ALBERT

Description: MicroRNAs have been suggested to modulate a variety of cellular events. Here we report that miR-24 regulates erythroid differentiation by influencing the expression of human activin type I receptor ALK4 (hALK4). Ectopic expression of miR-24 reduces the mRNA and protein levels of hALK4 by targeting the 3′-untranslated region of hALK4 mRNA and interferes with activin-induced Smad2 phosphorylation and reporter expression. Furthermore, miR-24 represses the activin-mediated accumulation of hemoglobin, an erythroid differentiation marker, in erythroleukemic K562 cells and decreases erythroid colony-forming and burst-forming units of CD34+ hematopoietic progenitor cells. ALK4 expression is inversely correlated with miR-24 expression during the early stages of erythroid differentiation, and the forced expression of miR-24 leads to a delay of activin-induced maturation of hematopoietic progenitor cells in liquid culture. Thus, our findings define a regulation mode of miR-24 on erythropoiesis by impeding ALK4 expression.

Description: Transforming growth factor-β (TGF-β) and its signaling mediators play crucial roles in vascular formation. Our previous microarray analysis identified monocyte chemoattractant protein-1 (MCP-1) as a TGF-β target gene in endothelial cells (ECs). Here, we report that MCP-1 mediates the angiogenic effect of TGF-β by recruiting vascular smooth muscle cells (VSMCs) and mesenchymal cells toward ECs. By using a chick chorioallantoic membrane assay, we show that TGF-β promotes the formation of new blood vessels and this promotion is attenuated when MCP-1 activity is blocked by its neutralizing antibody. Wound healing and transwell assays established that MCP-1 functions as a chemoattractant to stimulate migration of VSMCs and mesenchymal 10T1/2 cells toward ECs. Furthermore, the conditioned media from TGF-β–treated ECs stimulate VSMC migration, and inhibition of MCP-1 activity attenuates TGF-β–induced VSMC migration toward ECs. Finally, we found that MCP-1 is a direct gene target of TGF-β via Smad3/4. Taken together, our findings suggest that MCP-1 mediates TGF-β–stimulated angiogenesis by enhancing migration of mural cells toward ECs and thus promoting the maturation of new blood vessels.

