NOVEL THERAPEUTIC STRATEGIES IN MYELODYSPLASTIC SYNDROME

骨髓增生异常综合征（MDS）在许多患者的特点是 在存在细胞或细胞减少的情况下通过外周血细胞减少 骨髓虽然一部分患者最终会发展为急性白血病， 40%-50%的患者死于出血性或传染性疾病 并发症令人满意的治疗，以造血干细胞的形式 移植，仅适用于一小部分患者。新 需要治疗方式。最近的研究表明， 造血负调节因子，如肿瘤坏死因子（TNF）-α 以及MDS骨髓中的高凋亡率（程序性细胞死亡）。初步 研究表明，通过阻断负性造血细胞， 调节信号或通过消除这些信号的细胞源。的 申请人建议1）进行一系列临床试验以确定 TNFR：Fc（可溶性TNF受体）、抗胸腺细胞球蛋白（ATG， 抗-T-细胞剂）和flt 3-配体（早期活化细胞因子）单独和联合 联合治疗，改善外周血细胞减少和稳定造血， MDS患者; 2）对来自骨髓的骨髓进行体外/离体研究， 入组这些试验以表征形态学，免疫表型， TNF-α、Fas和Fas-配体的表达，以及细胞遗传学 治疗前后的异常，并与体外/离体相关 参数与体内治疗反应和反应的“质量”; 3） 开发利用新探针和试剂的其他治疗方法。 预计这些研究将产生数据，指导选择 患者未来的具体方案。反过来，治疗的优化， 应降低MDS相关的发病率和死亡率， MDS患者的生活质量。

Myelodysplastic syndrome (MDS) in many patients is characterized by peripheral blood cytopenias in the presence of cellular or hypocellular marrow. While a proportion of patients will eventually develop acute leukemia, 40 percent-50 percent of patients die with hemorrhagic or infectious complications. Satisfactory therapy, in the form of hemopoietic stem cell transplantation, is available only to a small proportion of patients. New treatment modalities are needed. Recent studies show increased expression of negative regulators of hemopoiesis such as tumor necrosis factor (TNF)-alpha and a high rate of apoptosis (programmed cell death) in MDS marrow. Preliminary investigations suggest that hemopoiesis can be improved by blocking negative regulatory signals or by eliminating the cellular source of those signals. The applicants propose to 1) conduct a series of clinical trials to determine the efficacy of TNFR:Fc (a soluble TNF receptor), antithymocyte globulin (ATG, an anti-T-cell agent), and flt3-ligand (an early activating cytokine) alone and in combination, in improving peripheral cytopenias and stabilizing hemopoiesis in patients with MDS; 2) to carry out in vitro/ex vivo studies on marrow from patients enrolled in those trials to characterize morphology, immunophenotype, expression of TNF-alpha, Fas and Fas-ligand, as well as cytogenetic abnormalities, before and after therapy and to correlate in vitro/ex vivo parameters with in vivo treatment responses and "quality" of response; 3) to develop additional treatment approaches utilizing new probes and reagents. These studies are expected to generate data that will guide the selection of patients for future specific protocols. Optimization of therapy, in turn, should reduce morbidity and mortality associated with MDS and improve the quality of life of patients with MDS.