Changes Of Cytokine Levels After Relapsed/refractory B-ALL Treated With CD19 CAR-T Cells And Its Clinical Significance

Background: Acute lymphoblastic leukemia(ALL)is one of the subtypes of acute lymphoblastic leukemia(ALL)in adults.It is mainly divided into B-ALL and T-ALL.Among them,B-ALL is the most common,and its incidence rate accounts for about 85% of ALL.Its traditional treatments can achieve complete remission in 78%to 93% of adult B-ALL patients,40% of long-term disease-free survival,but more than 50% of adult patients will relapse,and the prognosis after relapse is very poor,the overall survival rate Only 5%-8%.For patients with relapsed and refractory B-ALL,hematopoietic stem cell transplantation and targeted drug therapy are used to achieve remission,but some patients will eventually relapse or become resistant,and this part of the patient is almost incurable.In recent years,cell immunotherapy has made important progress,and CAR-T cells(chimeric antigen receptor T cell immunotherapy)have achieved good therapeutic effects in the treatment of B cell leukemia and lymphoma,the most representative of which is CD19 CAR.-T treatment of patients with relapsed refractory B-ALL.Because CD19 antigen is expressed more than 95% on B-ALL and is only expressed on the surface of normal and malignant B cells and is not expressed on other cells,CD19 antigen is CAR-T treatment of CD19-positive r/r B-The key point of ALL is that it can achieve good results in the treatment of relapsed/refractory B-ALL,with a complete response rate(CR)of 70-80%.In the treatment of CD19 CAR-T cells,in addition to the common adverse events in the treatment of leukemia such as infection,infusion reaction,tumor lysis syndrome,etc.,the unique adverse reaction associated with it is Cytokine release syndrome(CRS).CAR-T cell-related encephalopathy syndrome(CRI),B cell Aplasia,and financial toxicity,among which CRS is the most common,Most notable.Cytokine release syndrome(CRS)is triggered by T cell activation after binding of TCRs or CARs to cognate antigens expressed by tumor cells.Activated T cells and immune paracellular cells release large amounts of cytokines and chemokines,resulting in a brief sharp rise in cytokines in serum.For the treatment of CRS,in general,mild CRS can be used to support the treatment to effectively control the disease,but severe CRS patients may have serious consequences such as hypotension and organ failure,which poses a threat to life.It is currently reported that cytokines related to the severity of CRS have IL-6 and CRP,while other cytokines related to the severity of CRS are rarely reported.Whether changes in cytokine IL-6,IFN-?,IL-10,TNF-? and CRP levels before and after CD19 CAR-T cell infusion can be used as a laboratory reference indicator for judging the severity of CRS and to guide clinical targeted cells Factor antagonists,and have a predictive value for the efficacy of CD19CAR-T cells.Objective: to investigat the changes of cytokine levels in patients with relapsed/refractory B-ALL treated with CD19 CAR-T cells and its clinical significance.Methods: We selected 32 patients with relapsed/refractory B-ALL who received CD19 CAR-T cell therapy from August 2015 to February 2018 in our hospital.Among them,23 patients were tested for IFN-?,IL-10,TNF-? and IL-6 in serum before and after infusion using Cytometric Bead Array(CBA),electrochemical radiance and immunoturbidimetry and CRP levels.Patients with CRS according to CTCAE v4.0 were mild CRS.Groups(1 to 2)and severe CRS(3 to 5)were compared for differences in cytokines measured between the two groups and treatment response.There were 16 males and 7 females.The median age is 22 years old.All patients developed CRS after CD19 CAR-T cell reinfusion,including 16 cases of mild CRS(14 cases of grade 1 and 2 cases of grade 2),and 7 cases of severe CRS(5 cases of grade 3,2 cases of grade 4).Efficacy assessment was performed 4 weeks after the reinfusion,including 9 patients with complete remission(CR),9 patients with incomplete recovery of blood(CRi),and 5 patients without remission(NR).There were no significant differences in gender and age among all groups.Results:1.CD19 CAR-T cells before and after infusion of serum IL-6(2.00~ 28.5 vs 34.5 ~112.00),IFN-?(2.13 ~ 3.12 vs 4.35 ~ 10.07),IL-10(1.00 ~ 1.80 vs 4.01 ~39.92),TNF-?(2.91~4.60 vs 4.99~40.18)were statistically significant(P=0.000,0.000,0.001,0.002);2.mild CRS group compared with severe CRS group,serum IL-6(28.75~61.25 vs 91.00~1074.00),IFN-?(3.93~7.28 vs 12.53~15.30),IL-10(3.13~7.47 vs 39.92~84.97),TNF-?(4.60~15.77 vs 40.18~62.51)and CRP(4.95~46.86 vs 37.81~120.17)was statistically significant(P=0.004,0.004,0.003,0.000,0.045);3.There was no significant difference in the levels of cytokines and CRP between the complete remission(CR)(including patients with incomplete recovery of blood,CRi)and the non-remission(NR)group after CD19 CAR-T treatment(P=0.945,0.602,0.884,0.957,0.293);4.Patients with severe CRS with significantly elevated IL-6,fully recovered after treatment with IL-6 receptor antagonist.5 The number of primordial cells before CD19 CAR-T infusion was positively correlated with the concentration of IL-6,IFN-?,IL-10 and TNF-?cytokines after infusion(P=0.023,0.012,0.011,0.035).There was no correlation between CRP levels(P=0.187).Conclusions:Reducing the number of blasts before CD19 CAR-T cell infusion can reduce the levels of IL-6,IFN-?,IL-10,TNF-? cytokines after infusion,and these cytokine levels can be used as an experiment to judge the severity of CRS.Room reference indicators,and can guide clinical targeted selection of cytokine antagonists,but the predictive value of CD19 CAR-T efficacy needs further verification.