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Article(id=1240710434068689224, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1240710432898478399, articleNumber=null, orderNo=null, doi=10.14109/j.cnki.xyylc.2024.10.08, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1682611200000, receivedDateStr=2023-04-28, revisedDate=null, revisedDateStr=null, acceptedDate=1717344000000, acceptedDateStr=2024-06-03, onlineDate=1773738018767, onlineDateStr=2026-03-17, pubDate=1729785600000, pubDateStr=2024-10-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773738018767, onlineIssueDateStr=2026-03-17, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773738018767, creator=13701087609, updateTime=1773738018767, updator=13701087609, issue=Issue{id=1240710432898478399, tenantId=1146029695717560320, journalId=1205117082300743687, year='2024', volume='43', issue='10', pageStart='721', pageEnd='800', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773738018488, creator=13701087609, updateTime=1773738214158, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1240711253669237259, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1240710432898478399, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1240711253669237260, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1240710432898478399, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=772, endPage=778, ext={EN=ArticleExt(id=1240710434345513295, articleId=1240710434068689224, tenantId=1146029695717560320, journalId=1205117082300743687, language=EN, title=Application of cyclosporin blood concentration monitoring in patients with allogeneic hematopoietic stem cell transplantation, columnId=1207314218647392369, journalTitle=Chinese Journal of New Drugs and Clinical Remedies, columnName=Original Article, runingTitle=null, highlight=null, articleAbstract=
AIM

To explore the effect of cyclosporin blood drug concentration on the efficacy and safety of cyclosporin on patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the transplant bin.

METHODS

Clinical medical records of 94 allo-HSCT patients were collected. The first day of stem cell infusion was +1 day (d), and the transplantation time was divided into four groups: group A (-9 d to -1 d), group B (+1 d to +7 d,) group C (+8 d to +14 d) and group D (+15 d to +21 d). The plasma concentration of cyclosporin and its influencing factors,cell implantation, liver and kidney function indexes, acute graft-versus-host disease (aGVHD), and the occurrence of cyclosporin-related adverse reactions were observed in different periods and their relationships with the plasma concentration of cyclosporin were analysed. Receiver operating characteristic (ROC) curve was used to analyze the value of serum concentration of cyclosporin at different time periods in predicting safety.

RESULTS

The concentration of cyclosporin in allo-HSCT patients was 128 (99,160) ng·mL-1, with statistically significant differences between different time periods (P<0.001). In allo-HSCT patients, the implantation rate of leukocyte, platelet, and neutrophil in +21 d was 94%, 64%, and 51%, respectively. The incidence of liver injury, kidney injury, and aGVHD was 47% (44/94), 71% (67/94), and 16% (15/94), respectively. ROC analysis showed that the warning value of cyclosporin blood concentration in the group A for liver injury and kidney injury was 128.5 ng·mL-1 and 113.5 ng·mL-1, respectively, while the area under the curve was 0.712 (95%CI：0.578 to 0.847，P=0.002) and 0.752 (95%CI：0.637 to 0.868，P<0.001), respectively.

CONCLUSION

There are many factors affecting the blood concentration of cyclosporin which can affect the clinical efficacy and safety. Timely and accurate monitoring of cyclosporin blood concentration can better guide the clinical treatment of allo-HSCT patients in the transplant bin.

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目的

探索环孢素血药浓度对于移植仓内异基因造血干细胞移植（allo-HSCT）患者环孢素疗效和安全性的影响。

方法

收集94例allo-HSCT患者临床资料，以输注干细胞第一日为+1 d，将移植时间分为4段：A（-9 d~-1 d）、B （+1 d~+7 d）、C （+8 d~+14 d）和D （+15 d~+21 d）。观察各时段内环孢素血药浓度及其影响因素、细胞植活情况、肝肾功能指标、急性移植物抗宿主病（aGVHD）和环孢素相关不良反应发生情况及其与环孢素血药浓度的关系。采用受试者操作特征（ROC）曲线分析各时段环孢素血药浓度预测其安全性的价值。

结果

allo-HSCT患者在移植仓内环孢素中位血药浓度为128（99，160）ng·mL-1，各时段环孢素血药浓度有非常显著差异（P<0.001）。患者+21 d内白细胞、血小板、中性粒细胞植活率分别为94%、64%、51%；肝损伤发生率为47%（44/94），肾损伤发生率为71%（67/94），aGVHD发生率为16%（15/94）。ROC曲线分析显示，A时段环孢素血药浓度对肝损伤、肾损伤预警值分别为128.5 ng·mL-1、113.5 ng·mL-1，曲线下面积分别为0.712（95%Cl：0.578~0.847，P=0.002）、0.752（95%CI：0.637~0.868，P<0.001）。

