Efficacy And Safety Study Of Bridging Allogeneic Haematopoietic Stem Cell Transplantation After CAR-T Cells Therapy For Adult Relapsed/Refractory Acute B Lymphoblastic Leukemia

Background:Adult relapsed/refractory B cell acute lymphoblastic leukemia(r/r B-ALL)patients are known to have a poor prognosis,and chimeric antigen receptor T cell(CAR-T)therapy has achieved promising results.70-90%of r/r B-ALL patients can achieve complete remission(CR)with CAR-T cell therapy,but the disease relapse rate is>50%after 1 year.r/r B-ALL patients can achieve complete remission(CR)with CAR-T cell therapy,but the disease recurrence rate after 1 year is greater than 50%.r/r B-ALL patients who are treated with salvage chemotherapy have the opportunity to bridge to allogeneic hematopoietic stem cell transplantation(allo-HSCT)in approximately 5%of patients,and a higher percentage of patients can successfully achieve CR after CAR-T cell therapy.This study aims to further clarify the role of CAR-T cell in the transition to allo-HSCT.This study was designed to further define the efficacy and safety of bridging to allo-HSCT after CAR-T cell therapy.Methods:A retrospective analysis of the safety and efficacy of bridging allogeneic HSCT to CAR-T therapy in adult r/r B-ALL patients and CAR-T cell therapy alone was performed in two groups of patients at our centre.After pretreatment with the FC protocol,CAR-T cells were infused and patients with CR bone marrow morphology after 28 days were further included in the follow-up study.Patients were divided into cohort 1-CAR-T cell therapy followed by bridging transplantation and cohort 2-CAR-T cell therapy alone groups according to their willingness to transplant,availability of suitable donors and financial ability.Patients in cohort 1 were bridged to allo-HSCT approximately three months after CAR-T cell therapy,and cohort 2 continued to be monitored for disease status after CAR-T infusion.Patients in both cohorts were analysed at baseline and then compared for efficacy and safety between cohort 1 and cohort 2.Cohort 1 was assessed for safety by CRS,CRES,aGVHD,cGVHD,and for efficacy by time to graft implantation,relapse rate,relapse-related mortality,non-relapse-related mortality,relapse immunophenotype,median overall survival(OS)and median disease-free survival(DFS).Cohort 2 metrics to assess safety included CRS,CRES,metrics to assess effectiveness included:recurrence rate,recurrence-related mortality,non-recurrence-related mortality,recurrence immunophenotype,median OS and median DFS.the primary study endpoint was median DFS and secondary study endpoints were median OS,recurrence rate,recurrence-related mortality and non-recurrence-related mortality.Results:Between May 2016 and May 2022,51 adult r/r B-ALL patients completed CAR T cell therapy,and 44 patients achieved CR.Cohort 1 and cohort 2 had 21 and 23 patients,respectively.The median age was 26 years(18～52 years)for cohort 1 and 38 years(19～68 years)for cohort 2.Baseline information between the two cohorts,including gender,age,number of disease recurrences,number of previous treatments,central invasion,entry tumour load and pre-infusion tumour load were not statistically different.The median follow-up period for the cohort was 372.5 days(89 to 1752 days).The median disease-free survival(DFS)for cohort 1 and cohort 2 was 1099 days and 255 days respectively.In addition,the median overall survival(OS)for cohort 1 and cohort 2 was 1118 days and 396 days respectively.Although the difference in OS was not statistically significant(p=0.4957),the DFS was statistically different between the two groups(p=0.0277),with cohort 1 having a longer disease-free survival than cohort 2.Cumulative recurrence rates were 38.10%and 69.57%for cohort 1(bridged HSCT group)and cohort 2(non-bridged HSCT group)respectively(p=0.036).The tumour-related mortality rates were 28.57%and 47.83%for cohort 1(bridged HSCT group)and cohort 2(non-bridged HSCT group),respectively(p=0.074).The non-recurrence-related mortality rates were 14.29%and 0(p=0.058)for Cohort 1(bridged HSCT group)and Cohort 2(non-bridged HSCT group),respectively.The incidence and severity of CRS and CRES were not statistically different between cohort 1 and cohort 2.Conclusions:Patients with r/r B-ALL who received allo-HSCT after obtaining CR with CAR-T cell therapy had a longer median DFS,a significantly lower relapse rate and lower relapse-related mortality than the non-transplanted group.Bridging allo-HSCT after CAR-T cell therapy reduces the relapse rate while also increasing the risk of transplant-related mortality and higher non-relapse-related mortality.This may result in no statistically significant difference in median OS compared to patients without bridging allo-HSCT.This study suggests that identifying high-risk factors for relapse after CAR-T cell therapy and selective bridging of allo-HSCT after CAR-T cell therapy in high-risk patients is of greater importance.