| Objective:To investigate the correlation between the levels of cytokines TNF-α,IL-6,IL-10,IL-2 and IL-4 and the occurrence and severity of acute graft-versus-host disease(aGVHD)at different time points after allogeneic hematopoietic stem cell transplantation(allo-HSCT).Methods:Retrospective analysis of 89 patients who underwent allo-HSCT at the Department of Hematology,Oncology Center,the First Hospital of Jilin University between January2019 and November 2020,29 patients in the group that developed aGVHD and 60patients in the group that did not develop aGVHD.For patients eligible for enrollment,patient gender,age,HLA matching,transplant type,donor-recipient gender and relationship,donor-recipient ABO blood type,pretreatment regimen,primary disease,CD34+cell count,single nucleated cell count,hematopoietic stem cell source,platelet and leukocyte implantation status,HCTCI score,aGVHD prevention regimen,aGVHD time of occurrence,severity and treatment plan,and other basic information were collected.SPSS22.0 software was applied to compare between groups and analyze the correlation between the serum levels of cytokines TNF-α,IL-6,IL-10,IL-2,IL-4 at+7 days,+14 days,+21 days and+28 days in patients and the occurrence,severity and treatment effect of aGVHD.And we also explored the correlation between the presence of sepsis and implantation syndrome on aGVHD after allo-HSCT The effect of changes in cytokine levels in patients with aGVHD.Results:1.There were 89 evaluable patients,49 males and 40 females,with a median age of 34(2.75～61)years,including 40 cases of acute myeloid leukemia,22 cases of acute lymphoblastic leukemia,14 cases of myelodysplastic syndrome,5 cases of aplastic anemia,and 8 cases of chronic granulocytic leukemia.There were 63 haploidentical transplants,18 sibling allografts,2 umbilical cord blood transplants,and 6 cases of unrelated donors.All patients were successfully implanted,with a median granulocyte implantation time of 14(10～27)days,a median platelet implantation time of 15(10-45)days,a median infused mononuclear cell count of 8.28(1.49～18.30)×10~8/kg,and a median infused CD34+cell count of 3.62(0.91～8.24)×10~6/kg.aGVHD occurred in the test group with 29 patients,including 5 with sepsis and 5 with engraftment syndrome(ES).And 60 patients without aGVHD were control group,including 14 with sepsis and 5 with engraftment syndrome.2.Among 89 patients,29 patients with aGVHD occurred and 60 patients without aGVHD.Comparing cytokine levels in patients with aGVHD and those without aGVHD,the results showed that+7 days IL-4 levels were negatively correlated with the occurrence of aGVHD and were lower in the aGVHD group than in the group without aGVHD(P<0.001).+14 days IL-2 levels were positively correlated with the occurrence of aGVHD and were higher in the aGVHD group than in the group without aGVHD(P=0.004).+21 days IL-10 levels were positively correlated with aGVHD occurrence,and were higher in the group with aGVHD than in the group without aGVHD(P=0.023).+28 days IL-6 levels were negatively correlated with aGVHD occurrence,and were lower in the group with aGVHD than in the group without.The ratio of IL-2/IL-4 cytokines+7 days was positively correlated with the occurrence of aGVHD,and was higher in the aGVHD group than in the group without aGVHD(P<0.001).The ROC curve was applied to plot the Cut-off value of+7 days IL-2/IL-4of 1.103,which had a sensitivity of 0.731,a specificity of 0.784 and an area under the curve of 0.776.3.Among the 29 patients with aGVHD,5 patients with sepsis were excluded,and5 of the remaining 24 patients had combined ES.Comparison of cytokine levels at different time points between combined ES and uncomplicated ES showed no significant difference in cytokine levels at different time points between patients with aGVHD who developed ES and those who did not(P>0.05).4.Among the 29 patients with aGVHD,5 patients with ES were excluded,and 5of the remaining 24 patients had combined sepsis.Comparison of cytokine levels at different time points between combined and uncomplicated sepsis showed that IL-2levels at+14 days were positively correlated with sepsis,and patients with sepsis were higher than those without sepsis(P=0.021).+21 days IL-2 levels were positively correlated with sepsis and were higher in patients with sepsis than in those without sepsis(P=0.020).5.In 60 patients without aGVHD,5 patients with ES were excluded,and 14 of the55 evaluable patients without aGVHD were combined with sepsis,and comparing cytokine levels between patients with and without sepsis in patients with aGVHD,the results showed that+7 days IL-10 levels were positively correlated with the development of sepsis,and were higher in patients with sepsis than in patients without sepsis(P=0.005).+14 days TNF-α and IL-6 levels were positively correlated with the development of sepsis,and patients with sepsis were higher than those without sepsis(P=0.041,P=0.010).