JAMA：影响再生障碍性贫血复发率和死亡率的生物标记

据9月22/29日刊《美国医学会杂志》上的一项研究披露， 在那些接受免疫抑制疗法的严重再生障碍性贫血（一种骨髓无法产生血细胞的疾病）的患者中，其端粒的长度（它是染色体生物老化标记）与治疗的反应无关，但却与较高的疾病复发率（重新回到血细胞计数低的状态）及较低的总体存活率有关。

严重的再生障碍性贫血是以危及生命的血细胞数减少（血细胞数低于正常）为特征的，但这种疾病可以用骨髓移植或免疫抑制性药物来治疗。根据文章的背景资料，在老年病患中，以及在没有具备良好匹配性同胞捐赠者的时候，免疫抑制疗法可以是有效的，尽管病情的复发及克隆演变（在骨髓细胞中出现伴有血液系统恶性病变的染色体异常）会在许多病人中出现。最近，人们发现靶细胞异常是骨髓衰减的风险因素。文章的作者写道：“人们描述了在某些具有表观严重再生障碍性贫血的病人中的因端粒酶复合物基因突变而导致的极其短小的端粒。”端粒是染色体端的一种结构，它会随着每次细胞分裂而变短，其功能是在细胞分裂的时候它可作为一种保护性的盖子防止基因组的DNA受到侵蚀。遗传因子和环境中的应急因子可缩短端粒的长度。

马里兰州贝塞斯达国立卫生院的Phillip Scheinberg, M.D.及其同事开展了一项研究，旨在通过测量免疫抑制疗法之前端粒的长度来确定端粒耗损对获得性严重再生障碍性贫血的影响。该研究包括了在2000至2008年期间接受过治疗的183名患有严重再生障碍性贫血的病人。研究人员分析了免疫抑制疗法组的罹患严重再生障碍性贫血患者在治疗前的白细胞（白细胞参与机体的抗感染性疾病的过程）的经年龄校正的端粒长度，并将其与患者的临床后果进行了相关性研究。

有104位病人（占57%）对免疫抑制疗法有反应。研究人员发现，在端粒长度（在治疗之前所测量的端粒长度）与对治疗起反应的可能性之间没有相关性。病人的反应率在第一四分位数（即端粒长度最短的四分位数）中为56.5%，在第二四分位数中为54.3%，在第三四分位数中为60%，在第四四分位数中为56.5%。额外的分析证明，端粒长度与疾病的复发、克隆演化及死亡率有关。端粒的长度与疾病复发的可能性具有负相关性。在第一四分位数中，患者的克隆演化可能性要比第二至第四四分位数的可能性更高（24.5% vs. 8.4%）。

研究人员写道：“2组患者的存活率不同，在第一四分位中的患者的6年存活率为66%，而在第二至第四四分位中的患者的存活率为83.3%。”（生物谷Bioon.com）

原文摘要：

JAMA. doi:10.1001/jama.2010.1376

Association of Telomere Length of Peripheral Blood Leukocytes With Hematopoietic Relapse, Malignant Transformation, and Survival in Severe Aplastic Anemia

Phillip Scheinberg, MD; James N. Cooper, MD; Elaine M. Sloand, MD; Colin O. Wu, PhD; Rodrigo T. Calado, MD, PhD; Neal S. Young, MD

Context  Critically short telomeres produce apoptosis, cell senescence, and chromosomal instability in tissue culture and animal models. Variations in telomere length have been reported in severe aplastic anemia but their clinical significance is unknown.

Objective  To investigate the relationship between telomere length and clinical outcomes in severe aplastic anemia.

Design, Setting, and Patients  Single institution analysis of 183 patients with severe aplastic anemia who were treated in sequential prospective protocols at the National Institutes of Health from 2000 to 2008. The pretreatment leukocyte age-adjusted telomere length of patients with severe aplastic anemia consecutively enrolled in immunosuppression protocols with antithymocyte globulin plus cyclosporine for correlation with clinical outcomes were analyzed.

Main Outcome Measures  Hematologic response, relapse, clonal evolution, and survival.

Results  There was no relationship between hematologic response and telomere length with response rates of 56.5% of 46 patients in the first, 54.3% of 46 in the second, 60% of 45 in the third, and 56.5% of 46 in the fourth quartiles. Multivariate analysis demonstrated that telomere length was associated with relapse, clonal evolution, and mortality. Evaluated as a continuous variable, telomere length inversely correlated with the probability of hematologic relapse (hazard ratio [HR], 0.16; 95% confidence interval [CI], 0.03-0.69; P = .01). The probability of clonal evolution was higher in patients in the first quartile (24.5%; 95% CI, 8.7%-37.5%) than in quartiles 2 through 4 (8.4%; 95% CI, 3.2%-13.3%; P = .009), and evolution to monosomy 7 or complex cytogenetics was more common in the first quartile (18.8%; 95% CI, 3.5%-31.6%) than in quartiles 2 through 4 (4.5%; 95% CI, 0.5%-8.2%; P = .002). Survival between these 2 groups differed, with 66% (95% CI, 52.9%-82.5%) surviving 6 years in the first quartile compared with 83.8% (95% CI, 77.3%-90.9%) in quartiles 2 through 4 (P = .008).

Conclusion  In a cohort of patients with severe aplastic anemia receiving immunosuppressive therapy, telomere length was unrelated to response but was associated with risk of relapse, clonal evolution, and overall survival.