Abstract
Background: In vitro studies indicate that thalidomide alters the marrow microenvironment and also has an immunoregulatory role. We assessed various laboratory and clinical parameters to examine potential prognostic markers and to assess for changes during thalidomide therapy.
Methods: 75 patients with relapsed/refractory MM were enrolled in a multi-centre phase 2 trial using thalidomide (Blood. 2003;102:69–77). Platelet-poor plasma (PPP) and marrow biopsy were obtained at baseline and 3 monthly and immunohistochemistry for CD34, VWF, mast cell tryptase and CD57 performed. Flow cytometry on marrow aspirates was used to define the CD57+ population (T cell subsets, NK, NKT markers used). Vascular endothelial growth factor (VEGF), basic-Fibroblast growth factor (bFGF), interleukin-6 (IL-6) and Hepatocyte growth factor (HGF) were measured in PPP. Objectives were to examine for effect on response rate (RR), progression-free (PFS) and overall survival (OS).
Results: Overall RR was 28% with 55% stable disease. Only VEGF predicted response-no responses seen in patients with a level of 0, compared to a RR of 34% in those with VEGF > 0 (p=0.015). Microvessel density (MVD) did not predict for response, PFS or OS. The median number of CD57+ cells at baseline was 3 per HPF (range: 0–27) and flow cytometry confirmed that CD57+ cells were predominantly cytotoxic T cells. CD57+ cells did not predict for response, however on univariate analysis elevated levels were the major predictor of better OS (p=0.003). Predictors for inferior OS were raised baseline levels of IL-6 (p=0.014), and HGF (p=0.016). Multivariate analysis for OS which incorporated clinical variables demonstrated age >65 yrs (p=0.009), raised LDH (p=0.008) and zero baseline CD57+ cells (p=0.011) as predictors of inferior OS. MVD and VEGF fell significantly in responding patients although CD57+ cells did not change.
Conclusion: Levels of VEGF and MVD decline in thalidomide responders. However, high baseline angiogenic activity was not necessary to obtain a response. Increased age and elevated LDH are important predictors of poorer OS, with elevated baseline levels of CD57+ cells being an independent predictor of superior outcome.
NF-κ
B is involved in the regulation of CD154 (CD40 ligand) expression in primary human T cells
