Xinyu Wan, Yanjing Tang, Jiaoyang Cai, Lili Song, Tianyi Wang, Wenjie Li, Liu Yang, Xiang Wang, Chengjuan Luo, Hua Zhu, Kang An, Meng Su, Jing Zhang, Jing Yang, Wenhua Shi, Chengming Fei, Weidong Shen, Rujun Jia, Xiaomin Yang, Junqian Tang, Junxian Wu, Jiakang Gu, Jiayi Mo, Jun Huang, Yue Li, Geyao Zhou, Lixia Ding, Jianwei Liang, Jun Wang, Zichao Zhou, Xiaodong Wang, Qing Cao, Jian Zhang, Hong Ren, Juan Qian, Peifang Xiao, Hailong He, Hui Jiang, Shaoyan Hu, Ningling Wang, Yiping Zhu, Jingyan Tang, Longjun Gu, Jun Yang, Cheng Cheng, Jing Chen, Wenxia Kuai, Xiaoxi Lu, Jingbo Shao, Zhiwei Xie, Jun Lu, Wing Leung, Benshang Li, Ching-Hon Pui
In this nonrandomized clinical trial, bicistronic CD19/CD22 CAR T-cell therapy induced high rates of minimal residual disease-negative remission, with durable EFS in pediatric B-ALL. These findings support further evaluation in prospective trials.
IMPORTANCE: CD19-directed chimeric antigen receptor (CAR) T-cell therapy induces high remission rates in relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), but relapse, which is often due to antigen loss, remains a major challenge. Dual-targeting CD19/CD22 CAR T-cell strategies may be associated with reduced antigen-negative relapse and improved remission durability.
OBJECTIVE: To evaluate the safety and efficacy of bicistronic CD19/CD22 CAR T-cell therapy in pediatric patients with relapsed or refractory B-ALL.
DESIGN, SETTING, AND PARTICIPANTS: This open-label, multicenter, phase 2 nonrandomized clinical trial enrolled pediatric patients with B-ALL at 5 major medical centers in China from January 2022 to August 2024, with a data cutoff of February 28, 2026. Median follow-up was 35.7 months (IQR, 29.8-41.0 months). Of 346 screened, 38 (11.0%) were excluded and 308 (89.0%) were eligible. A safety run-in established the recommended phase 2 dose, followed by cohorts with refractory disease, hematologic relapse, or isolated extramedullary relapse.
INTERVENTION: CD3-positive T cells were activated and transduced with a bicistronic lentiviral vector that encoded anti-CD19 and anti-CD22 CARs, then infused fresh after 5 to 7 days in culture. Lymphodepleting chemotherapy included fludarabine and cyclophosphamide. Consolidative transplant was reserved for patients with KMT2A- or ZNF384-rearranged acute lymphoblastic leukemia.
MAIN OUTCOMES AND MEASURES: Primary end points were safety, recommended phase 2 dose, event-free survival (EFS), and toxic effects of bicistronic CAR-T therapy in relapsed or refractory B-ALL, with or without transplant.
RESULTS: Among 261 patients (98 girls [37.6%]; mean [SD] age, 8.2 [3.8] years) with relapsed or refractory disease, 259 (99.2%) achieved complete remission with negative minimal residual disease. EFS was 70.9% (95% CI, 65.6%-76.7%) at 12 months, 63.2% (95% CI, 57.6%-69.4%) at 24 months, and 61.7% (95% CI, 55.9%-68.0%) at 36 months. Consolidative transplant was associated with improved EFS; the 24-month EFS was 57.9% (95% CI, 51.6%-65.0%) in patients without a transplant vs 85.7% (95% CI, 76.5%-96.1%) in patients with a transplant (P = .004). In 20 patients with isolated central nervous system relapse and 20 with testicular relapse, 24-month EFS was 60.0% (95% CI, 43.6%-82.6%) and 80.0% (95% CI, 64.3%-99.6%), respectively. Grade 3 to 4 cytokine release syndrome occurred in 129 patients (49.4%), and immune effector cell-associated neurotoxic effects occurred in 34 patients (13.0%).
CONCLUSIONS AND RELEVANCE: In this nonrandomized clinical trial, bicistronic CD19/CD22 CAR T-cell therapy induced high rates of minimal residual disease-negative remission, with durable EFS in pediatric B-ALL. These findings support further evaluation in prospective trials.
TRIAL REGISTRATION: Chinese Clinical Trial Register Identifier: ChiCTR2000032211.