Efficacy and safety of ruxolitinib in the treatment of steroid-refractory graft-versus-host disease: a meta-analysis
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摘要: 目的 系统评价芦可替尼治疗激素难治性移植物抗宿主病的疗效和安全性。方法 计算机检索PubMed、Embase、Cochrane图书馆及ClinicalTrials.gov英文数据库、中国期刊全文数据库(CNKI)、维普和万方数据库，检索截至日期2020年8月。根据研究特点对纳入研究进行质量评价后采用R软件进行统计分析。结果 最终纳入21篇文献，共609例患者。Meta分析结果显示，芦可替尼治疗激素难治性移植物抗宿主病患者的有效率(ORR)为79%(95%CI72%~85%)，完全缓解率(CR)为29%(95%CI19%~42%)，部分缓解率(PR)为46%(95%CI37%~56%)。其中，急性移植物抗宿主病的ORR为76%(95%CI67%~82%)，CR率为33%(95%CI24%~45%)，PR率为42%(95%CI34%~49%)；慢性移植物抗宿主病的ORR为81%(95%CI70%~89%)，CR率为26%(95%CI11%~49%)，PR率为51%(95%CI34%~67%)。在安全性方面，使用芦可替尼后骨髓抑制、巨细胞病毒再激活及其他感染的不良反应率增加，血细胞减少发生率为17%(95%CI10%~28%)，巨细胞病毒再激活率为21%(95%CI15%~29%)，其他感染发生率为18%(95%CI9%~33%)。结论 芦可替尼用于成人急性GVHD和慢性GVHD患者的挽救性治疗，可获得较高的有效率，需关注骨髓抑制和感染的发生。
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关键词:
- 芦可替尼 /
- 异基因造血干细胞移植 /
- 移植物抗宿主病 /
- 挽救性治疗 /
- meta分析
Abstract: Objective To systematically evaluate the efficacy and safety of ruxolitinib in patients with steroid-refractory graft-versus-host disease(SR-GVHD).Methods The database including PubMed, Embase, Cochrane Library, ClinicalTrials. gov in English, CNKI, CBM, VIP and Wanfang were searched, and the references of the included studies were retrieved manually, with the retrieval time from inception to August 2020. The quality evaluation of included criteria based on the characteristics of the literature was evaluated, and the meta-analysis was conducted by using R version3.5 software.Results A total of 21 studies involving 609 patients were included. The results of meta-analysis showed that the overall response rate(ORR), complete remission(CR) rate and partial remission(PR) rate of ruxolitinib in the treatment of SR-GVHD were 79%(95%CI72%-85%), 29%(95%CI19%-42%), 46%(95%CI37%-56%), respectively. For patients with SR-aGVHD, the ORR, CR rate and PR rate were 76%(95%CI67%-82%), 33%(95%CI24%-45%) and 42%(95%CI34%-49%), while for patients with SR-cGVHD, the ORR, CR rate and PR rate were 81%(95%CI70%-89%), 26%(95%CI11%-49%) and 51%(95%CI34%-67%). In terms of safety, the adverse events of myelosuppression, cytomegalovirus reactivation and other infections increased after the use of ruxolitinib. The incidence of hemocytopenia was 17%(95%CI10%-28%), and the reactivation rate of cytomegalovirus was 21%(95%CI15%-29%), while the incidence of other infections was 18%(95%CI9%-33%).Conclusion Ruxolitinib can obtain high effective rate in the salvage treatment of adult patients with aGVHD and cGVHD. Attention should be paid to the occurrence of bone marrow suppression and infection. -
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表 1 纳入文献基本特征及文献质量评估
