Granulocytopenia in cancer patients treated in a phase I trial with recombinant human tumor necrosis factor

We have examined the effect of recombinant human tumor necrosis factor (TNF) upon granulocyte kinetics in cancer patients in a phase I clinical trial. TNF was given to each patient intravenously over 2 h at varying doses. A marked drop in the total white blood cell count, absolute polymorphonuclear leukocyte (PMN) count, and absolute monocyte count occurred reproducibly at 30 min after TNF initiation. Also noted was a drop in the absolute lymphocyte and eosinophil counts, both of which reached their nadir at approximately 4 h. A marked increase in immature PMN leukocytes (bands) was noted beginning at 1 h. These changes were statistically significant. Statistically significant increases in hemoglobin and hematocrit occurred at the 30 min time point but subsequently decreased to approximately 90% of pretreatment baseline. Additionally, the platelet count decreased, reaching its nadir approximately 6 h after TNF initiation. In four serial studies in patients on the highest dose of TNF, the granulocyte adhesion protein CD11b was shown to increase on the surface of the PMN leukocytes by as early as 7-15 min after initiation of TNF infusion. In each of these, expression of CD11b antigen increased prior to the disappearance of PMN leukocytes from the peripheral circulation. A similar finding was obtained for monocytes. This work indicates that within 30 min of intravenous infusion of TNF, mature granulocytes and monocytes have left the peripheral circulation. This is followed by an apparent bone marrow response indicated by an outpouring of bands. The initial granulocyte and monocyte emigration from the peripheral circulation is preceded at highest-dose TNF by increased cell surface expression of CD11b for both cell types, suggesting a causal relationship between these temporally linked events.