Shouval Roni, Strouse Christopher, Kim Soyoung, Oloyede Temitope, Ahmed Sairah, Awan Farrukh T, Luan Danny, Bachanova Veronika, Badar Talha, Bar Merav, Barba Pere, Beitinjaneh Amer M, Cashen Amanda, Dholaria Bhagirathbhai, Elsawy Mahmoud, Ganguly Siddhartha, Geethakumari Praveen Ramakrishnan, Greenbaum Uri, Hashmi Hamza, Hill LaQuisa C, Jain Michael D, Jain Tania, Kebriaei Partow, Kittai Adam S, Locke Frederick L, Lulla Premal D, Mead Elena, McGuirk Joseph P, Mussetti Alberto, Nishihori Taiga, Olson Amanda L, Pennisi Martina, Perales Miguel-Angel, Riedell Peter A, Saber Wael, Mirza Abu-Sayeef, Magalhaes-Silverman Margarida, Shpall Elizabeth J, Sorror Mohamed, Wudhikarn Kitsada, Turtle Cameron J, Moskop Amy, Pasquini Marcelo C
Adult BMT Service, Memorial Sloan Kettering Cancer Center, New York, New York; Weill Cornell Medicine, New York, New York.
Division of Hematology, Oncology and Blood & Marrow Transplantation, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, Iowa.
Transplant Cell Ther. 2025 Apr 25. doi: 10.1016/j.jtct.2025.03.011.
Chimeric antigen receptor T cell (CAR-T) therapy is an effective treatment for relapsed-refractory large B-cell lymphoma (LBCL). However, toxicities, particularly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), remain significant concerns. Analyze temporal trends, risk factors, and associations between these toxicities and their severity. In this registry study by the Center for International Blood and Marrow Transplant Research, we studied CRS and ICANS in 1916 LBCL patients treated with commercial CAR-T therapies (axicabtagene ciloleucel 74.9%, tisagenlecleucel 25.1%) between 2018 and 2020. Outcomes include development of CRS/ICANS, timing and severity according to ASTC grading, overall survival (OS). Risk factors were assessed using Cox proportional hazards model. Among patients developing CRS (75.2%), 11.3% had grade ≥3 CRS. Among patients developing ICANS (43.5%), 47.7% had grade ≥3 ICANS. Among patients developing CRS, severe CRS rates decreased from 14.0% in 2018 to 9.2% in 2020 (P< .01). However, the proportion of severe ICANS in patients who developed ICANS remained statistically unchanged (41.5% in 2018 to 53.7% in 2020, P= .10). CRS and ICANS were correlated: 57.1% of patients with CRS also experienced ICANS, and CRS was reported in 97.5% of ICANS cases, suggesting a potential continuum between toxicities. Axicabtagene ciloleucel was associated with higher risk of any grade CRS (OR, 4.6; 95% CI, 3.65 to 5.81) and ICANS (OR, 5.85; 95% CI, 4.48 to 7.64) as well as early and severe forms of both complications. Older age, lower performance status, and elevated lactate dehydrogenase levels prior to infusion also variably predicted these toxicities. In a landmark analysis starting 30 days postinfusion, patients with severe CRS or severe ICANS had shorter OS compared to those without these toxicities. High grades of CRS improved over time likely related to earlier intervention, development of ICANS is intrinsically related with CRS. These findings underscore the need for effective strategies to mitigate these toxicities and improve CAR-T safety.
嵌合抗原受体T细胞（CAR-T）疗法是复发难治性大B细胞淋巴瘤（LBCL）的一种有效治疗方法。然而，毒性反应，尤其是细胞因子释放综合征（CRS）和免疫效应细胞相关神经毒性综合征（ICANS），仍然是重大问题。分析这些毒性反应的时间趋势、危险因素以及它们之间的关联和严重程度。在这项由国际血液和骨髓移植研究中心开展的注册研究中，我们研究了2018年至2020年间接受商业CAR-T疗法（阿基仑赛74.9%，替雷利珠单抗25.1%）治疗的1916例LBCL患者中的CRS和ICANS。观察指标包括CRS/ICANS的发生情况、根据美国国立综合癌症网络（NCCN）分级的发生时间和严重程度、总生存期（OS）。使用Cox比例风险模型评估危险因素。在发生CRS的患者中（75.2%），11.3%为≥3级CRS。在发生ICANS的患者中（43.5%），47.7%为≥3级ICANS。在发生CRS的患者中，严重CRS发生率从2018年的14.0%降至2020年的9.2%（P<0.01）。然而，发生ICANS的患者中严重ICANS的比例在统计学上保持不变（2018年为41.5%，2020年为53.7%，P=0.10）。CRS和ICANS相关：57.1%的CRS患者也经历了ICANS，97.5%的ICANS病例报告了CRS，提示毒性反应之间可能存在连续性。阿基仑赛与任何级别的CRS（比值比[OR]，4.6；95%置信区间[CI]，3.65至5.81）和ICANS（OR，5.85；95%CI，4.48至7.64）以及两种并发症的早期和严重形式的风险较高相关。年龄较大、体能状态较低以及输注前乳酸脱氢酶水平升高也不同程度地预测了这些毒性反应。在输注后30天开始的一项标志性分析中，与没有这些毒性反应的患者相比，发生严重CRS或严重ICANS的患者OS较短。随着时间推移，高级别CRS有所改善，可能与早期干预有关，ICANS的发生与CRS内在相关。这些发现强调了需要有效的策略来减轻这些毒性反应并提高CAR-T的安全性。
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