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

Background. In a group of patients with metastatic melanoma treated wi th high dose immunotherapy, there was an unexpectedly high incidence o f severe cardiac adverse effects. Methods. Sixteen patients with metas tatic melanoma were treated with high dose interleukin-2 (IL-2) and al pha-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 scr eening was performed, including electrocardiogram (ECG), stress test, cardiac multiple uptake-gated acquisition (MUGA) scan, and echocardiog raphy. During therapy, patients were monitored with daily ECG and crea tine phospokinase measurements. Once cardiac damage was suspected, IL- 2 and alpha-IFN were discontinued, and echocardiography, stress test a nd MUGA-scan were repeated. If indicated, cardiac catheterization with endomyocardial biopsies was performed. Results. Despite pretreatment cardiac screening, seven patients (44%) exhibited myocardial injury. A cute myocardial infarction occurred in one patient, cardiomyopathy dev eloped in four, asymptomatic ECG changes appeared in one, and 1 patien t died of acute cardiac arrest. Echocardiography showed hypokinesis an d decreased left ventricular ejection fraction. These abnormalities di sappeared within 6 months. Cardiac catheterization in four affected pa tients revealed normal coronary arteries, but endomyocardial biopsies showed interstitial edema, vacuolation, and degeneration of myocytes. Electron-microscopic examination showed fragmentation of myofibrils, s welling of mitochondria and loss of mitochondrial cristae. Conclusions . This intensive treatment schedule of IL-2 and alpha-IFN is prohibite d by severe and life-threatening cardiac toxicity.