Cytokine serum levels during treatment with high-dose recombinant human IL-3 in a patient with severe aplastic anemia

Summary

A 37-year-old woman with severe aplastic anemia (SAA), who had relapsed 6 years after antilymphocyte globulin therapy, was treated with intravenous recombinant human IL-3 (4μg/kg/d) for 21 days. Subsequently, long-term therapy with subcutaneous rhIL-3 at the highest dose level tested so far (16μg/kg/kg/d) was initiated in order to maintain growth-factor response. Therapy was discontinued on day 73 due to progressive thrombocytopenia and increased petechial bleeding. Both treatment schedules resulted in a transient increase in leukocytes (twofold) due to an increase in monocytes, neutrophils, and eosinophils. RhIL-3 had no effect on hemoglobin values or platelet counts and only marginally improved colony formation of bone marrow CFU-GM in response to rhGM-CSF. Side effects of both treatment schedules were mild and did not exceed WHO grade II. Steady-state serum concentrations of IL-3, which are able to stimulate hematopoiesis in vitro (i.e.>1 ng/ml), were achieved by both low- and high-dose treatment, although high-dose treatment resulted in markedly higher serum levels of IL-3. On measuring cytokine serum levels (neopterin, IL-1β, IL-6, sIL-2R, GM-CSF, TNF-α, IFN-γ) we noticed a different cytokine pattern with both treatment modalities, resulting in a moderate induction of TNF-α and IFN-γ during low-dose, intravenous treatment, whereas during subcutaneous, high-dose treatment a profound increase of IL-6, sIL-2R, and, to a lesser extent, neopterin was detected. These results in a single patient with SAA indicate that further studies on IL-3 serum levels and IL-3-induced secondary cytokines in a larger group of patients are needed to optimize growth-factor treatment and to better understand the in vivo biological activity of IL-3.