目的:免疫抑制治疗(IST)是造血干细胞移植(HSCT)受限的重型再生障碍性贫血(SAA)患者的首选治疗方法,而限制其疗效的主要因素是残余造血干/祖细胞(HSPC)过少。Eltrombopag(EPAG),作为一种小分子血小板生成素受体激动剂,能刺激残留HSPC的增殖,恢复患者骨髓造血功能。近年来,许多研究观察到IST联合EPAG治疗SAA的疗效和安全性,但结果仍有争议。本研究的目的是系统评估IST联合或不联合EPGA治疗SAA的疗效和安全性。
方法:我们对截至2024年1月19日发表的所有相关文献进行了系统综述。计算汇总赔率比(OR)来比较这些比率,以及95%置信区间(CI)和p值,以评估ReviewManager5.4.1的结果是否具有统计学意义。通过Stata15.1计算每个亚组之间相互作用的p值。分别采用纽卡斯尔-渥太华量表和Cochrane偏倚风险评估工具,通过队列研究和随机对照试验评价文献质量。ReviewManager5.4.1和Stata15.1用于评估偏倚风险并进行荟萃分析。
结果:共纳入16项研究,涉及2148名患者。IST联合EPAG组在3个月(合并OR=2.10,95%CI1.58-2.79,p<0.00001)和6个月(合并OR=2.13,95%CI1.60-2.83,p<0.00001)时的总体缓解率(ORR)高于IST组,但两组在12个月时差异无统计学意义(合并OR=1.13,95%CI0.75-1.72,p=0.55).完全缓解率(CRR)的结果(3个月时的合并OR=2.73,95%CI1.83-4.09,p<0.00001,6个月=2.76,95%CI2.08-3.67,p<0.00001和12个月=1.38,95%CI0.85-2.23,p=0.19)与ORR相似。与IST组相比,IST联合EPAG组有较好的总生存率(OSR)(合并OR=1.70,95%CI1.15-2.51,p=0.008),但无事件生存率(EFSR)差异无统计学意义(合并OR=1.40,95%CI0.93-2.13,p=0.11),两组间的克隆演变率(合并OR=0.68,95%CI0.46-1.00,p=0.05)和其他不良事件.亚组分析结果显示,不同年龄是异质性的来源,但不同的研究类型和不同的随访时间没有。此外,所有交互作用的p值均大于0.05,提示治疗效果不受亚组特征的影响.
结论:在IST中添加EPAG使患者能够更早和更快地实现血液学反应,并具有更高的完全缓解率。虽然对整体EFSR没有影响,它改善了OSR,并且没有增加克隆进化和其他不良事件的发生率.
OBJECTIVE: Immunosuppressive therapy (IST) is the first choice for severe aplastic anemia (SAA) patients with hematopoietic stem cell transplantation (HSCT) limitation, and the main factor limiting its efficacy is too few residual hematopoietic stem/progenitor cells (HSPC). Eltrombopag (EPAG), as a small molecule thrombopoietin receptor agonist, can stimulate the proliferation of residual HSPC and restore the bone marrow hematopoietic function of patients. In recent years, many studies have observed the efficacy and safety of IST combined with EPAG in the treatment of SAA, but the results are still controversial. The aim of this study is to systematically evaluate the efficacy and safety of IST combined with or without EPGA in the treatment of SAA.
METHODS: We conducted a systematic
review of all relevant literature published up to January 19, 2024. Pooled odds ratio (OR) was calculated to compare the rates, along with 95% confidence intervals (CI) and p value to assess whether the results were statistically significant by
Review Manager 5.4.1. The p values for the interactions between each subgroup were calculated by Stata 15.1. The Newcastle-Ottawa Scale and the Cochrane bias risk assessment tools were respectively used to evaluate the quality of the literature with cohort studies and randomized controlled trials. The
Review Manager 5.4.1 and Stata 15.1 were used to assess bias risk and perform the meta-analysis.
RESULTS: A total of 16 studies involving 2148 patients were included. The IST combined with the EPAG group had higher overall response rate (ORR) than the IST group at 3 months (pooled OR = 2.10, 95% CI 1.58-2.79, p < 0.00001) and 6 months (pooled OR = 2.13, 95% CI 1.60-2.83, p < 0.00001), but the difference between the two groups became statistically insignificant at 12 months (pooled OR = 1.13, 95% CI 0.75-1.72, p = 0.55). The results of complete response rate (CRR) (pooled OR at 3 months = 2.73, 95% CI 1.83-4.09, p < 0.00001, 6 months = 2.76, 95% CI 2.08-3.67, p < 0.00001 and 12 months = 1.38, 95% CI 0.85-2.23, p = 0.19) were similar to ORR. Compared with the IST group, the IST combined with the EPAG group had better overall survival rate (OSR) (pooled OR = 1.70, 95% CI 1.15-2.51, p = 0.008), but there were no statistically significant differences in event-free survival rate (EFSR) (pooled OR = 1.40, 95% CI 0.93-2.13, p = 0.11), clonal evolution rate (pooled OR = 0.68, 95% CI 0.46-1.00, p = 0.05) and other adverse events between the two groups. The results of subgroup analysis showed that different ages were a source of heterogeneity, but different study types and different follow-up times were not. Moreover, all p-values for the interactions were greater than 0.05, suggesting that the treatment effect was not influenced by subgroup characteristics.
CONCLUSIONS: EPAG added to IST enables patients to achieve earlier and faster hematologic responses with a higher rate of complete response. Although it had no effect on overall EFSR, it improved OSR and did not increase the incidence of clonal evolution and other adverse events.