Department of Medicine V, University Hospital and Medical Faculty Heidelberg, Heidelberg, Baden-Württemberg, Germany
Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center, Heidelberg, Baden-Württemberg, Germany.
J Immunother Cancer. 2024 Oct 7;12(10):e009220. doi: 10.1136/jitc-2024-009220.
Chimeric antigen receptor (CAR) T-cell therapy has demonstrated significant benefits in the treatment of relapsed/refractory multiple myeloma (RRMM). However, these outcomes can be compromised by severe complications, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS) and immune effector cell-associated hematotoxicity (ICAHT), predisposing for life-threatening infections.
This retrospective observational study examined a total of 129 patients with RRMM who had received idecabtagene vicleucel (ide-cel) at two major myeloma centers in Germany and one center in the USA to assess the Endothelial Activation and Stress Index (EASIX) as a risk marker for an unfavorable clinical course and outcome after CAR T-cell therapy. EASIX is calculated by lactate dehydrogenase (U/L) × creatinine (mg/dL) / platelets (10 cells/L) and was determined before lymphodepletion (baseline) and at the day of CAR T-cell infusion (day 0). The analysis was extended to EASIX derivatives and the CAR-HEMATOTOX score.
An elevated baseline EASIX (>median) was identified as a risk marker for severe late ICAHT, manifesting with an impaired hematopoietic reconstitution and pronounced cytopenias during the late post-CAR-T period. Patients with high EASIX levels (>upper quartile) were particularly at risk, as evidenced by an increased rate of an aplastic phenotype of neutrophil recovery, severe late-onset infections and ICANS. Finally, we found associations between baseline EASIX and an inferior progression-free and overall survival. Moreover, the EASIX at day 0 also demonstrated potential to serve as a risk marker for post-CAR-T complications and adverse outcomes.
In conclusion, EASIX aids in risk stratification at clinically relevant time points prior to CAR T-cell therapy with ide-cel. Increased EASIX levels might help clinicians to identify vulnerable patients to adapt peri-CAR-T management at an early stage.
嵌合抗原受体 (CAR) T 细胞疗法在治疗复发/难治性多发性骨髓瘤 (RRMM) 方面显示出显著的益处。然而，这些结果可能会因严重的并发症而受到影响，包括细胞因子释放综合征、免疫效应细胞相关神经毒性综合征 (ICANS) 和免疫效应细胞相关血液毒性 (ICAHT)，从而导致危及生命的感染。
本回顾性观察性研究共纳入了在德国的两家主要骨髓瘤中心和美国的一家中心接受 idecabtagene vicleucel (ide-cel) 治疗的 129 例 RRMM 患者，以评估内皮激活和应激指数 (EASIX) 作为 CAR T 细胞治疗后不良临床过程和结局的风险标志物。EASIX 通过乳酸脱氢酶 (U/L) × 肌酐 (mg/dL) / 血小板 (10 细胞/L) 计算得出，在淋巴细胞耗竭前 (基线) 和 CAR T 细胞输注日 (第 0 天) 进行测定。该分析扩展到 EASIX 衍生物和 CAR-HEMATOTOX 评分。
基线 EASIX 升高 (>中位数) 被确定为严重迟发性 ICAHT 的风险标志物，表现为 CAR-T 后晚期造血重建受损和明显的血细胞减少。EASIX 水平较高 (>上四分位数) 的患者风险尤其高，表现为中性粒细胞恢复的再生障碍表型、严重迟发性感染和 ICANS 的发生率增加。最后，我们发现基线 EASIX 与无进展生存期和总生存期的降低有关。此外，EASIX 在第 0 天也显示出作为 CAR-T 后并发症和不良结局的风险标志物的潜力。
总之，EASIX 在 ide-cel 进行 CAR T 细胞治疗之前的临床相关时间点有助于进行风险分层。EASIX 水平升高可能有助于临床医生识别易受影响的患者，以便在早期阶段调整 CAR-T 期间的管理。