结论

环孢素血药浓度影响因素较多，其血药浓度可影响临床疗效和安全性，及时、准确进行环孢素血药浓度监测可指导移植仓内allo-HSCT患者的临床治疗。

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王磊
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孙文利，女，主管药师，硕士，主要从事临床药学的研究，E-mail:

王磊，男，主管药师，硕士，主要从事临床药学的研究，E-mail:

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孙文利，女，主管药师，硕士，主要从事临床药学的研究，E-mail:

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A：-9 d~-1 d，B：+1 d~+7 d，C：+8 d~+14 d，D：+15 d~+21 d。组间比较经Bonferroni法

, figureFileSmall=RePVFZ0zxyBkqBFpdYEr2Q==, figureFileBig=+82PqMYpIyGcJTYoFFz1Ew==, tableContent=null), ArticleFig(id=1240719598752952549, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710434068689224, language=EN, label=null, caption=null, figureFileSmall=+ysBZTgB+MkOrA9pn3j8/Q==, figureFileBig=F1TLqG7adVP70X/0XC/4gA==, tableContent=null), ArticleFig(id=1240719598841032935, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710434068689224, language=CN, label=图2, caption=急性移植物抗宿主病累积发生率, figureFileSmall=+ysBZTgB+MkOrA9pn3j8/Q==, figureFileBig=F1TLqG7adVP70X/0XC/4gA==, tableContent=null), ArticleFig(id=1240719598924919018, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710434068689224, language=EN, label=null, caption=null, figureFileSmall=KK/aHpQ34yaQ/FJCMn8RLg==, figureFileBig=7fKYsBo+I/Kxa3GWrRBs7g==, tableContent=null), ArticleFig(id=1240719599004610798, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710434068689224, language=CN, label=图3, caption=各时段是否发生肝损伤与环孢素血药浓度的关系

A：-9 d~-1 d，B：+1 d~+7 d，C：+8 d~+14 d，D：+15 d~+21 d，0：肝正常，1：肝功能损伤。比较经非参数Mann-Whitney U检验

, figureFileSmall=KK/aHpQ34yaQ/FJCMn8RLg==, figureFileBig=7fKYsBo+I/Kxa3GWrRBs7g==, tableContent=null), ArticleFig(id=1240719599088496879, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710434068689224, language=EN, label=null, caption=null, figureFileSmall=26+b7B+sZFR9TYibPfVVcA==, figureFileBig=39n8O+FWc77numxGhIt1oQ==, tableContent=null), ArticleFig(id=1240719599168188658, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710434068689224, language=CN, label=图4, caption=各时段是否发生肾损伤与环孢素血药浓度的关系

A：-9 d~-1 d，B：+1 d~+7 d，C：+8 d~+14 d，D：+15 d~+21 d，0：肾功能正常；1：肾损伤。比较经非参数Mann-Whitney U检验

, figureFileSmall=26+b7B+sZFR9TYibPfVVcA==, figureFileBig=39n8O+FWc77numxGhIt1oQ==, tableContent=null), ArticleFig(id=1240719599277240565, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710434068689224, language=EN, label=null, caption=null, figureFileSmall=iHZQopi6gQHxJXiycccBBw==, figureFileBig=YDw/yA+kDJHzoQqtenkQZg==, tableContent=null), ArticleFig(id=1240719599352738040, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710434068689224, language=CN, label=图5, caption=环孢素血药浓度预测肝损伤发生的受试者操作特征（ROC）曲线

A：-9 d~-1 d，B：+1 d~+7 d，C：+8 d~+14 d，D：+15 d~+21 d

, figureFileSmall=iHZQopi6gQHxJXiycccBBw==, figureFileBig=YDw/yA+kDJHzoQqtenkQZg==, tableContent=null), ArticleFig(id=1240719599445012729, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710434068689224, language=EN, label=null, caption=null, figureFileSmall=p/Ig7beW7wsO56sTQW1lZw==, figureFileBig=AIx3DqSEKvSeCJv/SBA2TQ==, tableContent=null), ArticleFig(id=1240719599533093114, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710434068689224, language=CN, label=图6, caption=环孢素血药浓度预测肾损伤发生的受试者操作特征（ROC）曲线

