Spotlight on histamine dihydrochloride in acute myeloid leukaemia.

Histamine dihydrochloride (Ceplene®) is a synthetic derivative of the biogenic amine histamine. Histamine dihydrochloride inhibits the formation of reactive oxygen species that suppress the activation of T cells and natural killer (NK) cells. When given in addition to the cytokine interleukin (IL)-2, histamine dihydrochloride enables the activation of T cells and NK cells by IL-2, resulting in the killing of cancer cells, including those of acute myeloid leukaemia (AML). In a large, 3-year, randomized, open-label, multicentre, phase III trial in adult patients with AML in first or subsequent remission, those who received subcutaneous histamine dihydrochloride and concomitant subcutaneous IL-2 as maintenance therapy had a significantly longer leukaemia-free survival (LFS; primary endpoint) than patients receiving no treatment. This difference was also shown for the subgroup of patients in first remission. The between-group difference in overall survival (OS) was not significant, although this trial was not powered to detect such a difference. Histamine dihydrochloride and IL-2 therapy had an acceptable tolerability profile in patients in the phase III trial. The majority of reported adverse events were of grade 1 or 2 severity. The most commonly reported grade 3 adverse events with active treatment were thrombocytopenia, headache, neutropenia, pyrexia, eosinophilia and diarrhoea; grade 4 adverse events were thrombocytopenia and leukopenia not otherwise specified. Serious adverse events were mostly relapse related. Histamine dihydrochloride and IL-2 as maintenance therapy significantly prolonged LFS compared with no treatment and had an acceptable tolerability profile in a large phase III trial in patients with AML. Although some issues remain to be addressed, most notably the effects of therapy on OS and the efficacy of treatment in older patients (who represent the majority of AML patients), histamine dihydrochloride in addition to IL-2 appears to be a useful maintenance therapy option for adult patients with AML in remission.