Remission maintenance therapy with histamine and interleukin-2 in acute myelogenous leukaemia

Peripheral blasts recovered from patients with acute myelogenous leukaemia (AML) were efficiently lysed by interleukin-2 (IL-2)-activated heterologous natural killer (NK) cells in vitro. The IL-2-induced killing of AML blasts was inhibited by monocytes, recovered from peripheral blood by centrifugal elutriation. Histamine, of concentrations within the micromolar range, abrogated the monocyte-induced inhibition of NK-cells; thereby, histamine and IL-2 synergistically induced NK-cell-mediated killing of AML blasts. The effect of histamine was apparently mediated by H₂-type histamine receptors (H₂R), since the H₂R antagonist ranitidine completely blocked the response. Based on these in vitro findings, seven patients with AML in first (n=2), second (n=3) or third (n=2) complete remission (CR) were given home therapy with interleukin-2 (IL-2; 0.9×10⁶ IU×2 s.c.) and histamine (0.4–0.7 mg×2 s.c.) in cycles of 21 d, separated by 6-week intervals. The patients also received treatment with low-dose cytarabine and thioguanine between cycles of histamine/IL-2. Toxicity was moderate and included local reactions to IL-2 at the site of injection and short-lasting flush, hypotension, and headache to histamine. The addition of histamine to treatment with IL-2 significantly enhanced the accumulation of CD25⁺ T cells in peripheral blood as compared to treatment with IL-2 alone (P<0.003). Five patients remain in complete remission at 9, 18, 21, 24 and 26 months; the two patients in CR3 relapsed after 8 and 33 months, respectively. In the five patients with earlier relapse, the duration of remission after treatment with histamine/IL-2 has in each case exceeded that of previous remissions. We conclude that (i) histamine and IL-2 synergize to kill human AML blasts in vitro, and (ii) histamine/IL-2 is a safe and feasible approach to immunotherapy of AML which merits further investigation.