Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA; Center for Cellular Immunotherapies and Cellular Therapy and Transplant, University of Pennsylvania, Philadelphia, USA; Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, USA.
Medical University of Vienna, Division of Hematology and Hemostaseology, Department of Medicine I Wien, Comprehensive Cancer Center, Vienna, Austria.
Ann Oncol. 2022 Sep;33(9):916-928. doi: 10.1016/j.annonc.2022.05.521. Epub 2022 Jun 9.
Anti-CD19 chimeric antigen receptor T-cell immunotherapy (CAR-T) is now a standard treatment of relapsed or refractory B-cell non-Hodgkin lymphomas; however, a significant portion of patients do not respond to CAR-T and/or experience toxicities. Lymphodepleting chemotherapy is a critical component of CAR-T that enhances CAR-T-cell engraftment, expansion, cytotoxicity, and persistence. We hypothesized that the lymphodepletion regimen might affect the safety and efficacy of CAR-T.
We compared the safety and efficacy of lymphodepletion using either fludarabine/cyclophosphamide (n = 42) or bendamustine (n = 90) before tisagenlecleucel in two cohorts of patients with relapsed or refractory large B-cell lymphomas treated consecutively at three academic institutions in the United States (University of Pennsylvania, n = 90; Oregon Health & Science University, n = 35) and Europe (University of Vienna, n = 7). Response was assessed using the Lugano 2014 criteria and toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and, when possible, the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading.
Fludarabine/cyclophosphamide led to more profound lymphocytopenia after tisagenlecleucel infusion compared with bendamustine, although the efficacy of tisagenlecleucel was similar between the two groups. We observed significant differences, however, in the frequency and severity of adverse events. In particular, patients treated with bendamustine had lower rates of cytokine release syndrome and neurotoxicity. In addition, higher rates of hematological toxicities were observed in patients receiving fludarabine/cyclophosphamide. Bendamustine-treated patients had higher nadir neutrophil counts, hemoglobin levels, and platelet counts, as well as a shorter time to blood count recovery, and received fewer platelet and red cell transfusions. Fewer episodes of infection, neutropenic fever, and post-infusion hospitalization were observed in the bendamustine cohort compared with patients receiving fludarabine/cyclophosphamide.
Bendamustine for lymphodepletion before tisagenlecleucel has efficacy similar to fludarabine/cyclophosphamide with reduced toxicities, including cytokine release syndrome, neurotoxicity, infectious and hematological toxicities, as well as reduced hospital utilization.
嵌合抗原受体 T 细胞免疫疗法（CAR-T）现已成为治疗复发或难治性 B 细胞非霍奇金淋巴瘤的标准治疗方法；然而，很大一部分患者对 CAR-T 无反应和/或出现毒性。淋巴细胞耗竭化疗是 CAR-T 的关键组成部分，可增强 CAR-T 细胞的植入、扩增、细胞毒性和持久性。我们假设淋巴细胞耗竭方案可能会影响 CAR-T 的安全性和疗效。
我们比较了在美国三所学术机构（宾夕法尼亚大学，n=90；俄勒冈健康与科学大学，n=35）和欧洲（维也纳大学，n=7）连续治疗的复发或难治性大 B 细胞淋巴瘤患者的两个队列中，分别使用氟达拉滨/环磷酰胺（n=42）或苯达莫司汀（n=90）进行淋巴细胞耗竭的安全性和疗效。使用卢加诺 2014 标准评估缓解，使用不良事件常用术语标准（CTCAE）版本 5.0 评估毒性，在可能的情况下，使用美国移植和细胞治疗协会（ASTCT）共识分级评估毒性。
与苯达莫司汀相比，氟达拉滨/环磷酰胺在输注 tisagenlecleucel 后导致更严重的淋巴细胞减少，但两组 tisagenlecleucel 的疗效相似。然而，我们观察到不良反应的频率和严重程度存在显著差异。特别是，接受苯达莫司汀治疗的患者细胞因子释放综合征和神经毒性的发生率较低。此外，接受氟达拉滨/环磷酰胺治疗的患者出现血液学毒性的比例较高。接受氟达拉滨/环磷酰胺治疗的患者的中性粒细胞计数、血红蛋白水平和血小板计数最低，血液计数恢复时间较短，血小板和红细胞输注较少。与接受氟达拉滨/环磷酰胺治疗的患者相比，接受苯达莫司汀治疗的患者感染、中性粒细胞减少性发热和输注后住院的发作次数较少。
在接受 tisagenlecleucel 治疗前，用苯达莫司汀进行淋巴细胞耗竭与氟达拉滨/环磷酰胺具有相似的疗效，但毒性降低，包括细胞因子释放综合征、神经毒性、感染和血液学毒性，以及降低了医院利用率。
