Background: Interleukin 10 (IL-10) exerts anti-inflammatory actions by counteracting many biological effects of interferon γ (IFN-γ). Aims: To investigate this in humans, we studied the effects of human recombinant IL-10 administration on IFN-γ production by patient leucocytes. Furthermore, we assessed the IFN-γ inducible molecule neopterin and nitrite/nitrate serum levels, which are indicative of endogenous nitric oxide formation. Methods: As part of two placebo controlled double blind studies, we analysed patients with chronic active Crohn's disease (CACD) who received either subcutaneous recombinant human IL-10 (n=44) or placebo (n=10) daily for 28 days, and patients with mild to moderate Crohn's disease (MCD) treated with either subcutaneous IL-10 (n=52) or placebo (n=16) daily for 28 days. Neopterin and nitrite/nitrate concentrations were measured in serum, and ex vivo IFN-γ formation by lipopolysaccharide or phytohaemagglutinin (PHA) stimulated whole blood cells were investigated before, during, and after IL-10 therapy. Results: In patients with CACD, the highest dose of 20 µg/kg IL-10 caused a significant increase in serum neopterin on days +15 and +29 of therapy compared with pretreatment levels. No changes were observed for nitrite/nitrate levels under either condition. In MCD, treatment with 20 µg/kg IL-10 resulted in a significant increase in PHA induced IFN-γ production. Conclusions: High doses of IL-10 upregulate the production of IFN-γ and neopterin. This phenomenon may be responsible for the lack of efficacy of high doses of IL-10 in the treatment of CACD and MCD.
BackgroundThalidomide maintenance therapy after stem cell transplantation resulted in increased progression-free survival and overall survival in a few trials, but its role in non-transplant eligible patients with multiple myeloma remains unclear. This study assessed the impact of thalidomide-interferon in comparison to interferon maintenance therapy in elderly patients with multiple myeloma. Design and MethodsOf 289 elderly patients with multiple myeloma who were randomized to thalidomide-dexamethasone or melphalan-prednisolone induction therapy, 137 finally completed 9 cycles of induction therapy with stable disease or better and thereby qualified for maintenance treatment. Of these, 128 have been randomized to either thalidomide-interferon or interferon alone. Primary study endpoints were progression-free survival and response rates; secondary endpoints were overall survival, toxicity and quality of life. ResultsThalidomide-interferon maintenance therapy led to a significantly longer progression-free survival compared to interferon (27.7 vs. 13.2 months, P=0.0068), but overall survival was similar in both groups (52.6 vs. 51.4 months, P=0.81) and did not differ between patients aged 75 years or older, or younger patients (P=0.39). Survival after disease progression tended to be shorter in patients on thalidomide-interferon maintenance therapy (P=0.056). Progression-free survival and overall survival tended to be shorter in patients with adverse cytogenetic (FISH) findings compared to the standard risk group but differences were not significant (P=0.084 and P=0.082, respectively). Patients on thalidomide-interferon presented with more neuropathy (P=0.0015), constipation (P=0.0004), skin toxicity (P=0.0041) and elevated creatinine (P=0.026). ConclusionsThalidomide plus interferon maintenance therapy increased progression-free survival but not overall survival and was associated with slightly more toxicity than maintenance with interferon alone. (ClinicalTrials.gov Identifier: NCT00205751).Key words: thalidomide, thalidomide-interferon, progression-free survival, overall survival. Haematologica 2010;95(9):1548-1554. doi:10.3324/haematol.2009 This is an open-access paper. Citation: Ludwig H, Adam Z, Tóthová E, Hajek R, Labar B, Egyed M, Spicka I, Gisslinger H, Drach J, Kuhn I, Hinke A, and Zojer N.Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma.Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma
SummaryWe report on a randomised trial that aimed to compare the efficacy of continued daily prednisolone treatment during the entire induction phase, with prednisolone given for 2 weeks of each cycle in combination with VMCP (vincristine, melphalan, cyclophosphamide, prednisolone)-interferon-a2b (IFN-a2b) treatment in 299 previously untreated elderly patients (median age: 67 years) with multiple myeloma. After completion of induction treatment patients were randomised to IFN-a2b with or without prednisolone, thrice weekly. Response rate was 62% in the continuous and 60% in the control arm (intent to treat analysis, P ¼ 0AE81). Progression-free survival [median: 20 months vs. 19 months; hazard ratio (HR): 0AE99, 95% confidence interval (CI): 0AE74-1AE33, P ¼ 0AE97] and overall survival (median: 34 months vs. 37 months; HR: 1AE16, 95% CI: 0AE85-1AE59, P ¼ 0AE35) were similar in both groups. Reduced performance status (Eastern Cooperative Oncology Group, grades 2-4) was the predominant risk factor for poor survival followed by age >65 years, high b2-microglobulin, and impaired renal function. There was more grades 3-4 dyspnoea and cardiac impairment and grades 1-2 hyperglycaemia, but less nausea, emesis and anaemia in patients on continuous prednisolone therapy. In conclusion, continuing prednisolone treatment during the entire duration of the induction phase with VMCP-IFN-a2b did not improve outcome.
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