Optimization and validation of the international metabolic prognostic index for CD19 CAR-T in large B-cell lymphoma

IF 11.6 1区 医学 Q1 HEMATOLOGY
Michael Winkelmann, Sandeep S. Raj, Michael D. Jain, Gloria Iacoboni, Fabian Müller, Leo Hansmann, Magdalena Corona, Alejandro Luna, Khushali Jhaveri, Gunjan L. Shah, Michael Scordo, Turab Mohammad, Erin A. Dean, Gabriel T. Sheikh, Wolfgang G. Kunz, Tobias Tix, Veit L. Bücklein, Akshay Bedmutha, Doris Leithner, Michael von Bergwelt-Baildon, Alexander P. Boardman, M. Lia Palomba, Jae H. Park, Gilles Salles, Miguel-Angel Perales, Heiko Schöder, Marion Subklewe, Pere Barba, Frederick L. Locke, Roni Shouval, Kai Rejeski
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Abstract

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 18FDG-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.

Abstract Image

CD19 CAR-T在大b细胞淋巴瘤中的国际代谢预后指标的优化和验证
虽然cd19靶向CAR - t细胞疗法代表了一种治疗复发/难治性大b细胞淋巴瘤(r/r LBCL)的转化性免疫疗法,但超过50%的患者最终进展或复发。最近,国际代谢预后指数(IMPI) -包括年龄,分期和代谢肿瘤体积(MTV) -被证明可以改善LBCL一线治疗的预后。在这里,我们研究了它在预测CAR-T受体的毒性和生存方面的效用。这项多中心观察性研究跨越6个国际站点,包括504名患者,在淋巴细胞耗竭前进行最后反应评估时使用18FDG-PET/CT成像。在发展队列(n = 256)中确定了最佳car - t适应MTV阈值,并将其纳入car - t特异性IMPI(“CAR-IMPI”)。CAR-IMPI的预后表现在一个独立队列中得到验证(n = 248)。CAR-IMPI风险分类,由中位数(1.35)和中位数(1.07,1.58)定义,在两个队列中显示出无进展生存期(PFS; p < 0.0001)和总生存期(OS; p < 0.0001)的显著差异。多变量Cox回归证实CAR-IMPI是一个独立的生存预测因子,考虑了淋巴细胞衰竭前LDH和CRP、运动状态、治疗中心和CAR-T产物。CAR-IMPI高危类别的患者CRS和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,CAR-IMPI与已建立的高危全身炎症指标(CAR-HEMATOTOX、InflaMix)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患者的临床结果风险分层提供一种有效且经过验证的基于pet的工具。我们的数据强调了结合临床和放射模式的效用,对患者选择和毒性管理的预期护理水平有影响。
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来源期刊
CiteScore
16.70
自引率
2.30%
发文量
153
审稿时长
>12 weeks
期刊介绍: Blood Cancer Journal is dedicated to publishing high-quality articles related to hematologic malignancies and related disorders. The journal welcomes submissions of original research, reviews, guidelines, and letters that are deemed to have a significant impact in the field. While the journal covers a wide range of topics, it particularly focuses on areas such as: Preclinical studies of new compounds, especially those that provide mechanistic insights Clinical trials and observations Reviews related to new drugs and current management of hematologic malignancies Novel observations related to new mutations, molecular pathways, and tumor genomics Blood Cancer Journal offers a forum for expedited publication of novel observations regarding new mutations or altered pathways.
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