A Preliminary Study On The Safety And Efficacy Of CD19-targeted Chimeric Antigen Receptor T Cells In The Treatment Of Relapsed/refractory Philadelphia Chromosome Positive Acute B Lymphocytic Leukemia

Objectives To study the safety and efficacy of CD19-targeted chimeric antigen receptor T cell(CD19 CAR-T)therapy in relapsed/refractory Philadelphia chromosome positive acute B lymphoblastic leukemia(R/R Ph+ B-ALL),and also to explore the possible prognostic factors.Methods From November 2016 to April 2019,14 patients with R/R Ph+ B-ALL were treated with murine CD19 CAR-T cells in our hospital.The data were collected about the patient's sex,age,disease subtype,whether had other molecular biological abnormalities,whether previously accepted allogeneic hematopoietic stem cell transplantation(allo-HSCT),whether previously had central nervous system leukemia(CNSL),tumor burden before infusion,gene transfection,infusion dose,cytokine release syndrome(CRS)grade and so on.CAR-T cells carrying the CD28co-stimulation threshold were prepared by intravenously extracting an appropriate amount of peripheral blood based on the patient's peripheral blood image and the number of T lymphocytes.Next,Fludarabine and cyclophosphamide(FC)regimen pretreatment chemotherapy should be given to the patients,and then the CAR-T cells needed to be infused intravenously into patients.To assess the safety of CAR-T cell therapy,We monitored the patient's vital signs changes,C-reactive protein(CRP),serum cytokines(IL-2,IL-6,IL-10,granzyme B,IFN-?)and other indicators.To evaluate the effect of CD19 CAR-T cell therapy on R/R Ph+ B-ALL,We compared the changes of blood routine,BCR/ABL1,minimal residual disease(MRD)in bone marrow and CAR DNA copies in peripheral blood before and after treatment.Results1.On the 28 th day after CAR-T cells infusion,the short-term efficacy of 14 patients was evaluated: the overall response rate(ORR)was 100%(14/14),including that the complete response(CR)rate was 92.86%(13/14)and the partial response(PR)rate was7.14%(1/14).2.After CAR-T cells infusion,12 cases(85.71%)developed cytokine release syndrome(CRS):1 case of grade 1 CRS,4 cases of grade 2 CRS,6 cases of grade 3 CRS,and 1case of grade 4 CRS;1 case of grade 3 CAR-T cell related encephalopathy syndrome(CRES);13 cases of all CR patients developed B cell hypoplasia.These side effects are controllable.On the 7th,14 th,21st and 28 th day after CAR-T cells infusion,there was no significant difference in CAR DNA copies between the glucocorticoid group and the non glucocorticoid group(P>0.05).There was a significant difference in the peak levels of IL-6,IL-10,granzyme B,IFN-? and CRP between grade 3-4 CRS and grade0-2 CRS(P<0.05).3.The median follow-up time of 14 patients was 441(182-923)days,and the median OS and PFS time were 515(95% CI 287-743)days and 207(95% CI 123-301)days respectively.In Kaplan Meier's univariate analysis,There was significant difference in OS time between P190 BCR-ABL1 and p210 BCR-ABL1 subtypes in 13 CR patients(P<0.05),and the significant difference was also found in PFS time between patients who received tyrosine kinase inhibitors(TKI)and those who didn't(P<0.05).Conclusions1.There is a preliminary confirmation of the efficacy of CD19 CAR-T cell treatment on relapsed/refractory Philadelphia chromosome positive acute B-lymphoblastic leukemia.But,the long-term effect needs to be further improved.2.In the course of CAR-T cell therapy,toxic and side effects such as CRS,CRES,and B-cell dysgenesis mainly occur and are controlled.Treatment of CRS with glucocorticoid does not inhibit CAR DNA copies in peripheral blood.The peak levels of IL-6,IL-10,IFN-?,granzyme B and CRP are obviously increased in patients with severe CRS.3.Among the 13 CR R/R Ph+ ALL patients treated with CAR-T cell therapy,and the additional application of TKI may be helpful to reduce the risk of relapse.