Rare incidence of congestive heart failure in gastrointestinal stromal tumor and other sarcoma patients receiving imatinib mesylate†
Article first published online: 2 NOV 2009
Copyright © 2010 American Cancer Society
Volume 116, Issue 1, pages 184–192, 1 January 2010
How to Cite
Trent, J. C., Patel, S. S., Zhang, J., Araujo, D. M., Plana, J.-C., Lenihan, D. J., Fan, D., Patel, S. R., Benjamin, R. S. and Khakoo, A. Y. (2010), Rare incidence of congestive heart failure in gastrointestinal stromal tumor and other sarcoma patients receiving imatinib mesylate. Cancer, 116: 184–192. doi: 10.1002/cncr.24683
For studies conducted involving human subjects, informed consent was obtained from the subject(s) and/or guardian(s).
- Issue published online: 11 JAN 2010
- Article first published online: 2 NOV 2009
- Manuscript Accepted: 9 APR 2009
- Manuscript Revised: 27 MAR 2009
- Manuscript Received: 9 JAN 2009
- Physician-Scientist Award
- National Institutes of Health/National Cancer Institute. Grant Number: 1K23CA109060-05
- Amschwand Sarcoma Cancer Foundation
- congestive heart failure;
- gastrointestinal stromal tumor
The authors sought to determine the incidence and severity of cardiovascular toxicity caused by imatinib mesylate in gastrointestinal stromal tumor (GIST) and other sarcoma patients, and to explore cardiotoxicity caused by imatinib mesylate using cell culture and in vitro models.
To determine the incidence and significance of serious cardiac adverse events in GIST and other sarcoma patients receiving imatinib mesylate, the authors performed a retrospective analysis of 219 consecutive patients treated with imatinib mesylate. In vitro studies of imatinib mesylate on cultured cardiomyocytes and biochemical studies of cardiac lysates from mice treated with imatinib mesylate were performed to define the potential cardiotoxic effects of imatinib mesylate.
Grade 3 or 4 potentially cardiotoxic adverse events (mostly edema or effusions) occurred in 8.2% of patients, were manageable with medical therapy, and infrequently required dose reduction or discontinuation of imatinib mesylate. Arrhythmias, acute coronary syndromes, or heart failure were uncommon, occurring in <1% of treated patients. However, administration of imatinib in a mouse model system resulted in inhibition of activation of protein kinases that are known to be important in the cardiac stress response.
The authors concluded that imatinib is an uncommon cause of cardiotoxicity, and that the cardiovascular adverse events that occur are manageable when recognized and treated. Nevertheless, our preclinical findings suggest that imatinib remains a potential cardiotoxin. Furthermore, the cardiac consequences of long-term imatinib therapy remain unknown. We therefore recommend treatment of risk factors for cardiovascular disease in imatinib-treated patients in accord with the American Heart Association guidelines for the prevention and treatment of heart failure. Cancer 2010. © 2010 American Cancer Society.
The use of imatinib mesylate as a therapy targeting an essential signaling pathway (Abl kinase) in patients with chronic myelogenous leukemia (CML) represents a new paradigm in rational drug design, and has shown remarkable efficacy in the treatment of patients with early chronic phase and advanced stage CML.1, 2 Similarly, imatinib mesylate has been shown to be extremely effective in patients with advanced gastrointestinal stromal tumor (GIST) through inhibition of the tyrosine kinase c-kit.3 The promise of molecularly targeted cancer therapy is based on the premise that by specifically inhibiting molecules associated with tumor growth, such therapies will be highly effective in treating cancer without adversely affecting normal organs.
