (SN: 6/17/06, p. 371: Next Line of Defense: New drugs take on resistant leukemia). Those patients are often given newer drugs that also inhibit Abl—and therefore could also cause heart problems, says leukemia specialist Michael Deininger of the Oregon Health and Science University in Portland.
But while the finding should prompt physicians to monitor patients taking imatinib for heart problems, it “isn’t going to stop people from taking Gleevec, because otherwise [the leukemia] is going to kill them,” Deininger says.