+28 days IL-6 levels were positively correlated with the development of sepsis,and patients with sepsis were higher than those without sepsis(P=0.010).6.The occurrence of sepsis and ES may affect cytokine levels,so 19 patients with sepsis and 10 patients with ES were excluded from the 89 patients,leaving 60 evaluable patients,19 with aGVHD and 41 without aGVHD,comparing cytokine levels at different time points in patients with and without aGVHD.And the results showed that+7 days IL-4 levels were negatively correlated with the occurrence of aGVHD and were higher in the aGVHD group than in the group without aGVHD(P=0.021).+14 days IL-2 levels were positively correlated with the occurrence of aGVHD and were higher in the aGVHD group than in the group without aGVHD(P=0.044).The ratio of IL-2/IL-4 cytokines on+7 days was positively correlated with the occurrence of aGVHD,and the ratio of IL-2/IL-4 cytokines+7 days was positively correlated with the occurrence of aGVHD and was higher than the group without aGVHD(P=0.018).The ROC curve was applied to plot the Cut-off value of+7 days IL-2/IL-4 of 0.989,which had a sensitivity of 0.688,a specificity of 0.758 and an area under the curve of 0.710.7.Cytokine levels were compared between patients who developed aGVHD and those who did not develop aGVHD in 19 patients who developed sepsis,5 patients with aGVHD and 14 patients without aGVHD.The results showed that+7 days IL-10 levels were negatively correlated with the occurrence of aGVHD,and IL-10 levels in the aGVHD group were lower than those in the group without GVHD(P=0.016).+14 days IL-2 levels were positively correlated with the occurrence of aGVHD,and IL-2 levels in the aGVHD group were higher than those in the group without GVHD(P=0.038).+28 days IL-6 levels were negatively correlated with the occurrence of aGVHD,and IL-6 levels in the aGVHD group were lower than those in the group without GVHD(P=0.003).8.Among the 19 patients with aGVHD excluding combined sepsis and ES,12(63.16%)had degree I aGVHD,7(36.84%)had degree II～IV aGVHD,13(68.42%)had cutaneous aGVHD,1(5.26%)had hepatic aGVHD,3(15.79%)had gastrointestinal aGVHD,and 2(10.53%)had cutaneous combined gastrointestinal aGVHD,comparing the cytokine levels of degree I aGVHD with those of degree II～IV aGVHD,the results showed that there was no significant correlation between cytokines and the severity of aGVHD at each time point(P>0.05).9.Univariate analysis of the risk of IL-2/IL-4 and aGVHD on+7 days showed that the risk of aGVHD was 8.87-fold increased in 89 patients with an IL-2/IL-4 ratio≥1.103 on+7 days(OR:9.870,95%CI:1.830～25.823,P=0.000).Excluding patients with ES and sepsis leaving 60 patients,the risk of aGVHD was increased 5.875-fold at+7days IL-2/IL-4 ratio≥1.103(OR:6.875;95%CI:1.830～25.823;P=0.004).10.19 patients with aGVHD excluding combined sepsis,all received first-line treatment with glucocorticoids(topical or intravenous infusion),15 treated to CR,including 12 cases(80%)with degree I aGVHD,3 cases(20%)with degree II～IV aGVHD.And 4 treated to NR,all with degree II～IV aGVHD,and second-line treatment was applied after ineffective hormonal treatment,including baliximab xiximab,tacrolimus,mesenchymal stem cell,lukotinib,and mortezumab therapy,etc.The results showed that+14 days TNF-αwas positively correlated with the treatment effect,and the treatment ineffective group had lower TNF-αlevels(P=0.034).+14 days IL-2 was positively correlated with the treatment effect,and the treatment ineffective group had lower IL-2 levels(P=0.034).+14 days IL-6/IL-10 ratio was negatively correlated with treatment effect,and IL-6/IL-10 ratio was higher in the treatment-ineffective group(P=0.025).Conclusions:1.Cytokines were correlated with the occurrence of aGVHD.IL-4 levels at+7days were negatively correlated with the occurrence of aGVHD,IL-2 levels at+14 days were positively correlated with the occurrence of aGVHD,and the ratio of IL-2/IL-4cytokines at+7 days was positively correlated with the occurrence of aGVHD.cytokine levels at the above time points can be used as a predictor of aGVHD occurrence after allo-HSCT.Among them,+7 days IL-2/IL-4 ratio≥0.989 suggests a 5.875-fold increased risk of aGVHD.2.Sepsis influenced the judgment of cytokines in predicting the occurrence of aGVHD,but the+7 days IL-2/IL-4 ratio was consistent with the trend of change in the absence of combined sepsis,and+7 days IL-2/IL-4 ratio≥1.103 in patients with combined sepsis suggested an 8.87-fold increased risk of aGVHD.3.Cytokine levels can predict the efficacy of first-line glucocorticoid therapy for aGVHD.An elevated IL-6/IL-10 ratio on+14 days suggests possible poor hormone therapy and early application of second-line therapy. |
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