The Thalidomide Analogue (Actimid) Induces T-Cell Activation at Day 28 in Patients with Relapsed Refractory Myeloma but Does Not Correlate with Improved Outcome.

Abstract

Introduction:Thalidomide analogues such as CC-4047 (Actimid, Celgene) have shown efficacy in treatment of relapsed myeloma but the exact mode of action remains unclear (Streetly M, et al ASH 2003). Preliminary work (Schey S, JCO 2004) suggests that thalidomide analogues can activate T-cells. We have demonstrated that measurement of serum free light chains at day 7 of treatment with Actimid can indicate likelihood of response (Patten P, et al, ASH 2003). Interleukin-2 (IL-2) secretion is increased in patients with myeloma on Actimid although this is not associated with clinical response (Ahsan G, et al Haematologica. Suppl.1 2005). We have now looked at expression of activation markers on T cells following 28 days of CC-4047.Aim:The aim of this study was to see if CC-4047 induces activation of T-cells and whether this correlated with clinical response as assessed by use of the serum free light chain (SFL) assay.Patients and Method:17 Patients (median age 59, range 34–75 years) participated in a phase I/II dose escalation study with CC-4047. All patients received treatment with oral CC-4047, on alternate day schedules. Serum was collected for IL-2 and serum free light chain. EDTA samples were taken for FACS analysis, which was performed on separated lymphocytes. 4 colour flow cytometry was performed using CD3/CD4/CD8/CD56 and CD69 monoclonal antibodies (Beckman Coulter, UK). Analysis for IL-2 and serum free light chains were performed as previously described (Ahsan et al Haematologica 2005 suppl.1)Results:Using conventional assessment 9/17 patients had evidence of response (CR, VGPR, PR) and 8 had stable disease (<25% reduction in paraprotein), In 9 patients there was complete serum free light chain data pre and at day 7. There was significant increased expression of CD69 (p=0.01) on the T-cells. A linear regression analysis was performed between changes in CD69 levels and changes in SFL ratio. There was no significant correlation found (R=0.1) table 1.Table 1PatientDose (mg)CD69 (Absolute count)Serum Free Light ChainBest responseAlt day10/lPrePostPrePost1128.426963SD223.65.516595SD3216.7--PR424961835.5CR552.4915065VGPR657.67.42527VGPR7510.652.315.41SD8515.210.63632SD9524.294830VGPR10531.19.75928SD11107.44.6--MR12101.77.9--VGPR13105.65.3--MRConclusions:This study showed that CD69 expression is increased on T cells in myeloma patients treated with CC-4047. This was detectable at day 28 of treatment. There did not appear to be a correlation between CD69 expression at day 28 and change in serum free light chain ratio. In line with other studies we have identified T cell activation in patients treated with the thalidomide analogue CC-4047. This does not appear to correlate with likelihood of response and it may be that response is due to activation of NK cells or that sustained activation of T-cells after 28 days is important for response. Further work is on-going to address these questions.