Although targeted cancer therapies are typically aimed at molecules that are aberrant in cancer cells, the fact remains that many receptor tyrosine kinases are expressed in normal tissues, and these molecules may play a role in the normal physiology of many organ systems, including the cardiovascular system. An example of this was seen in the treatment of breast cancer patients with the monoclonal antibody trastuzumab, whose target is the receptor tyrosine kinase ErbB2, the product of the HER-2/neu gene. Seven percent of patients treated with trastuzumab after anthracycline exposure developed cardiomyopathy, and 29% of the patients treated concurrently with trastuzumab and anthracycline developed cardiomyopathy.4 Subsequent preclinical studies demonstrated the essential role of ErbB2 signaling in normal cardiac development and in the cardiac response to stress.5-7
Recent work has demonstrated that imatinib mesylate can cause significant cardiac dysfunction when administered to mice at clinically relevant dosages.8, 9 Imatinib-treated mice developed depressed cardiac function, activation of the endoplasmic reticulum stress response within the heart, and mitochondrial abnormalities. Similar mitochondrial abnormalities were also seen in cardiac tissue obtained from patients treated with imatinib who also developed cardiac dysfunction and heart failure (HF).
This study led to widespread concern about the potential cardiotoxicity of imatinib mesylate and prompted a revision of the drug label to include careful monitoring of patients with cardiac disease or risk factors for HF. Subsequently, multiple studies reported a low incidence of clinically important HF in patients with both CML10 and GIST11, 12 treated with imatinib.
To further explore the effects of imatinib on cardiac function of GIST patients, we performed a retrospective analysis of our clinical trial database for analysis of potential cardiac adverse events. We found that adverse cardiac events in GIST patients treated with imatinib mesylate were uncommon and manageable and rarely required discontinuation of imatinib mesylate therapy. Consistent with these clinical findings, we found that in contrast to doxorubicin, imatinib did not cause apoptosis in cardiac myocytes in vitro. However, whereas in vivo administration of imatinib to mice did not cause overt cardiac failure, it did result in inhibition of the protein kinases Akt and Erk 1/2, both of which have been shown to play a cardioprotective role in the setting of vascular stress.13
MATERIALS AND METHODS
We reviewed all sarcoma patients enrolled in clinical trials with imatinib mesylate from December 27, 2000 to May 11, 2006, with institutional review board approval. From these databases, 219 consecutively treated patients were evaluated for the occurrence of grade 3 or 4 potential cardiac adverse events, including shortness of breath, dyspnea on exertion, chest pain, edema, pleural effusion, ascites, cardiac ischemia, and arrhythmia. The baseline characteristics of these patients are shown Table 1.
|Median age, y||58 (16-92)|
|Median imatinib mesylate dose||600 (400-800) mg daily|
In patients with potential cardiac adverse events, the clinical histories were reviewed in detail. Chest x-rays, echocardiograms, electrocardiograms, and relevant laboratory studies were reviewed for each patient to determine the possibility of cardiac toxicity. Signs and symptoms of HF that were specifically searched for in the chart review include orthopnea, paroxysmal nocturnal dyspnea, and jugular venous distention. Radiographic criteria used to diagnose HF include pulmonary vascular congestion and cardiac silhouette enlargement. Echocardiograms of all patients with potential cardiac adverse events were examined in detail by a single cardiologist (J.-C.P.), who was unaware of any clinical information.
HL-1 cardiomyocytes were used for in vitro studies and were grown in Claycomb media (SAFC Biosciences, Lenexa, Kan) as previously described,14 including 100 μM norepinephrine (Sigma-Aldrich, St. Louis, Mo) and 10% fetal bovine serum (SAFC Biosciences).
In Vitro Apoptosis Assay
Hl-1 cardiomyocytes were serum starved and treated with imatinib mesylate (Novartis, Basel, Switzerland) or vehicle control overnight. Cells pretreated with imatinib or control were exposed to doxorubicin (Sigma-Aldrich) for 2 hours in serum-free media. Lysates from drug-exposed cells were harvested, and caspase activity was measured as an index of cardiomyocyte apoptosis as previously described.15 Caspase activity was measured using the Caspase-Glo 3/7 Assay System (Promega, Madison, Wis).
