| Background B-cell hematological malignancy is one of the common hematological malignancies,the main treatments are including chemotherapy,radiotherapy and hematopoietic stem cell transplantation(HSCT).Most patients can respond to the first-line therapy,however,the high incidence of recurrence and poor prognosis make it refractory.For relapse/refractory(R/R)B-cell hematological malignancy,intensified chemotherapy showed poorer response and more severe toxicities.Transplantation can be considered if available,but donors,graft-versus-host disease(GVHD)and recurrence after transplantation remain major problems.New therapies for R/R B-cell hematological malignancies are urgently needed.Chimeric antigen receptor T cell therapy(CAR-T)is a novel and promising targeted cell therapy which can recognize and eliminated tumor cells.The mechanism of CAR-T therapy is transducing CARs to the surface of T cells by genetic engineering,after in vitro expansion,cells are infused to patients for treatment.CD19-targeted CAR-T cell therapy has achieved unprecedented success in patients with CD19-positive R/R B cell hematological malignancies.However,as an immunotherapy,immune-related toxicity is a challenge,and there are many problems to be solved in its prevention,management,and follow-up monitoring.Objective To explore the toxicities and relevant factors in patients with B-cell hematological malignancies after CD19-targeted CAR-T cell therapy.Methods Our study enrolled 67 patients with R/R B-cell hematological malignancies from October 2016 to January 2020,toxicities after treatment with CD19-targeting CAR-T cells were evaluated and relevant factors were analyzed.Results We reported the outcome of 77 episodes of CD19 CAR-T cell therapy in 67 patients with B-cell hematological malignancies,which shows the overall rate of complete remission(CR)was 75.3%(55/77).At the time of follow-up(11.4 months,median;range 1.2-41.1 months)of patients who achieved CR,for patients with acute B lymphoblastic leukemia(B-ALL),the estimated median event-free survival(EFS)and overall survival(OS)were 8.3 and 20.4 months,the rates of EFS and OS at 1 year were32.1% and 65.4%.The incidence of cytokine release syndrome(CRS)was 88.3%(68/77),grade 1-2,grade 3-4,and grade 5 CRS was 57.1%(44/77),28.6%(22/77),and 2.6%(2/77)respectively.Only one of the 10 patients who relapsed after umbilical cord blood transplantation(UCBT)had Grade ≥3 CRS.The incidence of neurotoxicity was 11.7%(9/77).Further analysis showed that patients with a history of transplantation have less severe CRS,dose escalation infusion of CAR-T cells can reduce the risk of severe CRS,and platelet count(PLT)after infusion in the first month were associated with severe CRS.Severe CRS was related to neurotoxicity and better response but unrelated to EFS or OS.46 of these patients were selected to evaluate coagulation dysfunction after CAR-T cell therapy.Among the 46 patients,37(80.4%)patients occurred coagulation disorders,including elevated D-dimer over 5mg/L(31/46,67.4%),prolonged APTT more than 10s(25/46,54.3%),prolonged TT(19/46,41.3%),decreased fibrinogen(22/46,47.8%),prolonged PT more than 3s(7/46,15.2%),and elevated FDP over 20mg/L(12/18,66.7%).Further analysis the changes of coagulation parameters were associated with dose escalation,the level of inflammatory factors after infusion,and the severity of CRS after infusion.Conclusion CD19 CAR-T cell therapy exhibited a high CR rate in the treatment of R/R B-cell hematological malignancies,and CRS was a common adverse event,which was correlated with a history of transplantation,dose escalation infusion,and levels of PLT after infusion.Severe CRS was related to neurotoxicity and better response but unrelated to long-time survival.Furthermore,the severity of CRS is significantly associated with coagulopathy after treatment,and dose escalation infusion can reduce the risk of coagulopathy. |
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