A：-9 d~-1 d，B：+1 d~+7 d，C：+8 d~+14 d，D：+15d~+21d

, figureFileSmall=p/Ig7beW7wsO56sTQW1lZw==, figureFileBig=AIx3DqSEKvSeCJv/SBA2TQ==, tableContent=null), ArticleFig(id=1240719599625367804, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710434068689224, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
指标数值
性别（男/女）/例53/41
年龄/岁26（1~59）
移植预处理方案/例（%）
以全身照射为基础40（43）
以白消安为基础54（57）
疾病类型/例（%）
急性髓系白血病39（42）
急性淋系白血病31（33）
骨髓异常综合征8（9）
急性混合型白血病3（3）
噬血细胞综合征4（4）
T淋巴母细胞白血病/淋巴瘤6（6）
急性单核细胞白血病1（1）
慢性粒单核细胞白血病2（2）
移植前状态/例（%）
完全缓解71（76）
部分缓解2（2）
未缓解21（22）
移植类型/例（%）
同胞全相合11（11）
亲缘单倍体75（80）
非血缘8（9）
供患血型/例（%）
血型相同52（55）
血型不同42（45）
供者性别/例（%）
同性46（49）
女供男18（19）
男供女30（32）
供者年龄/岁32（9~59）
干细胞来源/例（%）
外周血8（9）
外周血+脐血4（4）
骨髓1（1）
骨髓+外周血9（9）
骨髓+外周血+脐血72（77）
), ArticleFig(id=1240719599713448190, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710434068689224, language=CN, label=表1, caption=

患者的基本临床特征

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指标数值
性别（男/女）/例53/41
年龄/岁26（1~59）
移植预处理方案/例（%）
以全身照射为基础40（43）
以白消安为基础54（57）
疾病类型/例（%）
急性髓系白血病39（42）
急性淋系白血病31（33）
骨髓异常综合征8（9）
急性混合型白血病3（3）
噬血细胞综合征4（4）
T淋巴母细胞白血病/淋巴瘤6（6）
急性单核细胞白血病1（1）
慢性粒单核细胞白血病2（2）
移植前状态/例（%）
完全缓解71（76）
部分缓解2（2）
未缓解21（22）
移植类型/例（%）
同胞全相合11（11）
亲缘单倍体75（80）
非血缘8（9）
供患血型/例（%）
血型相同52（55）
血型不同42（45）
供者性别/例（%）
同性46（49）
女供男18（19）
男供女30（32）
供者年龄/岁32（9~59）
干细胞来源/例（%）
外周血8（9）
外周血+脐血4（4）
骨髓1（1）
骨髓+外周血9（9）
骨髓+外周血+脐血72（77）
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时段男性（n=53）女性（n=41）ZP
A106.0（90.0,131.0）105.0（81.0,124.0）-1.3190.187
B142.0（120.5,163.5）135.0（115.5,167.5）-0.9490.342
C135.0（113.0,156.0）136.0（113.5,161.0）-0.1330.894
D144.0（113.5,179.0）135.0（116.5,169.0）-0.8390.402
), ArticleFig(id=1240719599877026049, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710434068689224, language=CN, label=表2, caption=

各时段不同性别患者环孢素血药浓度比较

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时段男性（n=53）女性（n=41）ZP
A106.0（90.0,131.0）105.0（81.0,124.0）-1.3190.187
B142.0（120.5,163.5）135.0（115.5,167.5）-0.9490.342
C135.0（113.0,156.0）136.0（113.5,161.0）-0.1330.894
D144.0（113.5,179.0）135.0（116.5,169.0）-0.8390.402
), ArticleFig(id=1240719599935746305, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710434068689224, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
时段年龄≤14岁（n=34）年龄>14岁（n=60）ZP
A116.0（87.0,143.0）136.0（117.0,171.0）-3.1460.002
B117.5（88.5,147.0）135.5（113.3,162.8）-2.2310.026
C123.5（103.0,153.0）131.0（112.3,163.8）-1.2430.214
D116.0（91.5,140.3）135.0（113.0,164.0）-2.2980.022
), ArticleFig(id=1240719600019632387, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710434068689224, language=CN, label=表3, caption=

各时段不同年龄患者环孢素血药浓度比较

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时段年龄≤14岁（n=34）年龄>14岁（n=60）ZP
A116.0（87.0,143.0）136.0（117.0,171.0）-3.1460.002
B117.5（88.5,147.0）135.5（113.3,162.8）-2.2310.026
C123.5（103.0,153.0）131.0（112.3,163.8）-1.2430.214
D116.0（91.5,140.3）135.0（113.0,164.0）-2.2980.022
), ArticleFig(id=1240719600090935557, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710434068689224, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
变量系数标准误标准化系数P
年龄0.1670.1180.0710.159
性别-6.1094.082-0.0750.135
疾病类型-4.3981.262-0.1820.001
疾病状态2.7071.2420.1090.030
移植时间10.9101.7490.3000.000
移植类型-1.5344.646-0.0170.742
预处理方案4.1864.1870.0510.318
干细胞类型2.2491.6230.0690.167
供患血型2.0994.0230.0260.602
), ArticleFig(id=1240719600158044423, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710434068689224, language=CN, label=表4, caption=

