Safety and Efficacy of Bicistronic CD19/CD22 CAR T Cell Therapy in Childhood B Cell Acute Lymphoblastic Leukemia
Authors: Wan Xinyu , Li Wenjie , Cai Jiaoyang , Yang Xiaomin , Yang Liu , Yang Jing , Wang Tianyi , Li Yue , Zhou Zichao , Lu Xiaoxi , Xie Zhiwei , Shao Jingbo , Su Meng , Zhang Jing , Qian Juan , An Kang , Luo Chengjuan , Ding Lixia , Song Lili , Shi Wenhua , Lu Jun , Cheng Cheng , Tang Yanjing , Luo Xuefeng , Li Jingyu , Hua Jian , Li Benshang , Zhang Hua , Pui Ching-Hon 
Published: December 2024

Background: Our previous study on co-administration of CD19- and CD22-CAR T cell therapy demonstrated durable remission in children with relapsed or refractory B-lineage acute lymphoblastic leukemia (B-ALL) (Wang et al. J Clin Oncol 2023; 41:1670-83). To further improve outcomes, we developed a bicistronic CD19/CD22 CAR (B019) aimed at enhancing event-free survival (EFS) and overall survival (OS) in the treatment of relapsed or refractory childhood B-ALL. The primary objectives were to assess EFS, OS, and safety of bicistronic CD19/CD22 CAR T cell in the treatment of patients with relapsed or refractory B-ALL with or without consolidative allogeneic stem cell transplant after CAR-T therapy.
Methods: In this investigator-initiated trial using a new bicistronic construct, we enrolled 318 evaluable patients aged ≤ 18 years between January 2022 and April 2024. Median follow-up for patients who were alive at the time of analysis was 13.9 months (IQR 9.0-22.4). Throughout the trial, we evaluated the patients' clinical responses, side effects, and the expansion and persistence of CAR-T cells.
Results: The response rate (CR+CRi) was 99.1% among the 318 patients, all of whom were MRD negative (&lt;0.01%). The 12-month EFS and OS rates for 267 patients with isolated or combined hematologic relapse were 72.4% and 91.4% respectively. Consolidative transplantation was associated with favorable outcomes and was performed in 37 of 267 patients (13.9%). The 12-month EFS was 86.0% for those who received transplantation versus 71.4% for those who did not (p=0.04). However, regarding OS, transplantation did not provide a significant benefit, with 12-month OS rates of 94.2% for transplanted patients and 92.2% for non-transplanted patients (p=0.86). Among the 230 patients who did not undergo transplantation after CAR-T cell therapy, 69 patients relapsed with different loss of the antigens (45 CD19+/CD22+, 23 CD19-/CD22+, and 1 CD19-/CD22-). Most were treated with a second salvaged bicistronic CD19/CD22 CAR-T cell therapy, achieving complete remission again in 35 of 36 (97.2%) CD19+/CD22+ patients and 14 of 21 (66.7%) CD19-/CD22+ patients. Among the 49 patients who achieved complete remission, 42 (85.7%%) were still alive in remission for (1.0 to 22.1 months), 30 of whom received consolidative transplantation. For the 20 patients with isolated testicular relapse, the 12-month EFS and OS rates were 84.7% and 100.0%, respectively. For the 29 patients with isolated CNS relapse, the 12-month EFS and OS rates were 71.0% and 96.2%, respectively. Cytokine release syndrome developed in all patients, with grade III-IV CRS occurring in 48.7% (155 patients), resulting in two deaths. CAR T-cell neurotoxicity was observed in 52 patients (16.4%).
Conclusions: Bicistronic CD19/CD22-targeted CAR-T cell therapy is a safe and effective regimen which achieved durable remission in children with relapsed or refractory B-ALL, including those with isolated or combined extramedullary relapse.