A pilot study of the recombinant soluble human tumour necrosis factor receptor (p75)-Fc fusion protein in patients with myelodysplastic syndrome
A pilot study of the recombinant soluble human tumour necrosis factor receptor (p75)-Fc fusion protein in patients with myelodysplastic syndrome
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DOI：
10.1046/j.1365-2141.2002.03381.x
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发表时间：
2002-04-01
影响因子：
6.5
通讯作者：
Young, NS
中科院分区：
文献类型：
--
作者：
Maciejewski, JP;Ristiano, AM;Young, NS
实验室观察表明，在一些骨髓增生异常综合征(MDS)中，免疫机制可能导致血细胞生成受损。肿瘤坏死因子-α(TNF-α)是一种有效的造血抑制因子，已被认为在MDS中介导抑制作用：肿瘤坏死因子-α水平升高，并与骨髓细胞凋亡和细胞减少相关。使用可溶性肿瘤坏死因子受体(Enbrel)抑制肿瘤坏死因子-α的产生已经在类风湿性关节炎中成功，我们现在也将同样的原理应用于MDS。我们测定了MDS患者骨髓细胞自发产生的肿瘤坏死因子-α；在1/3的患者中，肿瘤坏死因子-α的产生升高(>；平均值+2倍标准差)，但与临床参数无关。16名患者参加了为期3个月的Enbrel先导性研究。该药耐受性良好，15名患者可评价。在这些患者中，有一人暂时(14周)不能输血。另1例中性粒细胞绝对计数(ANC)由0.5×10(9)/L升至0.84x10(9)/L，6例中性粒细胞减少患者中2例发生严重感染。观察到3名患者进展为转化中原始细胞增多的难治性贫血(RAEBt)或白血病。当研究Enbrel对造血集落形成的影响时，MDS未见明显增加，且与TNF-α水平无相关性。尽管在MDS使用的剂量下，Enbrel的抗肿瘤坏死因子治疗耐受性良好，但作为单一药物，其疗效似乎很低。
Laboratory observations suggest that, in some myelodysplastic syndromes (MDS), immune mechanisms may contribute to the impaired blood cell production. Tumor necrosis factor alpha (TNF-alpha), a potent inhibitor of haematopoiesis, has been hypothesized to mediate suppressive effects in MDS: TNF-alpha levels are elevated and correlated with marrow apoptosis and cytopenia. Inhibition of TNF-alpha production using the soluble TNF receptor (Enbrel) has been successful in rheumatoid arthritis, and we have now applied the same principle to MDS. We determined spontaneous TNF-alpha production by marrow cells in MDS; TNF-alpha production was elevated (> mean + 2 x SD of controls) in > 1/3 of patients, but did not correlate with clinical parameters. Sixteen patients participated in a 3-month pilot study of Enbrel. The drug was well tolerated and 15 patients were evaluable. Of these, one became temporarily (14 weeks) transfusion independent. In another patient, absolute neutrophil count (ANC) rose from 0.5 x 10(9)/l to 0.84 x 10(9)/l. Serious infections were seen in two out of six neutropenic patients. Progression to refractory anaemia with excess blasts in transformation (RAEBt) or leukaemia was observed in three patients. When the effects of Enbrel on haematopoietic colony formation were studied, no significant increase was seen in MDS and there was no correlation with TNF-alpha levels. Although anti-TNF therapy with Enbrel was well tolerated at the dosages used in MDS, its efficacy as a single agent appears low.