环孢素血药浓度影响因素

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变量系数标准误标准化系数P
年龄0.1670.1180.0710.159
性别-6.1094.082-0.0750.135
疾病类型-4.3981.262-0.1820.001
疾病状态2.7071.2420.1090.030
移植时间10.9101.7490.3000.000
移植类型-1.5344.646-0.0170.742
预处理方案4.1864.1870.0510.318
干细胞类型2.2491.6230.0690.167
供患血型2.0994.0230.0260.602
), ArticleFig(id=1240719600233541897, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710434068689224, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
指标时段植活/例（%）未植活植活ZP
白细胞（n=89）C54（57）139.0（110.0, 164.0）125.0（108.5, 152.5）-1.4310.152
D35（37）156.0（123.0, 192.0）132.0（107.0, 167.3）-2.9120.004
血小板（n=60）B4（4）139.5（117.4, 163.3）158.0（69.3, 189.8）-0.5430.606
C40（43）133.5（116.0, 155.0）136.0（100.5, 163.0）-0.2360.814
D16（17）132.5（111.0, 169.5）167.0（135.3, 186.8）-2.4950.013
中性粒细胞（n=48）C32（34）147.0（121.0, 163.3）118.2（95.3, 142.8）-3.3120.001
D16（17）137.5（115.8, 172.1）133.0（108.8, 172.0）-0.2010.841
), ArticleFig(id=1240719600304845067, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710434068689224, language=CN, label=表5, caption=

造血干细胞植活与未植活患者各时段环孢素血药浓度比较

, figureFileSmall=null, figureFileBig=null, tableContent=
指标时段植活/例（%）未植活植活ZP
白细胞（n=89）C54（57）139.0（110.0, 164.0）125.0（108.5, 152.5）-1.4310.152
D35（37）156.0（123.0, 192.0）132.0（107.0, 167.3）-2.9120.004
血小板（n=60）B4（4）139.5（117.4, 163.3）158.0（69.3, 189.8）-0.5430.606
C40（43）133.5（116.0, 155.0）136.0（100.5, 163.0）-0.2360.814
D16（17）132.5（111.0, 169.5）167.0（135.3, 186.8）-2.4950.013
中性粒细胞（n=48）C32（34）147.0（121.0, 163.3）118.2（95.3, 142.8）-3.3120.001
D16（17）137.5（115.8, 172.1）133.0（108.8, 172.0）-0.2010.841
), ArticleFig(id=1240719600367759629, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710434068689224, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
不良反应数值
感染26（28）
感染性发热36（38）
出血性膀胱炎16（17）
药物性肝损伤36（38）
胃肠道反应23（24）
药物性肾损伤7（7）
口腔溃疡、黏膜损害26（28）
巨细胞病毒阳性3（3）
EB病毒阳性1（1）
继发性高血压6（6）
), ArticleFig(id=1240719600422285583, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710434068689224, language=CN, label=表6, caption=

非血液学不良反应

, figureFileSmall=null, figureFileBig=null, tableContent=
不良反应数值
感染26（28）
感染性发热36（38）
出血性膀胱炎16（17）
药物性肝损伤36（38）
胃肠道反应23（24）
药物性肾损伤7（7）
口腔溃疡、黏膜损害26（28）
巨细胞病毒阳性3（3）
EB病毒阳性1（1）
继发性高血压6（6）
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环孢素血药浓度监测在异基因造血干细胞移植患者中的应用
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孙文利 1 , 王红春 2 , 李梦 2 , 刘瑞 1 , 赵颖 1 , 郭进艳 1 , 卢光泽 1 , 刘红星 1, 2, 3 , 王磊 1
中国新药与临床杂志 | 论著 2024,43(10): 772-778
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中国新药与临床杂志 | 论著 2024, 43(10): 772-778
环孢素血药浓度监测在异基因造血干细胞移植患者中的应用
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孙文利1 , 王红春2, 李梦2, 刘瑞1, 赵颖1, 郭进艳1, 卢光泽1, 刘红星1, 2, 3, 王磊1
作者信息
  • 1.河北燕达陆道培医院 检验医学科，河北 廊坊　065201
  • 2.北京陆道培医院 检验医学科，北京　100176
  • 3.北京陆道培血液病研究院，北京　100176

    • 孙文利，女，主管药师，硕士，主要从事临床药学的研究，E-mail:

    王磊，男，主管药师，硕士，主要从事临床药学的研究，E-mail:

通讯作者:

王磊
Application of cyclosporin blood concentration monitoring in patients with allogeneic hematopoietic stem cell transplantation
Wen-li SUN1 , Hong-chun WANG2, Meng LI2, Rui LIU1, Ying ZHAO1, Jin-yan GUO1, Guang-ze LU1, Hong-xing LIU1, 2, 3, Lei WANG1
Affiliations
  • 1.Medical Lab, Hebei Yanda Lu Daopei Hospital, Langfang HEBEI 065201, China
  • 2.Medical Lab, Beijing Lu Daopei Hospital, BEJING 100176, China
  • 3.Beijing Lu Daopei Institute of Hematology, BEJING 100176, China
出版时间: 2024-10-25 doi: 10.14109/j.cnki.xyylc.2024.10.08
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摘要
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目的

