Cardiotoxicity of Imatinib Is a "Surprise"

Zosia Chustecka

July 26, 2006

July 26, 2006 —The cardiotoxic effects related to the leukemia drug imatinib ( Gleevec in the United States, Glivec elsewhere; Novartis) "is a big surprise," says the researcher heading the team that describes the adverse effect in a paper published online July 23 in Nature Medicine.

Thomas Force, MD, professor of medicine at Thomas Jefferson University, Philadelphia, Pennsylvania, and colleagues describe 10 patients with chronic myelogenous leukemia (CML) who developed severe congestive heart failure (CHF) while being treated with imatinib. Myocardial biopsies from 2 of these individuals and also from mice treated with imatinib detected abnormalities in mitochondria and other organelles that were "suggestive of myocardial toxicity," the researchers write. Further experiments conducted in vitro demonstrated that imatinib induced changes within cardiomyocytes that eventually led to cell death.

"We found that the molecular target of the drug, the Abelson tyrosine kinase [Abl] protein, serves a maintenance function in cardiac-muscle cells and is necessary for their health," Dr. Force explained to reporters. "Imatinib is a wonderful drug, and patients with these diseases need to be on it," he continued. However, while the cancer is treated effectively, "there will be some percentage of patients who could experience significant left ventricular dysfunction and even heart failure from this."

"Cardiotoxicity is an unanticipated side effect of the inhibition of Abl by imatinib," the researchers write. They warn that the adverse effect might also be seen with similar drugs, although it is difficult to predict which, because each tyrosine kinase inhibitor is slightly different.

"We're trying to call attention to the fact that imatinib and other similar drugs coming along could have significant side effects on the heart, and clinicians need to be aware of this," Dr. Force commented.

Asked to comment on the paper, Michael Deininger, MD, from the Oregon Health & Science University Cancer Institute in Portland, said that cases of heart failure in patients taking imatinib have been reported previously, and so this finding was "not entirely surprising."

However, the theory explaining why imatinib may be cardiotoxic "is a very new and potentially very significant finding," Dr. Deininger told Medscape in an interview. "The researchers did a very good job of pinning down the pathophysiology and etiology, and as far as I can see all the controls are in place and the research is very sound." So, does this make him think that the theory is true? "Yes, the theory may absolutely be true, and it hasn't been picked up before in other studies, maybe because it hasn't been looked for." Dr. Deininger added that it would be important to look for any factors that would predispose patients to this adverse effect and to explore whether or not the cardiotoxicity was reversible.

Pinning Down the Mechanism of Toxicity

The 10 patients who developed CHF while taking imatinib were being treated at the University of Texas MD Anderson Cancer Center in Houston. They had no prior symptoms, and the heart failure — described by Dr. Force as "fairly severe" — developed 2 to 14 months after they started imatinib therapy. At the outset, the researchers were unable to tell whether the toxic effects came from the drug's effect on known targets or from an off-target or nonspecific effect. "Sorting that out is important," Dr. Force commented, because there are many more targeted therapies in development.

Second-generation therapies that target Abl, in particular, might have the same toxicity problem, he suggested. Two such CML drugs— nilotinib ( Tasigna, Novartis) and dasatinib ( Sprycel, Bristol-Myers Squibb) — were described recently in the New England Journal of Medicine (2006;354:2542-2551, 2531-2541, 2594-2596) as bringing hope to patients who develop resistance to imatinib. Dasatinib has just been launched, whereas Novartis will soon be filing nilotinib for approval. Both are more potent Abl inhibitors than imatinib.

Dr. Force's team showed that Abl was the guilty party by using viruses that coded for normal Abl and an imatinib-resistant mutant. Imatinib inhibited the normal enzyme but not the mutant, and the researchers showed that the mutant Abl "largely rescues cardiomyocytes from imatinib-induced death." The in vitro studies showed that imatinib appears to cause endoplasmic reticulum stress and loss of mitochondrial function, both of which lead to cell death.

"We've learned something about the biology of the heart — Abl is important for cardiomyocyte health," Dr. Force commented. "We can also learn something about how to stay away from these targets that are important and optimize the drugs."

For instance, imatinib has several targets in addition to Abl, and its blockade of the platelet-derived growth factor (PDGF) receptor is crucial to its efficacy in another cancer, gastrointestinal stromal tumors. A drug that blocks the PDGF receptor but not Abl might retain the efficacy and avoid the cardiotoxicity problem, the researchers speculate.

Plans to Set Up Registry of Patients

The Jefferson researchers are now collaborating with colleagues at MD Anderson, the Cleveland Clinic in Ohio, and several centers in Europe to draw up a registry of patients being treated with tyrosine kinase inhibitors. "As these drugs come out, we can more easily collect data on larger numbers of patients as they take the drugs to get an idea of the incidence of heart problems," Dr. Force said.