Description: Abstract 2474 Poster Board II-451 Background Imatinib is associated with significant long-term survival benefits in CP CML patients versus bone marrow transplantation (BMT). Despite the proven benefits of imatinib and its position in first line treatment of chronic CML in several countries, BMT remains a treatment option in first line treatment of CML China. This modelling study was designed to explore the cost-effectiveness of imatinib in the Chinese setting. Methods A model was built in Microsoft Excel, with quarterly time intervals for overall survival over a 2-year period due to the lack of longer term follow up cost data for BMT. Published survival curves for the Chinese population were not available for either imatinib or BMT; however survival data for both imatinib and BMT from previous published literature were found to be broadly consistent with those reported in an unpublished survival meta-analysis of imatinib and BMT in Chinese population. The overall survival curve for imatinib sourced from the IRIS study (Druker et al 2006) was reconstructed in order to populate the imatinib arm of the model, and transplantation survival curves from Hasford et al (ASH 2008) were used to populate the BMT arm in the model. It was assumed that all patients surviving in each cycle remained in remission. Costs were based on the Chinese payment system. Due to the lack of publicly available cost data in China, a retrospective analysis of patient billings was conducted in 3 top tier hospitals in China (2 in Shanghai and 1 in Beijing) using a paper-based data collection questionnaire, with a target of 60 patients in total. Costs included in the model were: average cost of transplantation (including pre-operative and post-operative care and the transplantation procedure, as well as donor costs), complications associated with BMT and imatinib, quarterly cost of imatinib to the patients, and average quarterly charges for tests and monitoring. Utilities used in the model were sourced from IRIS; the utility for imatinib patients in remission was 0.854. Due to lack of published utility values in BMT patients, it was assumed that transplantation patients in remission would experience the same utility as interferon plus low-dose cytarabine (0.71). The outcomes of the model were total costs of treatment, life years, quality adjusted life years (QALY). A discount rate of 5% was used for costs and 0% for outcomes (utilities and life-years). Results Based on a cohort of 500 patients in each arm, the use of imatinib in CP CML yielded 497 and 971 life years (424 and 829 QALYs) at 1 and 2 years for imatinib vs. 485 and 898 for BMT (345 and 637 QALYs). Incremental life years (QALYs) were 12 (80) and 73 (192) at 1 and 2 years comparing imatinib with BMT. Total costs for imatinib were 73,194,400 RMB and 143,380,400 RMB at 1 and 2 years vs. 134,789,745 RMB and 143,552,071 RMB for BMT. Therefore, the cost savings for imatinib vs. BMT were 61,595,345 RMB and 171,671 RMB at 1 and 2 years. Imatinib is a dominant strategy to BMT (i.e., lower cost and higher efficacy) at 1 and 2 years. The model results were most sensitive to varying costs of BMT and discounting rates. Conclusion The results of the model demonstrate that imatinib is associated with improved overall survival and lower costs compared with BMT for the first 2 years in treating CP CML patients in the Chinese setting. Imatinib should be the first line treatment in CP CML based on both clinical and economic evidence. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 2497 Poster Board II-474 Objective: HSCT(mainly allogeneic)is still used as a treatment option, and in some cases, first line option for chronic myeloid leukemia (CML) in China. The objective of this study is to understand the treatment outcomes of HSCT and imatinib for CML in China. Methods: All published original China CML research was reviewed and included in this analysis if they met the following criteria: studies are from institutions in China; HSCT or imatinib was used to treat CML; contained data on treatment effect and survival; the sample size reported was ≥ 5 patients. Meta-analysis was used to analyze the pooled data. The survival rate of CML patients for HSCT and imatinib were compared by confidence interval method. Results: The study reviewed 46 HSCT papers and 66 imatinib papers. Meta survival analysis was conducted for 6 HSCT and 6 imatinib studies that had completed 5-year survival data. All 12 papers studied CML patients treated from the top tier hospitals in China. Totally, 263 HSCT patients Objective: HSCT(mainly allogeneic)is still used as a treatment option, and in some cases, first line option for chronic myeloid leukemia (CML) in China. The objective of this study is to understand the treatment outcomes of HSCT and imatinib for CML in China. Methods: All published original China CML research was reviewed and included in this analysis if they met the following criteria: studies are from institutions in China; HSCT or imatinib was used to treat CML; contained data on treatment effect and survival; the sample size reported was ≥ 5 patients. Meta-analysis was used to analyze the pooled data. The survival rate of CML patients for HSCT and imatinib were compared by confidence interval method. Results: The study reviewed 46 HSCT papers and 66 imatinib papers. Meta survival analysis was conducted for 6 HSCT and 6 imatinib studies that had completed 5-year survival data. All 12 papers studied CML patients treated from the top tier hospitals in China. Totally, 263 HSCT patients (227 CP, 23AP, 5 BC) and 718 imatinib patients (442CP, 145AP, 131BC) were involved in the meta-analysis. The median age was 33.5 years (range 14-57 years) for HSCT patients and 41,5 years (range 5-79 years) for imatinib patients. Both HSCT and imatinib achieved much better results in chronic phase (CP) compared to other phases (AP or BC) of CML.HSCT for CML-CP achieved estimated 73% survival rate (95% CI 67-79%) at 5 years. The acute graft versus host disease (GVHD) rate ranged from 24% to 63%; chronic GVHD rate ranged from10% to 57%; mortality due to transplantation ranged from 16% to 34%; mortality due to relapse ranged from 2% to 10%. In CML-CP patients treated with imatinib therapy, 5-year KM-estimated survival rate was 88% (95% CI 84 - 92%). Imatinib was most effective in newly diagnosed CML-CP patients and was very effective in CML patients with failed interferon therapy or relapse after allogeneic stem cell transplantation. For CML-CP patients, imatinib showed significantly better survival than HSCT (88% vs. 73%, p