In Vivo Imatinib Administration
Imatinib mesylate was administered to mice at 50 mg/kg daily for a period of up to 6 weeks. All animal work was done according to animal protocols approved by the institutional animal care and use committee. Imatinib was dissolved in saline and administered by gavage. Control mice were administered identical amounts of vehicle control by gavage. Forty-eight hours after the final dosage of imatinib, mice were sacrificed, and hearts and lungs were immediately harvested for weighing. Hearts were then flash frozen in liquid nitrogen until ready to be used for biochemical analysis.
Protein lysates isolated from murine left ventricles were isolated using cell lysis buffer (Cell Signaling Technology, Danvers, Mass) with phosphatase inhibitors. Lysates were separated by gel electrophoresis and blotted using the Novex system (Invitrogen, Carlsbad, Calif). Blots were probed with antibodies directed against phosphorylated Akt (Ser473), phosphorylated Erk 1/2 (Thr202/Tyr204), total Akt, and total Erk 1/2 (Cell Signaling Technology). Probing with an antiglyceraldehyde phosphate dehydrogenase antibody (Sigma-Aldrich) was also performed to control for equal protein loading.
Of the 219 patients evaluated, 18 (8.2%) were identified as having a grade 3 or 4 potential cardiac adverse event. The specific characteristics, along with lists of the established risk factors for coronary artery disease (CAD) of these 18 patients, are shown in Table 2. Notably, the median age of patients with grade 3 or 4 potential cardiac adverse events was 65 years (range, 21-88 years). In total, 13 (72%) had metastatic disease, and 10 (56%) had a history of hypertension. The median imatinib mesylate dose in patients with potential cardiac adverse events was 600 mg (range, 400-800 mg) daily. The median number of days the patient was on imatinib mesylate before potential cardiac adverse event was 174 (range, 17-1588 days). None of these features was significantly different from those seen in the overall patient population.
|Patient No.||Age||Race||Sex||Tumor Stage||Maximum Dose of Imatinib||Duration of Rx Before AE, d||CAD/CAD Risk Factors||Potential Cardiac AE|
|1||32||W||M||Metastatic||800||55||Lower extremity edema|
|2||70||B||F||Metastatic||600||1588||CAD, HTN, CABG||Left ventricular dysfunction|
|4||54||B||M||Primary||800||11||HTN||Lower extremity edema|
|5||57||B||M||Primary||600||57||DM, hyperlipidemia||Acute coronary syndrome|
|6||54||W||M||Primary||600||17||CAD, PTCA, DM, hyperlipidemia, HTN||Stable angina|
|7||77||B||F||Primary||400||338||DM, HTN, atrial fibrillation||Atrial fibrillation|
|8||21||W||F||Metastatic osteosarcoma||800||56||Pleural effusion|
|11||61||W||F||Metastatic||400||756||DM, HTN||Lower extremity edema|
|12||71||W||M||Metastatic||400||843||HTN||Acute coronary syndrome|
|13||88||W||M||Metastatic||400||320||PVD||Pulmonary edema, lower extremity edema|
|15||74||W||F||Metastatic||400||31||Lower extremity edema|
|16||81||W||M||Metastatic||400||1138||HTN, hyperlipidemia, PVD||Carotid stenosis|
|17||76||A||M||Metastatic||400||1517||Lower extremity edema|
Of the 219 patients that we studied, 7 (3.2%) manifested grade 3 or 4 dependent edema or effusion, 5 (2.3%) had objective evidence of cardiac ischemia or chest pain, 2 (0.9%) had documented arrhythmias, 2 (0.9%) had grade 3 or 4 dyspnea, 1 (0.4%) had objective left ventricular (LV) dysfunction by echocardiography, and 1 (0.4%) went into cardiac arrest.
