Background: Anti-CD19 chimeric antigen receptor (CAR) T-cell is a promising therapy for patients with relapsed/refractory (R/R) large B-cell lymphoma. 29~37% of patients can achieve sustained complete remission (CR) after anti-CD19 CAR T-cell infusion, which means that approximately two-thirds of patients will eventually progress and have extremely poor survival. We conducted a pilot study to explore the safety and efficacy of CNCT19 (a second-generation anti-CD19 CAR T-cell) cellular immunotherapy in conjunction with high-dose chemotherapy and autologous stem-cell transplantation (HDT/ASCT). The preliminary results of the first 6 patients had been reported at the 61st ASH Meeting (Liu et al., 784a). Here we reported the updated enrollment, safety, efficacy, and follow-up of this study. This trial was registered at www.chictr.org.cn as ChiCTR1900025419.
Methods: Patients with large B-cell lymphoma refractory to primary or salvage therapy were eligible for this study. All patients must have received rituximab and anthracycline-containing treatment during their prior therapy. Conditioning regimen included GBC/M (gemcitabine, busulfan, and cyclophosphamide/melphalan) and BEAM (carmustine, etoposide, cytarabine, and melphalan, administered in one patient), and CNCT19 was infused on day +2, +3 or +4 following autologous stem-cell infusion.
Results: Between January 2018 and May 2020, 13 patients were enrolled. The median age was 48 years (range, 29~ 64 years), and there were 7 males. Diagnosis of lymphoma subtypes included diffuse large B-cell lymphoma (n=10), high-grade B-cell lymphoma with MYC, BCL2, and BCL6 rearrangement (n=1), primary mediastinal large B-cell lymphoma (n=1) and transformed follicular lymphoma (n=1). The patients received a median of 3 (range, 2~4) lines of prior therapy and 76.9% had disease that was resistant to last-line therapy. The median dose of infused stem cells was 2.54×106 per kilogram of body weight (range, 1.77~8.7×106) and the median dose of infused CNCT19 cells was 2×106 per kilogram of body weight (range, 1.7~4×106). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to the ASTCT criteria. After CNCT19 infusion, 92.3% of patients experienced grade 1 CRS, and no one experienced grade 2 or higher CRS. The median time after CNCT19 infusion until the onset of CRS was 1.5 days (range, 0~3), and the median time until resolution was 8 days (range, 6~10). Seven patients (53.8%) received tocilizumab and two patients (15.3%) received glucocorticoids for the management of CRS. ICANS occurred in two patients on day 5 and day 6 after CNCT19 infusion, respectively. Both of the ICANS were grade 4 and resolved after glucocorticoids treatment. The median times to neutrophil and platelet engraftment were 11 days (range, 8~32) and 17 days (range, 8~265), respectively. Ten patients were followed up for 3 or more months and evaluable for response. Eight of 10 patients achieved complete remission (CR), and the best overall response rate (ORR) and CR rate were both 80%. With a median follow-up of 11 months (range, 3~31) after CNCT19 infusion, the CR rate at 3 months and 6 months were 70% and 62.5%, respectively. Median progression-free survival (PFS) and overall survival (OS) were not reached. The estimated proportion of PFS and OS at 12 months was 66.7% and 77.1%, respectively.
Conclusion: CNCT19 infusion following HDT/ASCT could be safely administered in R/R large B-cell lymphoma patients. More patients achieved sustained remission compared with those who received anti-CD19 CAR T-cell therapy alone. The preliminary results of this pilot study support further investigation of the combination of CAR T cellular immunotherapy with HDT/ASCT.
Disclosures
Lv: Juventas Cell Therapy Ltd.: Current Employment.
Efficacy and Safety of CAR-T Therapy with Safety Switch Targeting Bcma for Patients with Relapsed/Refractory Multiple Myeloma in a Phase 1 Clinical Study