Long-Term Activity of Combining CNCT19 with HDT/ASCT in Refractory Large B-Cell Lymphoma: Two-Year Follow-up of a Prospective Phase 1/2 Clinical Trial

Background: We have previously reported the preliminary results of a phase 1/2 clinical trial of administrating CNCT19 (a second-generation anti-CD19 CAR T-cell) following high-dose chemotherapy and autologous stem-cell transplantation (HDT/ASCT) in large B-cell lymphoma (LBCL) patients with diseases refractory to first-line and/or subsequent lines of chemotherapy. Eight of 10 (80%) patients achieved complete response (CR), and the estimated proportion of progression-free survival (PFS) and overall survival (OS) at 12 months was 66.7% and 77.1%, respectively (Wei liu et al. ASH 2019, 2020). Here we reported this study's updated enrollment, efficacy, and follow-up. This trial was registered at www.chictr.org.cn as ChiCTR1900025419. Methods: Patients with LBCL with a history of refractory to first-line rituximab-containing anthracycline-based chemotherapy and/or subsequent salvage chemotherapy were eligible for this study. Conditioning regimen of GBC/M (Gemcitabine 600 mg/m2/h, infused for 3 hours with loading bolus of 75 mg/m2, day -7, -3, busulfan 105 mg/m2, day -7 until -5, cyclophosphamide 45mg/kg or melphalan 60 mg/m2, day -3, -2) was administered once the CNCT19 product was available. Autologous stem cells were infused on day 0, and CNCT19 cells were infused on day +3 (±1 day). Cytokine release syndrome (CRS) and CAR-T-cell-related encephalopathy syndrome (CRES) were graded according to the CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group criteria. Results: From December 2017 through May 2021, 21 subjects were consecutively enrolled in this study. CNCT19 cells were successfully manufactured for 20 subjects and administered to 18 subjects. The median age was 44 (range 23 to 64), and 56% were male. Patients included 11 (67%) with diffuse large B-cell lymphoma (not otherwise specified), 4 (22%) with high-grade B-cell lymphoma with MYC, BCL2 and/or BCL6 rearrangement, 2 (11%) with primary mediastinal large B-cell lymphoma and 1 (6%) with transformed follicular lymphoma. The median number of lines of prior therapy was 3 (range, 2 to 5). Eighty-nine percent of patients had a history of refractory to first-line immunochemotherapy of R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, prednisone) or R-DA-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and adriamycin), and 72% were refractory to subsequent platinum-based salvage therapy. TP53 deletion and/or mutation were detected in 7 of 11 (64%) patients. The median dose of infused stem cells was 2.6×106 (range, 1.8~8.7×106) per kilogram of body weight and the median dose of infused CNCT19 cells was 2×106 (range, 1.6~4.0×106) per kilogram of body weight. The CRS occurred in 16 patients (89%), and all were low grades (grade 1, 83%; grade 2, 6%). CRES occurred in two patients on day 5 and day 6 after CNCT19 infusion, respectively. Both of the ICANS were grade 4 and resolved completely after glucocorticoids treatment. We did not observe any unexpected toxicity or treatment-related death throughout the therapy. The median times to neutrophil and platelet recovery were ten days (range, 8 to 30 days) and 16.5 days (range, 8 to 265 days) after stem cells reinfusion, respectively. As of July 26, 2022, the median follow-up from CNCT19 infusion to the data-cutoff date was 28.2 (95% CI 16.9-39.1) months. The best overall response rate was 94.4%, with a best CR rate of 72.2%. The median PFS, duration of response (DOR), disease-free survival (DFS) and OS were not reached, and the probability of 2-year PFS, DOR, DFS and OS were 59.3% (95% CI 32.5%-78.4%), 63.5% (95% CI 35.9%-81.8%), 74.1% (95% CI 39.1%-90.9%) and 64.2% (95% CI 36.2%-82.4%), respectively. Of the patients who were in durable response at three months or six months post CNCT19 infusion, 66.7% and 83.3% were in ongoing response at the date of data cutoff, respectively. Conclusions: CNCT19 could be safely administered following HDT/ASCT in patients with relapsed or refractory LBCL. The strategy of combining CAR T-cell therapy with HDT/ASCT might improve response rate and prolong survival compared to CAR T-cell therapy alone.