Of the 7 (3.2%) patients who manifested edema or effusion, 2 (0.9%) had a pleural effusion, 4 (1.8%) had ascites, all 7 had lower extremity edema, and none had objective LV dysfunction or any signs, symptoms, or radiographic evidence of HF. Of the 4 (1.8%) patients who had echocardiograms after development of the potential cardiac adverse event, all had normal cardiac ejection fractions (EF >55%). Interventions in these 7 patients included diuretics for 6 (2.8%), angiotensin-converting enzyme (ACE) inhibitors and beta blockers for 2 (0.9%), thoracentesis and paracentesis for 5 (2.3%), a continued, unchanged imatinib mesylate dose for 3 (1.4%), a continued, reduced imatinib mesylate dose for 3 (1.4%), and discontinuation of imatinib mesylate for 1 patient (0.5%). This final patient had imatinib mesylate discontinued because of the combination of grade 3/4 edema and progression of disease while on 800 mg imatinib mesylate daily.
Of the 5 (2.3%) patients who had chest pain or possible cardiac ischemia, electrocardiograms revealed that 1 (0.5%) had new Q waves or ST-segment elevation, and 1 (0.5%) had new ST-segment depression or T-wave inversion. Two (0.9%) patients had elevated cardiac injury biomarkers. One (0.5%) patient had a positive stress test. Three (1.4%) patients required cardiac catheterization. Two (0.9%) patients had developed flow-limiting CAD. An ST-segment elevation and Q-wave myocardial infarction occurred in 1 patient in the postoperative period after neoadjuvant therapy with imatinib mesylate for GIST. This patient was diabetic, and had a history of hyperlipidemia. Another patient with multiple risk factors for CAD had a positive stress test 10 days after starting neoadjuvant imatinib mesylate as part of a preoperative evaluation. The patient had no symptoms. The patient was found to have severe flow-limiting CAD and had multiple coronary stents placed. All 5 (2.3%) patients above continued on imatinib mesylate without dose reduction.
We were able to identify only 1 (0.5%) patient who clearly developed HF associated with severe morbidity and mortality while on imatinib mesylate. The patient was a 61-year-old woman who was started on 400 mg imatinib mesylate daily for metastatic GIST. The patient's prior history included 2-vessel coronary artery bypass surgery but no history of HF or left ventricular dysfunction. After 2 years of imatinib mesylate therapy, the patient underwent surgical resection of the metastatic GIST. Preoperative evaluation revealed normal LV function and only mild anterior wall ischemia on stress testing. Postoperatively there was steady progression of the disease over a 2-year time period, which resulted in the subsequent increase in the imatinib mesylate dose to 800 mg daily. After further disease progression on imatinib mesylate, perifosine, an antiproliferative and proapoptotic agent under investigation, was added to the patient's treatment regimen. In hundreds of patients treated with perifosine, there has been no association with a decrease in cardiac function alone or in combination with kinase inhibitors. One month later, the patient presented with orthopnea, severe fatigue, and dyspnea. Echocardiography at the time of presentation with symptoms of congestive HF confirmed profound decrease in LV function (EF < 20%) compared with the preoperative echocardiography performed 2 years earlier (Fig. 1). Electrocardiogram revealed no evidence of new ischemic changes, troponin I levels were <0.1 and brain natriuretic peptide levels were 2399 pg/mL (normal < 50 pg/mL). After further progression of both GIST and congestive HF (CHF), the patient was treated with a regimen of diuretics, ACE inhibitors, and beta blockers with concurrent discontinuation of imatinib mesylate and perifosine therapy. The patient died several months later from progression of disease.
