Prediction And Control Strategy Of Cytokine Release Syndrome After CAR-T Treatment

Objective:Chimeric antigen receptor T cells are effective treatments for refractory/relapsed acute lymphoblastic leukemia.However,patients with high tumor burden will develop severe cytokine release syndrome(CSF)after CAR-T reinfusion,which seriously affects the survival of patients.Therefore,exploring how to reduce the tumor burden to reduce the occurrence of CRS storms has become the focus and difficulty in CAR-T cell therapy.This study aims to reduce the incidence and severity of CRS in patients with refractory recurrent R/R ALL by optimizing the pretreatment regimen prior to CAR-T infusion,and to explore molecular markers that can effectively predict severe CRS storms.Methods:1.In the pretreatment study of MVP+FC chemotherapy regimen,patients with recurrent high tumor burden,relapsed/refractory acute lymphoblastic leukemia,and bone marrow primitive immature cells were>28%;explore predictable biomarkers of CRS in CAR-T therapy In the study,patients with infection before CAR-T,cytokine expression not at normal levels,and recent antibody drug treatment were excluded.2.The CAR-T cells were prepared by the second generation CAR system,and the CAR-T cells were dose-incremented by 10%-30%-60%.3.Pretreatment with MVP+FC chemotherapy to reduce the tumor burden of patients before CAR-T treatment,thereby reducing the incidence,severity and CAR-T treatment-related mortality of CAR-T treatment-related CRS.4.Using commercial kits to detect the levels of seven cytokines in plasma IL-2,IL-4,IL-6,IL-10,IL-17A,TNF-? and IFN-? after CAR-T cell infusion.Dynamic changes,combined with statistical analysis models to explore predictive models of cytokine predictive of severe CRS storms,and to assess their predictive value in the occurrence and development of CRS.Results:1.In this study,9 patients with R/R ALL with high tumor burden received MVP+FC as a pretreatment regimen for reducing tumor burden and depleting lymphocytes before CAR-T treatment.From 45%before MVP treatment to 24%after MVP,after MVP+FC regimen chemotherapy,the proportion of malignant naive cells in the bone marrow of patients decreased from 45%before treatment to 7%,which significantly reduced tumor burden.The total response rate(ORR(CR+PR)of the 9 patients treated with MVP regimen was 33%.After MVP+FC regimen chemotherapy,the ORR(CR+PR)increased to 44%,and the response rate after CAR-T treatment(CR+)PR)was as high as 88.89%,of which hematologic remission rate was 86%(7/9);molecular remission rate was 67%(6/9).Only 3 patients had grade 3 CRS,and 6 patients had only grade 1-2 CRS.None of them had central nervous system toxicity,and the median granule loss time was 7(2-26)days.At a median follow-up of 12.8 months,9 patients had 77.78%and 55.56%of OS and DFS in June,and 33.33%in both OS and DFS in December.The cumulative recurrence rate was 55.56%.2.Statistical analysis of cytokines,tumor burden and CRS levels in patients treated with CAR-T found that IL-6,IL-10 and IFN-? have predictive value in the process of CRS,among which IL-6 The highest diagnostic efficiency(AUC=0.794,SEN=0.639,SPE=0.87);simultaneous multivariate analysis showed that IL-6 combined with IL-10 had the best predictive efficacy(AUC=0.841);IL-2,IL-4,IL-6.IL-10 and IFN-? have predictive value in the development of CRS from mild to moderately severe,and IFN-? has the highest diagnostic efficiency(AUC=0.792,SEN=0.6,SPE=0.923);similarly,multiple factors Combined analysis showed that IL-2+IFN-?,IL-10+IFN-?,IL-6+IL-10+IFN-? had the best predictive efficacy(AUC=0.788);and statistical results also found that tumor burden was significantly associated with CRS development(AUC)=0.817,SEN=0.8,SPE=0.885).Conclusions:The tumor burden degree of R/R ALL patients was positively correlated with the occurrence of CRS.The pretreatment regimen of MVP+FC significantly reduced the proportion of protoplasts in bone marrow,and then reduced the incidence of severe CRS.Seventy-five patients with R/R ALL were enrolled in 59 cases.Dynamic detection and statistical analysis of cytokine levels,univariate analysis showed that IL-6,IL-10 or IFN-?have potential predictive diagnostic value in the prediction of CRS occurrence;Analysis showed that IL-6 combined with IL-10 has the best predictive efficacy of CRS occurrence.On the other hand,IL-2,IL-4,IL-6,IL-10 and IFN-? have predictive value in the progression of CRS from mild to moderately severe;IL-2+IFN-?,IL-10 The combination of+IFN-? or IL-6+IL-10+IFN-? was the best predictive.In summary,the above molecules have potential diagnostic value for the development of CRS caused by CAR-T treatment.However,due to the relatively small sample size included in this study,prospective clinical trials should be designed in the future,and the number of eases should be increased to verify.