Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China.
Curr Med Res Opin. 2014 Jan;30(1):67-74. doi: 10.1185/03007995.2013.844116. Epub 2013 Oct 4.
Mammalian target of rapamycin (mTOR) inhibitors, temsirolimus and everolimus, are currently approved for the treatment of several malignancies. Hematological toxicities have been reported with these drugs, but overall incidence and relative risk remains undefined. We perform an up-to-date meta-analysis to determine the incidence and risk of hematologic toxicities associated with mTOR inhibitors.
Several databases were searched, including PubMed, Embase and Cochrane databases. Eligible studies included prospective phase II and III trials of temsirolimus and everolimus with adequate safety data profile reporting anemia, leucopenia, neutropenia or thrombocytopenia. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated by using either random effects or fixed effects models according to the heterogeneity of included studies.
A total of 5436 patients with a variety of solid tumors from 26 clinical trials were included for the meta-analysis. The overall incidences of mTOR inhibitor associated all-grade and high-grade hematologic toxicities were, respectively: anemia--38.8% and 7.5%; leucopenia--19.6% and 1.8%; neutropenia--14.9% and 5.6%; thrombocytopenia--33.1% and 3.6%. Compared to placebo/control arms, mTOR inhibitors were associated with a significantly increased risk of all-grade (RR 2.05, 95% CI: 1.52-2.77; p < 0.001) and high-grade anemia (RR 1.57, 95% CI: 1.20-2.05; p = 0.001), all-grade (RR 6.03, 95% CI: 2.76-13.14; p < 0.001) and high-grade thrombocytopenia (RR 2.73, 95% CI: 1.87-3.99; p < 0.001). Additionally, a non-significantly increased risk of all-grade leucopenia (RR 1.46, 95% CI: 0.66-3.23; p = 0.34) and neutropenia (RR 1.77, 95% CI: 0.80-3.93; p = 0.16) was observed in the mTOR inhibitor group, while the risk of high-grade leucopenia (RR 0.53, 95% CI: 0.31-0.90, p = 0.019) and neutropenia (RR 0.96, 95% CI: 0.62-1.51; p = 0.87) did not increase. Similar results were also observed in sub-group analysis according to mTOR inhibitor based regimens.
The use of mTOR inhibitors is associated with a significant increase in the risk of developing all-grade and high-grade anemia and thrombocytopenia compared with placebo/control arms.
哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂替西罗莫司和依维莫司目前被批准用于治疗多种恶性肿瘤。这些药物已报道有血液学毒性，但总体发生率和相对风险仍未确定。我们进行了一项最新的荟萃分析，以确定与 mTOR 抑制剂相关的血液学毒性的发生率和风险。
检索了包括 PubMed、Embase 和 Cochrane 数据库在内的多个数据库。纳入的研究包括替西罗莫司和依维莫司的前瞻性 II 期和 III 期临床试验，具有足够的安全性数据报告贫血、白细胞减少、中性粒细胞减少或血小板减少。使用随机效应或固定效应模型根据纳入研究的异质性计算总发生率、相对风险（RR）和 95%置信区间（CI）。
共有 26 项临床试验中的 5436 名患有各种实体瘤的患者被纳入荟萃分析。mTOR 抑制剂相关的所有级别和高级别血液学毒性的总发生率分别为：贫血 - 38.8%和 7.5%；白细胞减少 - 19.6%和 1.8%；中性粒细胞减少 - 14.9%和 5.6%；血小板减少 - 33.1%和 3.6%。与安慰剂/对照组相比，mTOR 抑制剂与所有级别（RR 2.05，95%CI：1.52-2.77；p<0.001）和高级别贫血（RR 1.57，95%CI：1.20-2.05；p=0.001）、所有级别（RR 6.03，95%CI：2.76-13.14；p<0.001）和高级别血小板减少症（RR 2.73，95%CI：1.87-3.99；p<0.001）的风险显著增加。此外，mTOR 抑制剂组还观察到所有级别白细胞减少症（RR 1.46，95%CI：0.66-3.23；p=0.34）和中性粒细胞减少症（RR 1.77，95%CI：0.80-3.93；p=0.16）风险的非显著增加，而高级别白细胞减少症（RR 0.53，95%CI：0.31-0.90，p=0.019）和中性粒细胞减少症（RR 0.96，95%CI：0.62-1.51；p=0.87）的风险没有增加。根据基于 mTOR 抑制剂的方案的亚组分析也观察到了类似的结果。
与安慰剂/对照组相比，使用 mTOR 抑制剂与发生所有级别和高级别贫血和血小板减少症的风险显著增加相关。