Our clinical data suggest that clinically apparent, imatinib mesylate-associated cardiac abnormalities are uncommon in GIST patients. However, this clinical observation does not exclude subclinical or delayed cardiovascular effects of imatinib. To further explore the cardiotoxic effects of imatinib, we used the HL-1 cardiomyocyte cell line as a model system. HL-1 cells are beating cardiomyocytes derived from a primary atrial tumor whose use as a model system for in vitro studies has been well validated.14 As has been described previously,16 we observed a dose-dependent increase in apoptosis, assayed by caspase 3/7 activation, in cardiomyocytes treated with doxorubicin (Fig. 2A). In contrast, treatment with imatinib mesylate over a broad concentration range had no effect on cardiomyocyte apoptosis in vitro (Fig. 2B). Furthermore, we did not observe enhancement of doxorubicin-mediated apoptosis by imatinib over a broad dose range (Fig. 2C). These findings importantly contrast the cardiotoxicity of imatinib with the well-established proapoptotic effects of anthracycline-based chemotherapy.17
To study the functional and biochemical effects of imatinib mesylate in the heart in the in vivo setting, we treated mice with imatinib mesylate in at 50 mg/kg/d for a period of 4 weeks; a dosage regimen similar to those used previously in vivo cancer efficacy studies.18-20 In imatinib-treated mice, we saw no evidence of overt cardiac dysfunction as measured by heart weight to body weight ratios (Fig. 3A) or lung weight to body weight ratios (not shown), an index of pulmonary edema. To further explore the effects of imatinib on the heart, we analyzed cardiac lysates from hearts of imatinib-treated mice for activation of established downstream targets of tyrosine kinases that are known to be cardioprotective under conditions of stress. Strikingly, we saw a marked reduction in levels of phosphorylated Akt (Fig. 3B) in cardiac tissue from imatinib-treated mice compared with controls. Multiple studies from a variety of mouse models implicate Akt as a central regulator of maintenance of cardiac eutrophy and as a regulator of the cardiac response to physiologic stress.21 In addition, we found a marked reduction in phosphorylation of the Erk 1/2 branch of the mitogen-activated protein kinase (MAPK) signaling pathway in imatinib-treated hearts compared with controls (Fig. 3C), obtaining a significant 50% decrease in the ratio of phosphorylated to total Erk 1/2 (Fig. 3D). Like Akt, Erk 1/2 activation has been shown to be critical for maintenance of cardiac function under conditions of stress.22 Notably, imatinib did not alter phosphorylation of the p38 branch of the MAPK signaling cascade (data not shown), whose role in cardiac protection is less well established.23 These findings suggest that although imatinib does not cause overt cardiac failure, it does affect signaling cascades that may predispose to the development of cardiac failure under conditions of physiologic stress.
In patients with GIST treated with imatinib mesylate, cardiac dysfunction does not appear to be causally related to development of severe edema or effusion in most cases. Overt CHF with new LV dysfunction during imatinib mesylate treatment in GIST patients occurred in 1 of 219 (0.4%) patients, and the causal relationship of imatinib or perifosine to the development of CHF in that case is not clear. GIST patients with preexisting heart disease or multiple risk factors for CAD were more likely to experience cardiac adverse events while being treated with imatinib mesylate than those with no history of cardiac disease. Because this study does not include a placebo arm for comparison, it is not possible to know whether this is any higher than the population of patients not treated with imatinib. Potential cardiac adverse events caused by imatinib mesylate in GIST patients are uncommon, manageable, and rarely require imatinib mesylate or other therapy to be discontinued or dose-reduced.
Furthermore, we used an in vitro assay to show that the effects of imatinib on cardiomyocytes are distinct from the established proapoptotic effects of doxorubicin. However, although administration of imatinib at clinically relevant dosages did not alter mouse cardiac function in vivo, we found that pathways that are known to be critical to the cardiac stress response are strongly inhibited after several weeks of imatinib therapy. Such findings suggest that imatinib treatment may increase the likelihood of development of cardiac dysfunction under conditions of stress. Alternatively, it is possible that compensatory mechanisms independent of activation of Akt and Erk 1/2 may minimize cardiac toxicity caused by imatinib under conditions of stress. Studies designed to investigate the effects of imatinib on the cardiac response to vascular stress are part of the ongoing work in our laboratory.
