Treatment with histamine dihydrochloride and interleukin-2 in patients with advanced metastatic malignant melanoma: a detailed safety analysis

Intravenous high dose bolus therapy with interleukin-2 (IL2) is associated with low overall response rates (15%) and significant toxicity. Phase II and III trials of a lower dose subcutaneous regimen of IL2 administered alone (n = 152) or in combination with histamine dihydrochloride (n = 239) have recently been completed. This article describes a comprehensive safety and toxicity analysis of the results of these two trials. The phase III trial demonstrated a survival benefit in patients with liver metastases in the histamine/IL2 arm. Eligible patients had stage IV malignant melanoma with at least one measurable lesion. Toxicity was graded using the National Cancer Institute (NCI) common toxicity scale. All reported adverse events were included in the analysis. Almost all toxicities in each treatment group were NCI grade 1 or 2. The incidence of toxicities expected to occur with histamine treatment, such as hypotension/vasodilation, headache and injection site reaction, were higher among patients receiving histamine. With the exception of headache, the incidence of grade 3 or 4 toxicities was similar across the treatment groups. The addition of histamine to the subcutaneous IL2 regimen did not result in a difference in the incidence of drug interruption, dose modification or discontinuation. Study-related deaths were low and were not impacted by the addition of histamine to the IL2 regimen.