CARDIOTOXICITY AS A DOSE-LIMITING FACTOR IN A SCHEDULE OF HIGH-DOSE BOLUS THERAPY WITH INTERLEUKIN-2 AND ALPHA-INTERFERON - AN UNEXPECTEDLY FREQUENT COMPLICATION

Background. In a group of patients with metastatic melanoma treated with high dose immunotherapy, there was an unexpectedly high incidence of severe cardiac adverse effects. Methods. Sixteen patients with metastatic melanoma were treated with high dose interleukin-2 (IL-2) and alpha-interferon (alpha-IFN). Each treatment cycle consisted of IL-2 at a dose of 12 MIU/m(2) and alpha-IFN at a dose of 3 MIU/m(2), given as intravenous bolus injections every 8 hours on Days 1-5, every 3 weeks for a total of three cycles. Before treatment, careful cardiologic screening was performed, including electrocardiogram (ECG), stress test, cardiac multiple uptake-gated acquisition (MUGA) scan, and echocardiography. During therapy, patients were monitored with daily ECG and creatine phospokinase measurements. Once cardiac damage was suspected, IL-2 and alpha-IFN were discontinued, and echocardiography, stress test and MUGA-scan were repeated. If indicated, cardiac catheterization with endomyocardial biopsies was performed. Results. Despite pretreatment cardiac screening, seven patients (44%) exhibited myocardial injury. Acute myocardial infarction occurred in one patient, cardiomyopathy developed in four, asymptomatic ECG changes appeared in one, and 1 patient died of acute cardiac arrest. Echocardiography showed hypokinesis and decreased left ventricular ejection fraction. These abnormalities disappeared within 6 months. Cardiac catheterization in four affected patients revealed normal coronary arteries, but endomyocardial biopsies showed interstitial edema, vacuolation, and degeneration of myocytes. Electron-microscopic examination showed fragmentation of myofibrils, swelling of mitochondria and loss of mitochondrial cristae. Conclusions. This intensive treatment schedule of IL-2 and alpha-IFN is prohibited by severe and life-threatening cardiac toxicity.