Maciejewski Jaroslaw P, Risitano Antonio M, Sloand Elaine M, Wisch Laura, Geller Nancy, Barrett John A, Young Neal S
Hematology Branch and Office of Biostatistics Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Br J Haematol. 2002 Apr;117(1):119-26. doi: 10.1046/j.1365-2141.2002.03381.x.
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.
实验室观察表明，在某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）是一种强大的造血抑制剂，据推测它在MDS中起介导抑制作用：TNF-α水平升高，且与骨髓凋亡和血细胞减少相关。使用可溶性TNF受体（恩利）抑制TNF-α的产生在类风湿关节炎中已获成功，我们现在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TNF-α的情况；超过1/3的患者TNF-α产生增加（>对照组平均值 + 2倍标准差），但与临床参数无关。16名患者参与了一项为期3个月的恩利试点研究。该药物耐受性良好，15名患者可进行评估。其中，1名患者暂时（14周）不再依赖输血。在另一名患者中，绝对中性粒细胞计数（ANC）从0.5×10⁹/L升至0.84×10⁹/L。6名中性粒细胞减少患者中有2名出现严重感染。3名患者病情进展为转化中的原始细胞过多的难治性贫血（RAEBt）或白血病。当研究恩利对造血集落形成的影响时，在MDS中未观察到显著增加，且与TNF-α水平无关。尽管在MDS中使用的剂量下，恩利抗TNF治疗耐受性良好，但其作为单一药物的疗效似乎较低。
