Possible Factors On Efficacy And Safety Of CAR-T Therapy In Relapsed Or Refractory Lymphomas

【Objective】To investigate the efficacy,safety and its possible factors of chimeric antigen receptor T cell therapy in treatment of relapsed or refractory lymphomas.【Methods】From March 2017 to January 2018,25 patients were enrolled into our clinical trial of Safety and Efficacy of Chimeric Antigen Receptor T Cell(CAR-T)Treating Relapsed/Refractory CD19/CD20/CD22/CD30 Postive Lymphoma(NCT03196830).Patients received conditioning treatment(low-dose cyclophosphamide,300 mg/m2 per day,and fludarabine,30 mg/m2 per day)on days-5,-4,and-3 before the administration of autologous CAR-T cells.The primary endpoint was the proportion of patients with an objective response.Secondary endpoints included duration of response(DOR),progression-free survival(PFS)and common adverse events.【Results】Among the 25 patients who were enrolled,the median age was 51 years(range,19 to 68).Diffuse large B-cell lymphoma was the underlying disease in 18 patients(72%),Angioimunoblastic T cell lymphoma in 2(8%),Hodgkin lymphoma in 2(8%),Marginal zone lymphoma in 1(4%),Burkitt lymphoma in 1(4%),Mantle cell lymphoma in 1(4%).All of the patients had stage III or IV disease;and received at least two lines of therapy.Before receive CAR-T cell therapy,6/25 patients were in complete remission(CR),5/25 were in partial remission(PR),and 14/25 were in stable disease(SD)or progressive disease(PD).At the time of the primary analysis(February 15,2018),8(61%)of 13 evaluable patients who were not in SD or PD had an objective response,with 4 achieving CR a and 4 achieving a PR,of which 5 patients had an ongoing response(from 0.5 to 10.5 months).10 of 11 evaluable patients who were in CR or PR had an ongoing response.With a median follow-up of 4.5 months,including 24 evaluable patients showed a median PFS of 3.5 months.Kaplan-Meier estimate of the PFS showed that patients who had a CR/PR after CAR-T therapy had a longer progression-free survival than those with a SD.The most common adverse events during treatment were neutropenia in 22(88%)of 25 patients,anemia in 19(76%)patients,thrombocytopenia in 18(72%)patients,hypogammaglobulin in 18(72%)patients,and pyrexia in 17(68%)patients.The cytokine release syndrome(CRS)occurred in 17 patients(68%).Most cases were of low grade(28% of grade 1 and 16% of grade 2),with 24% of grade 3 or higher(12% of grade 3,8% of grade 4,and 4% of grade 5).Grade 3 or higher neurologic events occurred in 16% of the patients.The total number of infused CAR-T cells had no significant correlation with efficacy,but it had significant correlation with grade of CRS and neurologic events.However,the peak level of CAR-T cell in peripheral blood had no significant correlation with efficacy,grade of cytokine release syndrome or neurologic events.In univariable analyses,we found the associations of peak serum interleukin-2,-6,-10,INF-γ,ferritin,C-reactive protein(CRP)concentrations and the level of lactate dehydrogenase(LDH)before therapy with the grade 3 or higher CRS,as well as peak serum interleukin-6,-10,INF-γ,CRP,ferritin and the level of LDH before therapy with grade 3 or higher neurologic events.【Conclusions】Our study demonstrates the efficacy and safety of CAR-T therapy in relapsed or refractory lymphomas.The patients who developed grade 3 or higher CRS and neurologic events had a high level of LDH before therapy and had larger total number of infused CAR-T cells,which suggest that we should improve safety by reducing tumor burden before CAR-T cells infusion or adjusting infused CAR-T cells according to the tumor burden.We found no one relapsed when patients got a remission after treating by anti-CD19 CAR-T cells combined with other targets CAR-T cells,but further studies are needed to prove whether it can prevent recurrence.Due to the small number of enrolled cases,no possible factors on efficacy have been found in our study,this needs further explore by expanding the number of study cases.