Clinical Study Of Chimeric Antigen Receptor T Cell In Relapsed/Refractory B Cell Non-Hodgkin’s Lymphoma

Part I Chimeric Antigen Receptor T Cell in Relapsed/Refractory B Cell Non-Hodgkin’s lymphoma:A Phase II Clinical TrialObjective:To evaluate the safety and efficacy of chimeric antigen receptor T(CAR-T)therapy in treatment of relapsed or refractory B cell non-Hodgkin’s lymphoma(R/R B-NHL),and to investigate the possible factors that may affect prognosis.Methods:We performed a prospective one-arm phase Ⅱ clinical trial(NCT03196830)to evaluate the safety and efficacy of CAR-T therapy in RIR B-NHL patients.The major inclusion criteria included:(1)CD19/CD20/CD22/CD30 positive R/R B-NHL patients with measurable lesions confirmed by pathological immunohistochemistry or flow cytometry;(2)age 18-70 years;(3)Eastern Cooperative Oncoloy Group(ECOG)score is 0-2;(4)Prior therapy≥ two lines.The primary endpoint of this study is overall response rate(ORR);and secondary endpoints included complete response rate(CR),progression-free survival(PFS),overall survival(OS)and security.Results:Between March 2017 and July 2019,a total of 52 R/R B-NHL patients were recruited in the study and completed CAR-T cell infusion.As of October 2019,analysis was performed on 47 patients who completed treatment and evaluation,35(74.5%)patients achieved response and 21(44.7%)patients achieved complete response.The median time to response was 1.2 month(range,0.7 to 5.7).Among 35 patients who achieved ORR after CAR-T therapy,six patients underwent hematopoietic stem cell transplant(HSCT).The median follow-up time was 18,2 months,2-year PFS and OS were 51.7%and 67.9%,respectively.Further analysis found that patients underwent HSCT after CAR-T had better 2-year PFS(100.0%vs.44.0%,P=0.019)and 2-year OS(100.0%vs.61.3%P=0.078)than CAR-T alone.The results of the subgroup analysis showed that CAR-T therapy showed same good clinical benefit in the patients with International Prognostic Index(IPI)score of 3 or above and in the double expressor lymphoma(DEL)patients(IPI≥3 vs.IPI<3s PFS 41.3%vs.49.4%,P=0.276,OS 53.5%vs.64.1%,P=0.092,DEL vs.Non-DEL PFS 54.5%vs.37.8%,P=0.646,OS 53.0%vs.59.9%,P=0.355).Multivariate analysis showed that the prior treatment lines greater than 3 lines and achieved CR after CAR-T were independent factors affecting OS.In terms of safety,cytokine release syndrome(CRS)and neurotoxicity were the most common adverse events.38 patients(73.1%)and 6 patients(11.5%)occurred CRS and neurotoxicity during therapy,respectively.Patients with severe CRS and neurotoxicity(grade 3 and above)were 12(23.1%)and 5(9.6%),respectively.Hypotension,fever and hypoxia were most common symptoms in patients with ≥ 3 grade CRS.The infusion dose of CAR-T cell was associated with the occurrence of grade 2 and above CRS(P=0.020)and grade 3 and above neurotoxicity(P=0.012).Most patients had symptomatic relief after symptomatic supportive treatment,except two patients died of severe CRS.Conclusion:This study confirmed the safety and effectiveness of CAR-T therapy in the treatment of patients with R/R B-NHL.For some patients,CAR-T therapy bridging HSCT may lead to better clinical prognosis.In the patients with IPI score of 3 or higher and in the double expressor lymphoma patients,it showed the same good clinical benefit,providing a certain evidence-based basis for further research.In addition,infusion dose of CAR-T cells had potentially negatively affect to safety.Part Ⅱ Comparison of CAR-T therapy and Autologous Stem Cell Transplantation for Relapsed/Refractory B cell Non-Hodgkin’ s LymphomaObjective:Compare the safety and efficacy of chimeric antigen receptor T cell(CAR-T)and autologous stem cell transplantation(ASCT)in relapsed or refractory B-cell non-Hodgkin’s lymphoma(R/R B-NHL)patients,and explore the best salvage treatment for R/R B-NHL patients.Methods:We conducted a prospective one-arm phase Ⅱ clinical study of CAR-T therapy in 29 patients with R/R B-NHL and compared the outcomes with 27 contemporaneous patients who received ASCT to compare the safety and efficacy of both treatments.The primary endpoint of this study is overall response rate(ORR);and secondary endpoints included complete response rate(CR),progression-free survival(PFS),overall survival(OS)and security.Ruselts:From March 2017 to September 2018,fifty-six patients were treated and analyzed.The CAR-T group exhibited better rates of complete response(48.0%vs.20.8%,P=0.046)and 1-year overall survival(74.4%vs.44.5%,P=0.044)compared with the ASCT group.Subpopulation analysis showed that patients with International Prognostic Index scores of at least 3 achieved a significantly higher objective response rate and CR rate in the CAR-T group than in the ASCT group(ORR 72.0%vs.10.0%,P=0.002,and CR 38.9%vs.0%,P=0.030,respectively).In the CAR-T group,the most common severe adverse events were cytokine release syndrome,neurotoxicity,and infection compared with cytopenia,gastrointestinal toxicity,and infection in the ASCT group.Additionally,the incidence of nonhematologic severe adverse events was markedly lower in the CAR-T group than in the ASCT group(20.7%vs.48.1%,P=0.030).Conclusion:CAR-T therapy may exhibit superior clinical outcomes in safety and efficacy over ASCT in patients with R/R B-NHL,suggesting that CAR-T may be a recommended alternative to ASCT.Howerer,prospective randomized controlled trials with more number of patients are needed for further study.