Thalidomide exerts distinct molecular antileukemic effects and combined thalidomide/fludarabine therapy is clinically effective in high-risk chronic lymphocytic leukemia
Thalidomide exerts distinct molecular antileukemic effects and combined thalidomide/fludarabine therapy is clinically effective in high-risk chronic lymphocytic leukemia
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DOI：
10.1038/leu.2009.98
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发表时间：
2009-10-01
期刊：
影响因子：
11.4
通讯作者：
Bullinger, L.
中科院分区：
文献类型：
--
作者：
Giannopoulos, K.;Dmoszynska, A.;Bullinger, L.
沙利度胺是一种有前途的免疫调节药物，靶向白血病细胞和肿瘤微环境。我们用沙利度胺/氟达拉滨联合方案治疗慢性淋巴细胞白血病（CLL）患者，并在氟达拉滨治疗前监测沙利度胺诱导的体内细胞和分子变化。每天给予沙利度胺（100 mg p.o.在每个4周周期（最多6个周期）内，在第7 - 11天给予氟达拉滨（25 mg/m2，i.v./天）。20例患者接受沙利度胺/氟达拉滨作为一线治疗，20例患者既往接受过治疗。36例患者中发现未突变的IgVH突变状态，13例存在高危细胞遗传学畸变（del17 p，del11 q）。未治疗和既往治疗患者的总体缓解率分别为80%和25%。沙利度胺虽然降低了CLL细胞的数量，但CD3淋巴细胞的数量无明显变化，但CD4（+）CD25（hi）FOXP3（+）调节性T细胞（TcR）的数量显著降低。基因表达谱分析揭示了沙利度胺诱导的签名包含已知具有免疫调节药物作用功能的靶标以及新的候选基因。沙利度胺/氟达拉滨联合治疗对高危CLL患者有效。此外，我们的研究为沙利度胺效应提供了新的生物学见解，沙利度胺可能通过增强CLL细胞的凋亡和降低TcR起作用，从而实现T细胞依赖性抗肿瘤作用。Leukemia（2009）23，1771 - 1778; doi：10.1038/leu.2009.98; 2009年5月14日在线发表
Thalidomide represents a promising immunomodulatory drug that targets both leukemia cells and the tumor microenvironment. We treated patients with chronic lymphocytic leukemia (CLL) with a combined thalidomide/fludarabine regimen and monitored cellular and molecular changes induced by thalidomide in vivo before fludarabine treatment. Thalidomide was given daily (100 mg p.o. per day) and fludarabine was administered on days 7-11 (25 mg/m(2) i.v. per day) within each 4-week cycle (maximum of 6 cycles). Twenty patients received thalidomide/fludarabine as first-line therapy and 20 patients were previously treated. Unmutated IgVH mutation status was found in 36 cases and 13 had high-risk cytogenetic aberrations (del17p, del11q). The overall response rate was 80 and 25% for untreated and previously treated patients, respectively. Although thalidomide reduced the number of CLL cells, the number of CD3 lymphocytes showed no significant change, but the number of CD4(+)CD25(hi)FOXP3(+) regulatory T cells (Tregs) was significantly decreased. Gene expression profiling revealed a thalidomide-induced signature containing both targets known to have a function in immunomodulatory drug action as well as novel candidate genes. Combined thalidomide/fludarabine therapy demonstrated efficacy in high-risk patients with CLL. Furthermore, our study provides novel biological insights into thalidomide effect, which might act by enhancing apoptosis of CLL cells and reducing Tregs, thereby enabling T-cell-dependent antitumor effect. Leukemia (2009) 23, 1771-1778; doi: 10.1038/leu.2009.98; published online 14 May 2009