Cardiotoxicity as a dose-limiting factor in a schedule of high dose bolus therapy with interleukin-2 and alpha-interferon. An unexpectedly frequent complication

Abstract

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 (α‐IFN). Each treatment cycle consisted of IL‐2 at a dose of 12 MIU/m2 and α‐IFN at a dose of 3 MIU/m2, given as intravenous bolus injections every ß 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 α‐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 α‐IFN is prohibited by severe and life‐threatening cardiac toxicity.

Cancer therapy and cardiotoxicity: The need of serial Doppler echocardiography

“…Advanced breast cancer patients receiving epirubicin 90 mg/m 2 + paclitaxel 200 mg/m 2 showed reduction of two-dimensional EF from baseline median value of 60% to median value of 50% after 8 courses [52]. Hypokinesis and decreased EF were observed after high-dose bolus of interleukin-2 and interferon-α in 16 patients treated for metastatic melanoma [53]. Of interest, while the imatinib mesylate administration may increase cardiac morbidity in advanced chronic myelogenous leukaemia treated by successive allogenic stem cell transplantation with busulphan/cyclophoshamide conditioning [54], the same drug appears able to induce a rapid, echocardiographically detected, reversion of Loeffler's endocarditis in early stage of clonal hypereosinophilic syndrome [55].…”

Mito-Tempol and Dexrazoxane Exhibit Cardioprotective and Chemotherapeutic Effects through Specific Protein Oxidation and Autophagy in a Syngeneic Breast Tumor Preclinical Model

“…However, there is a need for better cardioprotectants because dexrazoxane does not eliminate the potential for cardiomyopathy by anthracyclines and newer anticancer agents that cause cardiotoxicity, such as trastuzumab, interleukin-2, and tyrosine kinase inhibitors, which are not known to elicit cardiotoxicity through iron-mediated oxidative stress [26]–[28]. In addition to testing dexrazoxane and the autophagic response in the SHR/SST-2 model, the novel therapeutic mitochondrialy-targeted Tempol (Mito-T) was also investigated.…”

Mitochondria in Pathogenesis

“…Our data may also of be of import to chemotherapy, where it might provide a rationale for the unexplained cardiotoxicity and hepatotoxicity of IL-2 and treatment (e.g., Kruit et al, 1994;Nakagawa et al, 1996). Patients undergoing such treatment regimes for renal carcinoma, for example, develop chronic-fatigue-like symptoms as well as organ toxicities.…”