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All febrile episodes (a total of 276) which occurred in 85 patients with acute myelogenous leukaemia treated in four Norwegian centres during the period 1990-1994 were studied retrospectively in order to assess the efficacy of antibiotic treatment. 72% of these episodes were initially treated with benzyl penicillin and aminoglycoside (standard treatment), while alternative empirical treatment was given in the remaining cases. The treatment was successful in 94% of the febrile episodes initially treated with standard treatment and in 96% of the episodes which received alternative antibiotics. For both types of treatment, a change to second line antibiotic regimen was made for various reasons in a majority of cases. The combination benzyl penicillin and aminoglycoside seems to be a safe empirical treatment for febrile neutropenia in patients with acute myelogenous leukaemia in our treatment centres, provided that the treatment is modified in patients with unsatisfactory clinical response.

Intensive chemotherapy for acute leukaemia is followed by a period of severe chemotherapy-induced leukopenia. We used a limiting dilution assay to investigate whether remaining CD4+ and CD8+ T lymphocytes derived from such leukopenic patients could be activated and undergo clonogenic proliferation. The activation signal in our model was accessory cells (irradiated normal peripheral blood mononuclear cells) + phytohaemagglutinin (PHA) + interleukin-2 (IL-2). During severe leukopenia a majority of circulating lymphocytes were CD4+ T cells. Clonogenic proliferating T lymphocytes were detected for all patients. Higher frequencies of clonogenic cells were detected in the CD8+ subset as compared to the CD4+ subset. However, for both subsets frequencies of proliferating cells were decreased compared with healthy individuals. The CD4+ and CD8+ lymphocytes were also capable of proliferation in response to alloactivation, and accessory cells mainly containing acute myelogenous leukaemia blast were efficient as accessory cells for activation. For the CD4+ cells, increased proliferation was detected in the presence of acute myelogenous leukaemia (AML) blasts compared with normal accessory cells. Based on our results we conclude that: (1) although acute leukaemia patients with therapy-induced leukopenia have both a quantitative and a qualitative T-cell defect, (2) the remaining T-cell population includes a subset capable of clonogenic proliferation. However, (3) proliferation of the clonogenic CD4+ cells can be modulated by AML blasts.

T lymphocyte functions in acute leukaemia patients with severe chemotherapy-induced leucopenia were investigated using 3 different approaches: (i) analysis of serum concentrations of the T cell cytokine interleukin 4 (IL4) demonstrated that serum IL4 levels increased during complicating bacterial infections. However, this response was modulated by a concomitant increase in serum levels of the potential IL4 antagonist soluble IL4 receptor alpha chain (sIL4R alpha). (ii) Even during leucopenia a subset of T lymphocytes derived from leucopenic patients expressed the activation markers CD25 (IL2 receptor), CD71 (transferrin receptor) and HLA-DR. (iii) Subsets of circulating CD4+ and CD8+ T lymphocytes could undergo clonogenic proliferation in vitro, and a majority of these clones secreted IL4. CD4+ clones showed higher IL4 levels than CD8+ clones. Our results indicate that T lymphocytes can be activated and contribute to cytokine responses in acute leukaemia patients with severe chemotherapy-induced cytopenia.

Normal peripheral blood mononuclear cells (PBMC responders) were cultured together with non-irradiated allogeneic PBMC (more than 95% leukaemia blasts) derived from patients with acute leukaemia (referred to as leukaemic PBMC stimulators). Cytokine secretion was determined as cytokine concentrations in supernatants. Both normal PBMC and enriched CD4+ and CD8+ T cells responded to allostimulation with interferon (IFN gamma) secretion. Interleukin-I (IL-1) receptor antagonist and IL-2-neutralizing antibodies decreased IFN gamma secretion. Exogenous IL-1 beta, IL-2 and IL-7 increased allostimulated IFN gamma secretion, whereas decreased levels were seen in the presence of IL-6, IL-10 and granulocyte-colony-stimulating factor (G-CSF). During allorecognition IFN gamma-neutralizing antibodies decreased acute myelogenous leukaemia (AML) blast secretion of G-CSF. We conclude that (i) both CD4+ and CD8+ T cells show allostimulated cytokine secretion in response to allogeneic stimulator cells containing a dominating population of native, cytokine-secreting leukaemia blasts, and (ii) IFN gamma released during this response can modulate the function of allogeneic AML blasts.