The effects on cardiac Akt and Erk 1/2 phosphorylation caused by imatinib are distinct but are possibly additive to the effects of imatinib on the cardiac evoked stress response that have been previously reported.8 The upstream targets of imatinib that result in blockade of activation Akt and Erk 1/2 are of great interest. Several reports suggest that Abl kinase is a critical target of imatinib in the cardiomyocyte.8, 9 Although the MAPK and Akt pathways are putative effectors of Abl kinase signaling, a direct effect on this signaling pathway in cardiac myocytes caused by imatinib has not previously been described.
Another possibility is that imatinib exerts its effects on the heart via inhibition of platelet-derived growth factor (PDGF) receptor signaling. PDGF receptor is an established target of imatinib,24 and both the Akt and MAPK pathways are key effectors of PDGF receptor signaling.25 Although the role of PDGF receptor signaling in the heart is largely unexplored, recent work suggests that activation of PDGF receptor in the cardiomyocyte may exert a cardioprotective role through effects on Akt signaling.26 The relative contributions of inhibition of Abl, PDGF receptor, or other targets to the effects of imatinib on the MAPK and Akt pathways in cardiomyocytes are the subject of intense study in our laboratory.
Our preclinical findings highlight several important points about the clinical cardiovascular effects of imatinib that are worthy of mention. First of all, previous reports and our clinical findings suggest that patients with underlying cardiovascular disease may be at greater risk for developing the cardiovascular abnormalities associated with imatinib therapy.8, 10 It should be noted that there is as yet no conclusive evidence that these adverse events are indicative of drug toxicity. One weakness of our study is that it did not include careful evaluation of a control group with similar cardiac histories but without GIST or imatinib treatment. Another weakness of our study and of other studies that have determined the incidence of potential cardiac adverse events putatively caused by imatinib and other tyrosine kinase inhibitors is that these studies have been retrospective in nature, and have not relied on careful, prospectively defined measurements of cardiac function. The clinical diagnosis of HF in cancer patients can be enormously challenging to make without the use of prospective, well-defined endpoints, because of the overlap of the cardinal symptoms of HF—dyspnea, fatigue, and edema—which are very common in cancer patients, including GIST patients treated with imatinib. Thus, the reported incidence of HF caused by imatinib therapy, particularly when mild and subclinical, may be underestimated by our study and others. Furthermore, little is known about the effects of long-term administration of imatinib and other tyrosine kinase inhibitors on cardiac function. Prospective studies with cardiac monitoring will be required to answer these questions, and based on our preclinical findings, we believe that such studies are warranted.
Although we await such studies, we believe that the wealth of evidence suggests that cardiac complications in patients treated with imatinib are manageable and should not be a reason to withhold imatinib therapy from cancer patients who would derive benefit. At the same time, in light of the current mechanistic studies and clinical observations, a practical approach to preventing potential cardiac complications of imatinib is needed. One such approach that seems to be applicable to patients treated with imatinib is based on the recently published guidelines from the American Heart Association for the management of CHF (Fig. 4). In this classification scheme, a new area of focus is the so-called stage A patient, a patient without clinical evidence of cardiac dysfunction but at risk for HF. Management of such patients involves modification of risk factors that may predispose the patient to HF, including treatment of blood pressure and hypercholesterolemia and encouragement of smoking cessation (Fig. 4).
Recently, the US Food and Drug Administration has approved the adjuvant use of imatinib for patients who have had their GIST resected without specifying the duration of therapy. Although these patients may be cured of their GIST, they may be taking imatinib for many years. Early detection and management of HF of any etiology is important in this patient population. Therefore, based on its potential cardiotoxicity, chronic administration, and long-term patient survival, we believe that patients treated with imatinib can be thought of as stage A patients (at risk for HF), and that application of the American Heart Association guidelines for the stage A patient is a reasonable approach to prevent long-term cardiac complications that occur in patients treated with this remarkable drug.
CONFLICT OF INTEREST DISCLOSURES
This work was supported by an institutional Physician-Scientist Award (J.C.T., A.Y.K.), National Institutes of Health/National Cancer Institute grant 1K23CA109060-05 (J.C.T.), and the Amschwand Sarcoma Cancer Foundation (J.C.T.).