纳入研究 例数 中位年龄/岁 男∶女/例 原发疾病/例 移植类型/例 GVHD分型(急性∶慢性∶混合)/例 随访时间/月 NOS评分 Assouan(2018)[4] 10 52 (26~65) 7∶3 ALL(4)，MDS(2)，MF(2)，HL(1)，MPN(1) MSD(5)，MUD(5) 8∶0∶2 4.5 (1.4~15.2) 7 Bonmann(2017)[7] 19 58 (18~74) 12∶7 NA MSD(3)，MUD(12)，MMUD(3) 19∶0∶2 NA 6 Ecsedi(2015)[8] 5 43 (21~66) 5∶0 AML(1)，ALL(1)，PM(2)，T-PLL(1) MUD(2)，MMUD(1)，Sibling(2) 4∶2∶1 3.0 (2.3~9.3) 3 Ferreira(2018)[9] 20 46.5 (23~68) 11∶9 NA MRD(10)，URD(4)，Haploidentical(6) 0∶20∶2 12.0 (4.0~19.0) 7 Escamilla Gomez(2020)[10] 79 51 (0~73) 48∶31 AML(30)，ALL(12)，MDS(11)，MF(4)，HL(2)，NHL(13)，MM(3)，其他(4) MSD(33)，URD(39)，Haploidentical(7) 22∶57∶2 NA 7 Hurabielle(2017)[11] 12 47 (21~67) 7∶5 AML(4)，ALL(2)，MDS(2)，MF(2)，FL(1)，DLBCL(1) MUD(8)，Sibling(4) 0∶12∶2 >6 5 Khoury(2018)[6] 19 53 (28~73) 11∶8 ALL(2)，CLL(1)，CMML(3)，MDS(5)，HL(1)，MPN(1)，T细胞淋巴瘤(1) URD(13)，Sibling(6) 0∶19∶0 最大随访时间：24.0 5 Lupo-Stanghellini(2017)[12] 5 57(39~67) NA NA NA 0∶4∶1 28.9 7 Modi(2019)[5] 46 49 (21~77) 26∶20 AML(15)，ALL(10)，CLL(2)，MDS(6)，MF(2)，HL(2)，NHL(6)，急性红系白血病(1) MUD(16)，MMUD(5)，Sibling(10) 0∶46∶0 最大随访时间：8.7 7 Niittyvuopio(2017)[13] 6 50 (19~59) 6∶0 AML(3)，ALL(1)，MDS(1)，MM(1) MUD(4)，Sibling(2) 6∶0∶0 NA 4 Poyatos-Ruiz(2016)[14] 13 46 (32~51) 6∶7 NA NA 5∶8∶0 NA 5 Spoerl(2014)[15] 14 NA NA NA NA 10∶4∶0 NA 4 Syed Abd Kadir(2016)[16] 9 63 (46~74) NA NA MSD(2)，MUD(3)，MMUD(4) NA NA 4 Zeiser(2015)[17] 95 aGVHD：51 (21~75)；cGVHD：55 (22~74) 66∶29 aGVHD：AML(26)，ALL(6)，CLL(2)，MDS(5)，MF(2)，HL(4)，MM(4)，T-PLL(1)，CMML(1)，HLH(1)；cGVHD：AML(21)，CLL(5)，MDS(3)，MF(5)，HL(3)，MPN(1)，MM(1)，CMML(1) NA 54∶41∶0 aGVHD：6.2 (0.7~25.0)；cGVHD：5.2 (0.7~31.5) 6 Zeiser(2015)[18] 52 NA NA NA NA 32∶20∶0 NA 6 赵菲(2020)[21] 42 40(8~63) 29∶13 aGVHD：AML(9)，ALL(1)，MDS(4)，NHL(1)，AA(2)，CML(2)，CMML(1)；cGVHD：AML(7)，ALL(5)，MDS(4)，NHL(1)，AA(3)，CML(1)，MPN(1) aGVHD：MSD(5)，MMRD(13)，URD(2)；cGVHD：MSD(16)，MMRD(4)，URD(2) 20∶22∶0 8.8 (0.2~25.0) 5 黄小丽(2019)[24] 42 23(3~55) 19∶23 AML(14)，ALL(9)，MDS(5)，AA(6)，HLH(1)，CML(2)，HAL(2)，地贫(3) MSD(13)，MMRD(29) 0∶42∶0 4.0 (1.0~19.0) 6 季艳萍(2020)[23] 47 25 (7~54) 23∶24 AML(30)，ALL(9)，MDS(4)，SAA(2)，CML(2) NA 0∶47∶0 6.9 (1.1~13.7) 6 花京剩(2019)[20] 26 22 (10~51) 13∶13 AML(14)，ALL(8)，HAL(2)，NHL(1)，MDS(1) NA 11∶15∶0 3.0 (2.0~10.0) 4 艾昊(2018)[19] 10 30(17~37) 7∶3 AML(6)，ALL(2)，CMML(1)，MDS(1) NA 3∶7∶0 3.3(2.0~5.0) 4 黄晓雯(2019)[22] 38 26(10~58) 19∶19 AML(15)，ALL(17)，HAL(2)，NHL(2)，MDS(2) NA 19∶19∶0 8.0 (1.0~15.0) 5 ALL：急性淋巴细胞白血病；AML：急性髓系白血病；MDS骨髓增生异常综合征；HAL：急性杂合细胞白血病；CMML：慢性粒单核细胞白血病；MF：骨髓纤维化；HL：霍奇金淋巴瘤；DLBCL：弥漫大B细胞淋巴瘤；FL：滤泡淋巴瘤；MPN：骨髓增殖性肿瘤；T-PLL：T淋巴细胞白血病；CLL：慢性淋巴细胞白血病；NHL：非霍奇金淋巴瘤；MM：多发性骨髓瘤；HLH：噬血细胞性淋巴组织细胞增多症；AA：再生障碍性贫血；SAA：重型再生障碍性贫血；MMRD：亲缘半相合供者；MMUD：非亲缘半相合供者；MSD：匹配同胞供者；URD：非血缘(无关)供者；MUD：相合无关(非血缘)供者；Haploidentical：单倍体；Sibling：同胞供者；NA：不详。 
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