Korell Felix, Entenmann Lukas, Romann Sebastian, Giannitsis Evangelos, Schmitt Anita, Müller-Tidow Carsten, Frey Norbert, Dreger Peter, Schmitt Michael, Lehmann Lorenz H
Department of Hematology, Oncology & Rheumatology, University Hospital Heidelberg, Heidelberg, Germany.
Department of Cardiology, Angiology & Pulmonology, University Hospital Heidelberg, Heidelberg, Germany.
EClinicalMedicine. 2024 Feb 27;69:102504. doi: 10.1016/j.eclinm.2024.102504. eCollection 2024 Mar.
Assessment of cardiovascular risk is critical for patients with cancer. Previous retrospective studies suggest potential cardiotoxicity of CAR T cell therapies. We aimed to prospectively assess cardiotoxicity and the predictive value of cardiac biomarkers and classical risk factors (age, cardiac function, diabetes, arterial hypertension, smoking) for cardiac events and all-cause mortality (ACM).
In this prospective cohort study, all patients treated with CAR T cell constructs (axi-cel, tisa-cel, brexu-cel, ide-cel, or the 3rd generation CAR HD-CAR-1) from Oct 1, 2018, to Sept 30, 2022 at the University Hospital Heidelberg were included. Surveillance included cardiac assessment with biomarkers (high-sensitive Troponin T (hs-cTnT), N-terminal brain natriuretic peptide (NT-proBNP)), 12-lead-ECG, and 2D echocardiography. ACM was defined as the primary study endpoint, while cardiotoxicity, defined by clinical syndromes of heart failure or decline in ejection fraction, served as a secondary endpoint.
Overall, 137 patients (median age 60, range 20-83, IQR 16), were included in the study. 46 patients died during the follow up period (median 0.75 years, range 0.02-4.33, IQR 0.89) 57 month, with a median survival of 0.57 years (range 0.03-2.38 years, IQR 0.79). A septal wall thickness above 11 mm (HR 2.48, 95%-CI = 1.10-5.67, = ) was associated with an increased risk of ACM, with a trend seen for reduced left ventricular ejection fraction prior to therapy (LVEF <40%; HR 9.17, 95%-CI = 1.30-183.11, = ). Secondary endpoint was reached by 93 patients while no baseline parameter was able to predict an elevated risk. However, hs-cTnT change from baseline of 50% or more during the first 14 days after CAR infusion predicted ACM (HR 3.81, 95%-CI = 1.58-9.45; = ). None of the baseline characteristics was able to predict the incidence of cardiac events.
Reduced pre-lymphodepletion ejection fraction and early post-infusion biomarker kinetics may be associated with increased ACM and cardiotoxicity events. These findings may help to identify patients who could benefit from intensified cardio-oncological surveillance.
The German Center for Cardiovascular Research, German Research Foundation, and the Federal Ministry of Education and Research.
评估心血管风险对癌症患者至关重要。既往回顾性研究提示CAR-T细胞疗法可能存在心脏毒性。我们旨在前瞻性评估心脏毒性以及心脏生物标志物和经典风险因素（年龄、心功能、糖尿病、动脉高血压、吸烟）对心脏事件和全因死亡率（ACM）的预测价值。
在这项前瞻性队列研究中，纳入了2018年10月1日至2022年9月30日在海德堡大学医院接受CAR-T细胞构建体（axi-cel、tisa-cel、brexu-cel、ide-cel或第三代CAR HD-CAR-1）治疗的所有患者。监测包括使用生物标志物（高敏肌钙蛋白T（hs-cTnT）、N末端脑钠肽（NT-proBNP））进行心脏评估、12导联心电图和二维超声心动图。ACM被定义为主要研究终点，而由心力衰竭临床综合征或射血分数下降定义的心脏毒性作为次要终点。
总体而言，137例患者（中位年龄60岁，范围20-83岁，IQR 16）纳入研究。46例患者在随访期间死亡（中位0.75年，范围0.02-4.33年，IQR 0.89），中位生存期为0.57年（范围0.03-2.38年，IQR 0.79）。间隔壁厚超过11 mm（HR 2.48，95%CI = 1.10-5.67， = ）与ACM风险增加相关，治疗前左心室射血分数降低（LVEF<40%）有此趋势（HR 9.17，95%CI = 1.30-183.11， = ）。93例患者达到次要终点，而没有基线参数能够预测风险升高。然而，CAR输注后前14天内hs-cTnT较基线变化50%或更多可预测ACM（HR 3.81，95%CI = 1.58-9.45； = ）。没有基线特征能够预测心脏事件的发生率。
淋巴细胞清除前射血分数降低和输注后早期生物标志物动力学变化可能与ACM和心脏毒性事件增加相关。这些发现可能有助于识别可从强化心脏肿瘤学监测中获益的患者。
德国心血管研究中心、德国研究基金会和联邦教育与研究部。