In a written statement to Medscape, imatinib manufacturer Novartis pointed out that the cases of the 10 patients who developed CHF while taking the drug were already reported in the August 2005 issue of the Journal of Cardiac Failure (2005;11:S104, S126). The company notified health authorities of the finding at that time and told Medscape that these patients had been treated with ACE inhibitors and carvedilol with a significant improvement in symptoms, and some patients resumed imatinib without recurrence of heart failure.

There have been infrequent reports from clinical trials of cardiac failure in patients taking imatinib, with an estimated incidence of 0.1% to 1.0%, and similarly infrequent postmarketing reports, Diane Young, MD, vice president of clinical development at Novartis, and an oncologist herself, told Medscape in an interview. Imatinib has now been used by more than 100,000 patients worldwide, totaling more than 200,000 patient-years of exposure, she noted. Also, the CML patient population tends to be elderly, usually older than 60 years, so reports of heart failure are not surprising given the comorbidities in these patients.

The current paper in Nature Medicine describes preclinical studies that hypothesize how tyrosine kinase inhibitors affect cellular function, and the authors speculate that the development of CHF is related to the inhibition of Abl. Dr. Young emphasized that this explanation for the finding is at present just a theory, and more studies are needed to understand whether there is a relationship between these preclinical findings and the infrequent reports of heart failure from the clinic.

No Impact on Patient Care or Benefit/Risk Ratio

"At present, these findings should have no immediate impact on patient care or the value of this drug," Dr. Young said. In particular, she emphasized that patients should not stop taking the drug, pointing out that imatinib has revolutionized the treatment of CML and has prolonged patients' lives.

"The observations of this preclinical study do not change the positive benefit/risk ratio for imatinib for [the] thousands of patients being treated for cancer and other life-threatening diseases for which the drug is approved or being studied," Novartis said in the written statement.

Dr. Deininger told Medscape that, at present, the benefit/risk ratio of imatinib in the overall CML patient population has not changed and that any risk of cardiotoxicity is "hugely oversurpassed by the life-years gained from treating CML with this drug." Whereas previously the median survival was perhaps 5 years, now more than 90% of CML patients treated with imatinib survive 5 years. "The perception of CML has changed very considerably since the launch of imatinib" (in May 2001), he commented. "Ten years ago this was a deadly disease, and patients underwent allogeneic transplants at the cost of immense toxicity because this was the only reasonable approach to improve survival." In contrast, imatinib is "extremely well tolerated, with relatively rare and minor toxicities, and we mustn't forget how much it has added to the survival of CML patients."

However, Dr. Deininger added that for patients who develop heart failure while taking imatinib, the benefit/risk ratio has changed and needs to be reassessed. He also suspects that there have been many more instances of cardiac failure than appear in reports, because some could have been reported as fluid retention; a differential diagnosis is not possible unless specific tests are carried out, he pointed out.

Fluid retention is a relatively common side effect of imatinib therapy, Dr. Deininger added. In their paper, Dr. Force and colleagues note that clinical trials reported a relatively high incidence of peripheral edema (63% – 66%), some of which was classified as severe (4% – 5%). In addition, dyspnea has been reported in 12% to 16% of patients and classified as severe in 4% to 5%. "Although these signs and symptoms are difficult to evaluate in individuals with CML, it has become apparent to us in clinical practice that many individuals, including the 10 patients reported herein, have developed left ventricular dysfunction and even frank CHF without a prior history of heart disease," they write. "We suggest that individuals who are [taking] imatinib ... be followed closely for symptoms and/or signs of left ventricular dysfunction."

Also approached for a comment on the new research, Fred Appelbaum, MD, from the Fred Hutchinson Cancer Research Center in Seattle, Oregon, told Medscape that he found "the clinical results very interesting and the laboratory studies convincing." But he is not so sure that he would agree that the findings have no impact on patient care. "At a minimum, the results should alert physicians that fluid retention with imatinib is not always benign.

"Perhaps more important is the question of whether this toxicity will be seen with increasing frequency at higher imatinib dosing. While the [Food and Drug Administration] FDA-approved dose is 400 mg/day, many physicians treat at higher doses (up to 800 mg/day) in the hope of obtaining more complete molecular responses," Dr. Appelbaum commented. "There are several ongoing trials comparing standard [and] higher dosing, and the findings reported by Force et al provide further reason to perform and complete such studies before simply assuming that more is better."

The US Leukemia and Lymphoma Society has been receiving telephone calls from CML patients concerned about the cardiac risks and worried that the drug might be taken off the market, Hildy Dillon, vice president of patient services and disease programs, told Medscape. "We have been pointing out that the incidence of heart failure reported is very low, and at this point it's not clear that the incidence is any greater than would be expected in a similarly aged population not taking imatinib," she said. "We have also been advising patients to discuss concerns with their doctors."

Nat Med. Published online July 24, 2006.



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