The alpha interferons: clinical overview.

The clinical development of the recombinant alpha interferons has provided a prototype for the clinical development of biological compounds. With over 5,000 patients now treated with these compounds, some general principles have emerged that have wider implications for phase I-II strategies for testing other biologicals. There is a suggestion of dose-response relationships and a clearer picture of schedule dependence. The extent of tumor burden and identification of sensitive subtypes of patients also appear to be critical factors in evaluating the true potential activity of biological compounds. The toxicity profile of the alpha interferons is unusual. Fever and flu-like symptoms occur in all doses and schedules and are usually dose limiting. Somnolence and other CNS effects occur in a small percentage of patients. Hematologic toxicity occurs but is minimal at lower doses and is noncumulative and rapidly reversible at all doses. Gastrointestinal toxicity is mild. No other unusual or unexpected toxicities have been reported, and early reports of cardiovascular toxicity have not been confirmed in large trials. The use of these pioneer recombinant DNA products raised concerns about the potential development of antibodies and serum-neutralizing factors. Reports with small patient numbers confirmed the occasional development of serum-neutralizing activity to some alpha interferons. The significance of this neutralizing activity and the reasons for an apparent higher incidence of this phenomenon with some alpha interferon preparations remain to be determined. The full role of alpha interferon by itself or in combination with other available therapies will be resolved in coming years. This review presents current safety, efficacy, and neutralizing antibody data.