Bone Marrow Transplantation and Cellular Therapies Program, Division of Hematology, The Ohio State University James Cancer Hospital, Columbus, Ohio, USA.
Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
J Immunother Cancer. 2021 Aug;9(8). doi: 10.1136/jitc-2020-002303.
Chimeric antigen receptor T-cell (CAR-T) infusion is associated with early toxicity. Yet, whether early toxicity development holds ramifications for long-term outcomes is unknown.
From a large cohort of consecutive adult patients treated with CAR-T therapies for relapsed or refractory lymphomas from 2016 to 2019, we assessed progression-free survival (PFS), by toxicity development (cytokine release syndrome (CRS), neurotoxicity, or cardiotoxicity]. We also assessed the relationship of toxicity development to objective disease response, and overall survival (OS). Multivariable regression was utilized to evaluate relationships between standard clinical and laboratory measures and disease outcomes. Differences in outcomes, by toxicity status, were also assessed via 30-day landmark analysis. Furthermore, we assessed the effects of early anti-CRS toxicity therapy use (at ≤grade 2 toxicity) on maximum toxicity grade observed, and long-term disease outcomes (PFS and OS).
Overall, from 102 CAR-T-treated patients, 90 were identified as treated with single-agent therapy, of which 88.9% developed toxicity (80 CRS, 41 neurotoxicity, and 17 cardiotoxicity), including 28.9% with high-grade (≥3) events. The most common manifestations were hypotension at 96.6% and fever at 94.8%. Among patients with cardiac events, there was a non-significant trend toward a higher prevalence of concurrent or preceding high-grade (≥3) CRS. 50.0% required tocilizumab or corticosteroids. The median time to toxicity was 3 days; high grade CRS development was associated with cardiac and neurotoxicity. In multivariable regression, accounting for disease severity and traditional predictors of disease response, moderate (maximum grade 2) CRS development was associated with higher complete response at 1 year (HR: 2.34; p=0.07), and longer PFS (HR: 0.41; p=0.02, in landmark analysis), and OS (HR: 0.43; p=0.03). Among those with CRS, relative blood pressure (HR: 2.25; p=0.004), respectively, also associated with improved PFS. There was no difference in disease outcomes, or maximum toxicity grade (CRS, neurotoxicity, or cardiotoxicity) observed, based on the presence or absence of the use of early CRS-directed therapies.
Among adult lymphoma patients, moderate toxicity manifest as grade 2 CRS after CAR-T infusion may associate with favorable clinical outcomes. Further studies are needed to confirm these findings.
嵌合抗原受体 T 细胞（CAR-T）输注与早期毒性有关。然而，早期毒性的发展是否会对长期结果产生影响尚不清楚。
从 2016 年至 2019 年接受 CAR-T 治疗的复发性或难治性淋巴瘤的大量连续成年患者队列中，我们评估了无进展生存期（PFS）与毒性发展（细胞因子释放综合征（CRS）、神经毒性或心脏毒性）之间的关系。我们还评估了毒性发展与客观疾病反应和总生存期（OS）之间的关系。利用多变量回归评估标准临床和实验室指标与疾病结局之间的关系。通过 30 天的标志分析，还评估了毒性状态差异对结局的影响。此外，我们评估了早期抗 CRS 毒性治疗（≤2 级毒性）对观察到的最大毒性分级和长期疾病结局（PFS 和 OS）的影响。
总体而言，在 102 名接受 CAR-T 治疗的患者中，有 90 名被确定为接受单药治疗，其中 88.9%发生了毒性（80 例 CRS、41 例神经毒性和 17 例心脏毒性），包括 28.9%的高等级（≥3 级）事件。最常见的表现是低血压 96.6%和发热 94.8%。在发生心脏事件的患者中，同时或先前存在高等级（≥3 级）CRS 的比例存在非显著趋势。50.0%需要使用托珠单抗或皮质类固醇。毒性发生的中位时间为 3 天；高等级 CRS 发展与心脏和神经毒性相关。在多变量回归中，考虑到疾病严重程度和疾病反应的传统预测因素，中度（最大等级 2 级）CRS 发展与 1 年时更高的完全缓解率相关（HR：2.34；p=0.07），更长的 PFS（HR：0.41；p=0.02，在标志分析中）和 OS（HR：0.43；p=0.03）。在 CRS 患者中，相对血压（HR：2.25；p=0.004）也与 PFS 改善相关。根据早期 CRS 靶向治疗的使用与否，疾病结局或观察到的最大毒性分级（CRS、神经毒性或心脏毒性）没有差异。
在成人淋巴瘤患者中，CAR-T 输注后表现为 2 级 CRS 的中度毒性可能与良好的临床结局相关。需要进一步的研究来证实这些发现。