探索环孢素血药浓度对于移植仓内异基因造血干细胞移植（allo-HSCT）患者环孢素疗效和安全性的影响。

方法

收集94例allo-HSCT患者临床资料，以输注干细胞第一日为+1 d，将移植时间分为4段：A（-9 d~-1 d）、B （+1 d~+7 d）、C （+8 d~+14 d）和D （+15 d~+21 d）。观察各时段内环孢素血药浓度及其影响因素、细胞植活情况、肝肾功能指标、急性移植物抗宿主病（aGVHD）和环孢素相关不良反应发生情况及其与环孢素血药浓度的关系。采用受试者操作特征（ROC）曲线分析各时段环孢素血药浓度预测其安全性的价值。

结果

allo-HSCT患者在移植仓内环孢素中位血药浓度为128（99，160）ng·mL-1，各时段环孢素血药浓度有非常显著差异（P<0.001）。患者+21 d内白细胞、血小板、中性粒细胞植活率分别为94%、64%、51%；肝损伤发生率为47%（44/94），肾损伤发生率为71%（67/94），aGVHD发生率为16%（15/94）。ROC曲线分析显示，A时段环孢素血药浓度对肝损伤、肾损伤预警值分别为128.5 ng·mL-1、113.5 ng·mL-1，曲线下面积分别为0.712（95%Cl：0.578~0.847，P=0.002）、0.752（95%CI：0.637~0.868，P<0.001）。

结论

环孢素血药浓度影响因素较多，其血药浓度可影响临床疗效和安全性，及时、准确进行环孢素血药浓度监测可指导移植仓内allo-HSCT患者的临床治疗。

环孢素  /  造血干细胞移植  /  移植物抗宿主病  /  肝损伤  /  肾损伤
AIM

To explore the effect of cyclosporin blood drug concentration on the efficacy and safety of cyclosporin on patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the transplant bin.

METHODS

Clinical medical records of 94 allo-HSCT patients were collected. The first day of stem cell infusion was +1 day (d), and the transplantation time was divided into four groups: group A (-9 d to -1 d), group B (+1 d to +7 d,) group C (+8 d to +14 d) and group D (+15 d to +21 d). The plasma concentration of cyclosporin and its influencing factors,cell implantation, liver and kidney function indexes, acute graft-versus-host disease (aGVHD), and the occurrence of cyclosporin-related adverse reactions were observed in different periods and their relationships with the plasma concentration of cyclosporin were analysed. Receiver operating characteristic (ROC) curve was used to analyze the value of serum concentration of cyclosporin at different time periods in predicting safety.

RESULTS

The concentration of cyclosporin in allo-HSCT patients was 128 (99,160) ng·mL-1, with statistically significant differences between different time periods (P<0.001). In allo-HSCT patients, the implantation rate of leukocyte, platelet, and neutrophil in +21 d was 94%, 64%, and 51%, respectively. The incidence of liver injury, kidney injury, and aGVHD was 47% (44/94), 71% (67/94), and 16% (15/94), respectively. ROC analysis showed that the warning value of cyclosporin blood concentration in the group A for liver injury and kidney injury was 128.5 ng·mL-1 and 113.5 ng·mL-1, respectively, while the area under the curve was 0.712 (95%CI：0.578 to 0.847，P=0.002) and 0.752 (95%CI：0.637 to 0.868，P<0.001), respectively.

CONCLUSION

There are many factors affecting the blood concentration of cyclosporin which can affect the clinical efficacy and safety. Timely and accurate monitoring of cyclosporin blood concentration can better guide the clinical treatment of allo-HSCT patients in the transplant bin.

