Winkelmann Michael, Raj Sandeep S, Jain Michael D, Iacoboni Gloria, Müller Fabian, Hansmann Leo, Corona Magdalena, Luna Alejandro, Jhaveri Khushali, Shah Gunjan L, Scordo Michael, Mohammad Turab, Dean Erin A, Sheikh Gabriel T, Kunz Wolfgang G, Tix Tobias, Bücklein Veit L, Bedmutha Akshay, Leithner Doris, von Bergwelt-Baildon Michael, Boardman Alexander P, Palomba M Lia, Park Jae H, Salles Gilles, Perales Miguel-Angel, Schöder Heiko, Subklewe Marion, Barba Pere, Locke Frederick L, Shouval Roni, Rejeski Kai
Department of Radiology, LMU University Hospital, LMU Munich, Munich, Germany.
German Cancer Consortium (DKTK), Partner Site Munich, a partnership between the DKFZ Heidelberg and LMU University Hospital, Munich, Germany.
Blood Cancer J. 2025 Aug 26;15(1):144. doi: 10.1038/s41408-025-01338-1.
While CD19-directed CAR T-cell therapy represents a transformative immunotherapy for relapsed/refractory large B-cell lymphoma (r/r LBCL), more than 50% of patients ultimately progress or relapse. Recently, the International Metabolic Prognostic Index (IMPI) - incorporating age, stage, and metabolic tumor volume (MTV) - was shown to improve prognostication for LBCL frontline treatment. Here, we examine its utility to predict toxicity and survival in CAR-T recipients. This multicenter observational study spanning six international sites included 504 patients with available FDG-PET/CT imaging at last response assessment prior to lymphodepletion. Optimal CAR-adapted MTV thresholds were identified in a development cohort (n = 256) and incorporated into a CAR-T-specific IMPI ("CAR-IMPI"). The prognostic performance of CAR-IMPI was validated in an independent cohort (n = 248). CAR-IMPI risk categories, defined by the median (1.35) and terciles (1.07, 1.58), demonstrated significant discrimination for progression-free survival (PFS; p < 0.0001) and overall survival (OS; p < 0.0001) in both cohorts. Multivariate Cox regression confirmed CAR-IMPI as an independent predictor of survival, accounting for pre-lymphodepletion LDH and CRP, performance status, treatment center, and CAR-T product. Patients in the CAR-IMPI high-risk category experienced increased severity of CRS and ICANS, and higher rates of intensive care unit (ICU) admissions. In an exploratory analysis, combining CAR-IMPI with established indices of high-risk systemic inflammation (CAR-HEMATOTOX, InflaMix) further enhanced survival stratification. The CAR-IMPI may provide a potent and validated PET-based tool for risk stratification of clinical outcomes in patients with r/r LBCL receiving CD19 CAR-T therapy. Our data highlight the utility of combining clinical and radiological modalities, with implications for patient selection and the anticipated level-of-care for toxicity management.
虽然针对CD19的嵌合抗原受体(CAR)T细胞疗法是复发/难治性大B细胞淋巴瘤(r/r LBCL)的一种变革性免疫疗法,但超过50%的患者最终会进展或复发。最近,国际代谢预后指数(IMPI)——纳入了年龄、分期和代谢肿瘤体积(MTV)——已被证明可改善LBCL一线治疗的预后评估。在此,我们研究其在预测CAR-T接受者的毒性和生存方面的效用。这项涵盖六个国际地点的多中心观察性研究纳入了504例在淋巴细胞清除前最后一次缓解评估时可获得氟代脱氧葡萄糖正电子发射断层扫描/计算机断层扫描(FDG-PET/CT)成像的患者。在一个开发队列(n = 256)中确定了最佳的CAR适配MTV阈值,并将其纳入特定于CAR-T的IMPI(“CAR-IMPI”)。CAR-IMPI的预后性能在一个独立队列(n = 248)中得到验证。由中位数(1.35)和三分位数(1.07、1.58)定义的CAR-IMPI风险类别在两个队列中对无进展生存期(PFS;p < 0.0001)和总生存期(OS;p < 0.0001)均显示出显著的区分能力。多变量Cox回归证实CAR-IMPI是生存的独立预测因素,同时考虑了淋巴细胞清除前的乳酸脱氢酶(LDH)和C反应蛋白(CRP)、体能状态、治疗中心和CAR-T产品。CAR-IMPI高风险类别的患者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)的严重程度增加,重症监护病房(ICU)入院率更高。在一项探索性分析中,将CAR-IMPI与既定的高风险全身炎症指标(CAR-HEMATOTOX、InflaMix)相结合进一步增强了生存分层。CAR-IMPI可能为接受CD19 CAR-T治疗的r/r LBCL患者的临床结局风险分层提供一种有效且经过验证的基于PET的工具。我们的数据突出了结合临床和放射学方法的效用,对患者选择以及毒性管理的预期护理水平具有启示意义。
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