After a Scare, Gleevec Appears Safe for the Heart
In late July, some news organizations reported that 10 patients had experienced heart failure while taking the cancer drug imatinib (Gleevec). That's when Dr. Brian Druker's phone at the Oregon Health & Science University Cancer Institute started ringing.
Dr. Druker led the team that developed imatinib for treating chronic myelogenous leukemia (CML), a potentially fatal disease, in the late 1990s. When the news reports appeared this summer, he was unaware of evidence that imatinib might harm the heart.
But as articles with headlines such as "'Miracle' Cancer Drug May Hurt Heart" began to circulate online, Dr. Druker received hundreds of messages from anxious patients worried about heart failure.
The articles were about a study in the August Nature Medicine that referred to 10 patients who developed heart failure while taking imatinib and were treated successfully.
"I was surprised by the study because we hadn't seen any heart failure in patients, and now that we're looking for it, we're still not seeing it," says Dr. Druker, who nonetheless took the concerns seriously and has been monitoring the cardiac health of patients.
His team has not found any abnormalities, and even the hearts of patients who have taken imatinib for 5 or 6 years have appeared normal when tested. In a database of 500 patients, only 1 had died of heart failure.
But back in July, Dr. Druker recalls, "There was a lot of panic." Today, 4 months later, the panic has passed, and some of the concerns about imatinib have been addressed.
The drug's label carries a new precaution, and the drug's maker, Novartis, sent letters to health care professionals about the rare occurrence of severe congestive heart failure, particularly among patients who have risk factors such as diabetes and high blood pressure. CML tends to occur in older patients who have other health conditions.
Also, clinicians are monitoring cardiac health more carefully now and collecting data to study the issue. At present, the available data suggest that the drug, taken by 100,000 patients worldwide for CML and gastrointestinal tumors, is very safe for most patients.
For most patients with CML, a slight risk of heart failure is worth the potential benefit. Without the drug, half of patients with CML would die within 5 years, while 90 percent of patients taking imatinib survive 5 years or more.
The best estimate of the incidence rate is that heart failure occurs in 1 percent of patients. This figure, from a 2003 study in the New England Journal of Medicine involving 1,100 patients, had been on imatinib's label.
In the randomized clinical trial, heart failure was less common in the imatinib group than among patients in the control group taking interferon plus cytarabine, which has no links to heart problems (0.7 percent versus 0.9 percent).
"Our review of the data showed how uncommonly cases of heart failure are reported and that in many of the cases, patients had other risk factors that would contribute to heart failure," says Dr. Diane Young, head of Clinical Development at Novartis Oncology.
Novartis and heart failure researchers knew about the cases. They had been reported at a meeting in September 2005 by the authors of the Nature Medicine paper, which itself was a follow-up looking at potential mechanisms by which imatinib might affect cardiac cells. The experiments were done primarily in human cells and in mice.
"There was a pretty big overreaction to the paper on the part of the press, and this inflamed the situation," says lead investigator Dr. Thomas Force, clinical director of the Center for Translational Medicine at Jefferson Medical College.
"Our report was simply designed to point out that heart failure can occur and therefore needs to be monitored," he says. "I think the drug will probably turn out to be quite safe if patients are watched."
The findings appeared at a time when many are concerned about the cardiac side effects of some "targeted" cancer therapies.
Drugs such as dasatinib (Sprycel), bevacizumab (Avastin), and sunitinib (Sutent) may slightly increase the risk of heart failure. This has led to calls for better monitoring of cardiac function early in clinical trials and beyond (rare side effects often appear after a drug is on the market).
"This study should encourage us to look more carefully for cardiotoxic side effects with these drugs because it does seem to be becoming a larger problem," says Dr. Douglas Mann, chief of cardiology at Baylor College of Medicine at the Texas Heart Institute at St. Luke's Episcopal Hospital.
"We know far less than we need to know about imatinib and cardiac side effects," adds Dr. Mann, who wrote an accompanying commentary in Nature Medicine.
He stresses the critical importance of monitoring heart function in patients. Physical examinations may not detect the milder forms of heart failure in patients with no symptoms, yet these patients need to be monitored and, if necessary, treated.
"We need prospective studies," adds Dr. Force. The only reliable way to assess the risk of cardiotoxicity is through studies that test heart function prior to treatment and periodically during the treatment, he says. (Retrospective reviews of clinical trials only detect patients with relatively advanced heart failure.)
But in the meantime, he cautions against scaring patients away from drugs that can help them.
Imatinib has been so effective that some patients were skeptical of the initial news reports. A woman who had just completed a triathlon and another who had been hiking in the San Francisco hills each left Dr. Druker messages, saying "I've never felt better."
"But people certainly heard the news and were concerned, and I had to spend a lot of time reassuring patients," Dr. Druker says.
He expects that research groups with large numbers of patients will eventually publish data on the incidence of heart failure and imatinib in the scientific literature, and "this will set the record straight."
By Edward R. Winstead