cyclosporin  /  hematopoietic stem cell transplantation  /  graft versus host disease  /  liver injury  /  kidney injury
孙文利, 王红春, 李梦, 刘瑞, 赵颖, 郭进艳, 卢光泽, 刘红星, 王磊. 环孢素血药浓度监测在异基因造血干细胞移植患者中的应用. 中国新药与临床杂志, 2024 , 43 (10) : 772 -778 . DOI: 10.14109/j.cnki.xyylc.2024.10.08
Wen-li SUN, Hong-chun WANG, Meng LI, Rui LIU, Ying ZHAO, Jin-yan GUO, Guang-ze LU, Hong-xing LIU, Lei WANG. Application of cyclosporin blood concentration monitoring in patients with allogeneic hematopoietic stem cell transplantation[J]. Chinese Journal of New Drugs and Clinical Remedies, 2024 , 43 (10) : 772 -778 . DOI: 10.14109/j.cnki.xyylc.2024.10.08
正文
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异基因造血干细胞移植（allogeneic hematopoietic stem cell transplantation, allo-HSCT）是治疗恶性血液病的有效方法，而急性移植物抗宿主病（acute graft versus host disease, aGVHD）是allo-HSCT患者主要的并发症和死亡原因，显著影响着移植成功率[1]。在allo-HSCT患者中，aGVHD发生率为30%~50%,其中中重度aGVHD发生率为13%~47%。环孢素是allo-HSCT中预防aGVHD及同种异体移植排斥反应的主要药物[2]，其血药浓度监测有益于移植物植活及降低药物毒性、减轻排异反应[3]。目前关于环孢素血药浓度对allo-HSCT患者长期疗效及安全性影响的研究较多[4, 5]，而对短期疗效的影响关注较少；相关指南推荐的环孢素血药浓度临床参考范围较宽，移植预处理期间及移植后近期的环孢素浓度尚无确切参考范围。故本研究拟探讨血药浓度监测对移植仓内allo-HSCT患者环孢素疗效和安全性的影响及推荐的剂量范围，以期为移植仓内allo-HSCT患者环孢素的应用提供参考。
资料与方法
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一般资料
回顾性收集2020年1月至2021年5月在河北燕达陆道培医院移植仓内行allo-HSCT患者的临床资料，均符合2016版世界卫生组织造血和淋巴组织肿瘤分类标准[6, 7]，并结合骨髓形态学、免疫分型、细胞遗传学和基因检测结果进行综合诊断，患者均符合移植指征且为allo-HSCT。以输注干细胞第1日为+1 d，均从-9 d开始给予环孢素（Novartis Pharma Schweiz AG，规格为5 mL：250 mg，进口药品注册证号为H20150095）静脉滴注（静滴），初始剂量为1.25 mg·kg-1每12 h给药1次，根据谷浓度调整剂量，待胃肠道反应消失后，改为环孢素胶囊口服。排除标准：二次移植和移植仓内死亡，病历资料或信息不完整，抽血错误导致的环孢素血药浓度检测结果明显异常，移植仓内使用他克莫司，治疗开始为环孢素口服，环孢素使用前肝肾功能明显异常。本研究经河北燕达陆道培医院医学伦理委员会审查并通过，伦理批件号为〔2020-13〕号。共纳入患者94例，疾病类型、移植物来源等临床特征见表1。
血药浓度监测
移植仓内allo-HSCT患者静滴环孢素防治aGVHD，待环孢素血药浓度达稳态后，经给药对侧手臂采集患者晨起空腹静脉血，根据王磊等[8, 9]建立的高效液相色谱串联质谱（HPLC-MS/MS）法进行环孢素血药浓度测定。比较-9 d~-1 d（A）、+1 d~+7 d （B）、+8 d~+14 d（C）和+15 d~+21 d（D）各时段[10，11]的环孢素血药浓度，并观察性别、年龄等对血药浓度的影响。
造血干细胞植活评价[12, 13]
连续3 d白细胞计数≥1.0×109·L-1为白细胞植活，连续3 d中性粒细胞绝对计数（ANC）≥0.5×109·L-1为粒细胞植活，连续7 d血小板计数≥20×109·L-1为血小板植活。
aGVHD分析
依照中国异基因造血干细胞移植治疗血液系统疾病专家共识（Ⅲ）：急性移植物抗宿主病（2020年版）[1]中aGVHD的诊断标准，分析患者移植后+21 d内aGVHD的发生情况。
相关不良反应评价
1　肝肾功能异常
收集患者肝肾功能各指标数据，并根据美国国立癌症常规毒性判断标准（NCI-CTCAE 4.0）评价。肝功能评价指标：丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、谷氨酰转移酶（GGT）、总胆红素（TBI）、直接胆红素（DBI），其中任意一项指标升高大于正常上限两倍计入肝损伤。肾功能评价指标：血肌酐（Cr）、尿素氮（BUN）、尿酸（UA）、尿蛋白，其中任意一项指标升高均计入肾损伤。肝肾功能采用美国贝克曼库尔特公司AU5800系列全自动生化分析仪及配套试剂盒检测。
