Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
Transplant Cell Ther. 2022 Feb;28(2):72.e1-72.e8. doi: 10.1016/j.jtct.2021.11.014. Epub 2021 Nov 28.
Chimeric antigen receptor (CAR) T cells achieve response and durable remission in patients with relapsed/refractory (R/R) B cell malignancies. Following collection of patient T cells, chemotherapy ("bridging chemotherapy") is utilized during the manufacture of CAR T cells. However, the optimal bridging chemotherapy has yet to be defined. Our objective in this study was to report clinical outcomes following bridging chemotherapy in a cohort of pediatric/young adult patients with R/R B cell acute lymphoblastic leukemia (B-ALL) treated with CAR T cell therapy. This retrospective study included patients enrolled on clinical trial NCT01860937 or referred to Memorial Sloan Kettering Cancer Center for commercial CAR T cell therapy (tisagenlecleucel). Bridging chemotherapy (given after T cell collection and before CAR T cell infusion) was defined as high intensity if myelosuppression was expected for >7 days. Outcome comparison analyses were performed in high-intensity versus low-intensity bridging chemotherapy, 1 cycle versus ≥2 cycles of bridging chemotherapy, disease burden at the start of bridging chemotherapy, disease burden at the start of bridging chemotherapy with chemotherapy intensity, tumor debulking by bridging chemotherapy, and disease burden pre-lymphodepleting chemotherapy (LDC) for CAR T cell treatment. The outcomes of this analysis showed that the incidence of grade ≥3 infection was significantly higher (94% versus 56%; P = .019) and overall survival (OS) was significantly lower (hazard ratio, 3.73; 95% confidence interval, 1.39 to 9.97; P = .006) in patients who received ≥2 cycles versus 1 cycle of bridging chemotherapy. No difference in incidence was found for cytokine release syndrome (P > .99) or neurotoxicity/immune effector cell-associated neurotoxicity syndrome (P = .70). Disease burden at the start of bridging chemotherapy, disease burden prior to LDC, and tumor debulking by bridging chemotherapy also did not significantly affect outcomes after CAR T cell therapy in this cohort. In this study, patients receiving ≥2 cycles of bridging chemotherapy had higher rates of infection and lower OS but no difference in CAR-specific toxicity. Clinicians should carefully consider the use of additional cycles of chemotherapy during the bridging period as it delays treatment with CAR T cells and increases the risk of infectious complications. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
嵌合抗原受体 (CAR) T 细胞可使复发/难治性 (R/R) B 细胞恶性肿瘤患者获得缓解和持久缓解。在收集患者 T 细胞后，CAR T 细胞的制备过程中会使用化疗（“桥接化疗”）。然而，最佳的桥接化疗方案仍有待确定。我们在这项研究中的目的是报告接受 CAR T 细胞治疗的 R/R B 细胞急性淋巴细胞白血病 (B-ALL) 儿科/年轻成人患者队列中，桥接化疗后的临床结果。这项回顾性研究包括登记在临床试验 NCT01860937 中的患者或因商业 CAR T 细胞治疗转诊至 Memorial Sloan Kettering 癌症中心的患者。桥接化疗（在 T 细胞采集后和 CAR T 细胞输注前给予）如果预期骨髓抑制超过 7 天，则定义为高强度。在高强度与低强度桥接化疗、1 个周期与≥2 个周期桥接化疗、桥接化疗开始时疾病负担、桥接化疗开始时化疗强度与疾病负担、桥接化疗肿瘤减瘤作用以及 CAR T 细胞治疗前淋巴细胞耗竭化疗（LDC）前疾病负担方面进行了疗效比较分析。该分析的结果表明，接受≥2 个周期桥接化疗的患者发生≥3 级感染的发生率显著更高（94%比 56%；P =.019），总生存率（OS）显著更低（风险比，3.73；95%置信区间，1.39 至 9.97；P =.006）。细胞因子释放综合征（P>.99）或神经毒性/免疫效应细胞相关神经毒性综合征（P =.70）的发生率无差异。桥接化疗开始时的疾病负担、LDC 前的疾病负担以及桥接化疗的肿瘤减瘤作用也未显著影响该队列中 CAR T 细胞治疗后的结果。在这项研究中，接受≥2 个周期桥接化疗的患者感染发生率更高，OS 更低，但 CAR 特异性毒性无差异。临床医生应谨慎考虑在桥接期使用额外周期的化疗，因为这会延迟 CAR T 细胞治疗并增加感染并发症的风险。