2　其他
统计应用环孢素后出现的其他非血液学不良反应，包括感染及胃肠道反应等。
统计学处理
采用SPSS 22.0软件和Graphpad prism 8.3.0版软件对数据进行分析。计量资料以M（P25，P75）表示，组间比较采用非参数Mann-Whitney U检验和Kruskal-Wallis H检验，进一步两两比较采用Bonferroni法。计数资料以例（%）表示。采用多元线性回归对影响环孢素血药浓度各因素进行相关分析，采用Log-rank分析和Kaplan-Meier生存曲线分析allo-HSCT患者aGVHD累积发生率。建立受试者操作特征（ROC）曲线并计算曲线下面积（AUC），分析环孢素血药浓度预警肝肾损伤的效能。P<0.05为差异有显著意义。
结果
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环孢素血药浓度
1　血药浓度分布
94例患者共进行了1 365次环孢素血药浓度检测，中位数为128（99，160）ng·mL-1。对不同时段环孢素血药浓度进行Kruskal-Wallis H检验，结果显示不同时段的环孢素血药浓度存在非常显著差异（H=141.702，P<0.001）。进一步采用Bonferroni法进行分析显示，A时段环孢素血药浓度显著低于其他时段（P<0.001），见图1。
2　不同性别患者环孢素血药浓度
各时段男女患者环孢素血药浓度比较，无显著差异（P>0.05），见表2。
3　不同年龄患者环孢素血药浓度
对成人和儿童患者环孢素血药浓度进行分析，A、B、D时段>14岁患者环孢素血药浓度高于儿童患者（P<0.05），见表3。
4　影响因素
采用多元线性回归模型分析环孢素血药浓度与患者年龄、性别、疾病类型、移植前疾病状态、移植时间和类型、预处理方案、干细胞来源等是否存在相关性，结果显示环孢素血药浓度与疾病类型、疾病状态、移植时间具有相关性，见表4。
造血干细胞植活情况
94例患者白细胞、血小板、中性粒细胞植活时间分别为14（12,16）d、11（9,15）d、13（11,15）d，白细胞、血小板、中性粒细胞植活率分别为94%、64%和 51%。C时段中性粒细胞植活患者环孢素血药浓度显著低于未植活者（P<0.01）；D时段白细胞植活患者环孢素血药浓度显著低于未植活者（P<0.01），血小板植活患者环孢素血药浓度显著高于未植活者（P<0.05），见表5。
aGVHD累积发生率
94例患者aGVHD发生率为16%（15/94），发生时间为12（2~19）d。发生aGVHD患者与未发生者环孢素血药浓度比较，无显著差异（Z=-1.213，P=0.225）。根据MARTIN等[14]的研究，以干细胞输注后1周内（B时段）环孢素血药浓度138（113，167）ng·mL-1作为截点分析aGVHD发生率，结果显示环孢素血药浓度<113 ng·mL-1、113~167 ng·mL-1和 >167 ng·mL-1时的aGVHD发生率分别为27%（6/22）、12%（8/67）和20%（1/5）；经Kaplan-Meier法估计，随着移植后时间的延长，环孢素血药浓度降低，aGVHD累积发生率增加，且经Log-rank分析显示以上不同环孢素血药浓度组aGVHD发生率无显著差异（P=0.208），见图2。
环孢素血药浓度与不良反应
1　肝损伤
肝损伤发生率为47%（44/94），A、D时段患者发生肝损伤时的环孢素血药浓度显著高于肝功能正常时（P<0.05），见图3。
2　肾损伤
肾功能损伤发生率为71%（67/94），A时段患者发生肾损伤时的环孢素血药浓度显著高于肾功能正常时（P<0.001），见图4。
预警作用
1　环孢素血药浓度对肝损伤的预警作用
A时段ROC曲线的AUC为0.712（95%CI：0.578~0.847，P=0.002），对应的截断值为128.5 ng·mL-1，灵敏度和特异性分别为62.5%和81.2%。B时段ROC曲线的AUC为0.564（95%CI：0.447~0.680，P=0.291），对应的截断值为138 ng·mL-1；C时段ROC曲线的AUC为0.565（95%CI：0.448~0.682，P=0.315），对应的截断值为113.5 ng·mL-1；D时段ROC曲线的AUC为0.664（95%CI：0.535~0.793，P=0.016），对应的截断值为197 ng·mL-1。见图5。
2　环孢素浓度对肾功能损伤的预警作用
A时段ROC曲线的AUC为0.752（95%CI：0.637~0.868，P<0.001），对应的截断值为113.5 ng·mL-1，灵敏度和特异性分别为73.9%和67.9%。B时段ROC曲线的AUC为0.525（95%CI：0.405~0.644，P=0.693），对应的截断值为131.5 ng·mL-1；C时段ROC曲线的AUC为0.597（95%CI：0.472~0.722，P=0.162），对应的截断值为119 ng·mL-1；D时段ROC曲线AUC为0.513（95%CI：0.368~0.659，P=0.851），对应的截断值为130 ng·mL-1。见图6。
其他非血液学不良反应
移植仓内患者使用环孢素出现了一系列非血液学不良反应，主要有感染、感染性发热、药物性肝肾损伤和胃肠道反应，见表6。巨细胞病毒（CMV）阳性的3例患者和EB病毒阳性的1例患者均在移植后短期内发生。
讨论
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目前，环孢素在临床上广泛用于造血干细胞移植前后aGVHD的预防和治疗，大大降低了aGVHD发生率，提高了移植的成功率。本研究中环孢素血药浓度呈现个体差异，移植后环孢素血药浓度明显高于移植前预处理，移植后1个月内保持较高的环孢素血药浓度对于降低aGVHD的发生至关重要[3]。男性与女性患者环孢素血药浓度比较无显著差异，提示性别对血药浓度无显著影响。本研究还发现≤14岁患者使用环孢素后多个时段内环孢素血药浓度显著低于>14岁患者，与说明书中提到儿童对环孢素的清除较快相符，且与王亚妮等[4]的环孢素血药浓度与年龄关系结果一致。本研究结果显示，环孢素血药浓度受移植时间、疾病类型和疾病状态的影响，与专家共识[1]中不同移植时间、疾病类型及疾病严重程度的环孢素用药方案不同相符。另外，患者的免疫状态直接影响植活成功的时间，随着移植时间的延长植活率升高。本研究中aGVHD发生率为16%，较专家共识中的aGVHD发生率13%~47%[1]偏低，可能与观察时间较短有关，并且环孢素血药浓度较低时aGVHD的累积发生率较高，与既往研究结果[15]相符。由于环孢素主要经肝脏代谢，其血药浓度与肝损伤的发生密切相关，本研究中A和D时段肝损伤发生与环孢素血药浓度有关，肝损伤时的环孢素血药浓度显著高于肝功能正常时，说明环孢素血药浓度过高时肝毒性大，与裴云萍等[15]的研究结果一致。肾损伤的一个普遍标准是血肌酐水平大于等于2倍基线水平[5]，鉴于本研究中的患者大部分存在营养不良，会导致肌酐水平偏低，故评价肾损伤主要依据尿素氮、尿酸、尿蛋白指标，结果显示，A时段肾损伤时的环孢素血药浓度高于肾功能正常时，且未见其他时段中肾损伤与环孢素血药浓度的关联，可能与急性肾毒性通常不会引起永久性肾损伤，环孢素减量或停用后肾功能恢复有关[16]。此外，本研究还通过ROC曲线分析了各时段环孢素血药浓度对肝肾损伤的预警作用，发现A时段ROC曲线的AUC较大，提示此时段环孢素血药浓度预测肝肾损伤的意义较大，且环孢素血药浓度大于128.5 ng·mL-1时肝损伤发生概率较高，血药浓度大于113.5 ng·mL-1时肾损伤发生概率较高；而B、C和D时段ROC曲线的AUC偏小，提示这些时段环孢素血药浓度预测患者肝肾损伤的准确性不高，可作为辅助指标。本研究有23例（24%）患者出现胃肠道反应，其中有1例发生aGVHD患者出现消化道出血,可能与肠道aGVHD、感染、重度血小板减少等并发症有关[17]。另外有16例（17%）患者发生出血性膀胱炎，由于环磷酰胺的主要不良反应是出血性膀胱炎，而在本研究纳入的allo-HSCT患者预处理方案中环磷酰胺的使用率为88%，因此该不良反应可能与环磷酰胺有关。其他主要非血液学不良反应发生情况与与环孢素药品说明书及既往研究报道[16，18]一致。
综上所述，环孢素血药浓度影响因素较多，建议临床密切监测血药浓度并结合临床症状及时调整用药剂量，从而提高治疗效果。在临床上allo-HSCT患者普遍采用三唑类抗真菌药物进行抗感染治疗，而环孢素血药浓度易受三唑类抗真菌药物的影响，建议同时监测环孢素及三唑类抗真菌药物浓度并及时调整给药剂量，但本研究未讨论联合用药对环孢素血药浓度的影响，且本研究为单中心回顾性研究，移植仓内allo-HSCT患者环孢素血药浓度的确切影响及其意义有待多中心、大样本临床试验进一步探讨。
基金
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  • 河北省医学研究课题(20210319)
文献
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参考文献 引证文献
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2024年第43卷第10期
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doi: 10.14109/j.cnki.xyylc.2024.10.08
  • 接收时间：2023-04-28
  • 首发时间：2026-03-17
  • 出版时间：2024-10-25
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  • 收稿日期：2023-04-28
  • 录用日期：2024-06-03
基金
河北省医学研究课题(20210319)
作者信息
    1.河北燕达陆道培医院 检验医学科，河北 廊坊　065201
    2.北京陆道培医院 检验医学科，北京　100176
    3.北京陆道培血液病研究院，北京　100176

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2种不同金属材料的力学参数
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Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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