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

Abstract

Metabolic prognostic index; CD19 CAR-T; Large B-cell lymphoma

Índex pronòstic metabòlic; CD19 CAR-T; Limfoma de cèl·lules B grans

Índice de pronóstico metabólico; CD19 CAR-T; Linfoma de células B grandes

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.

The work was supported by funding from the research program “Förderung für Forschung und Lehre (FöFoLe) project number 1147” of the Medical Faculty of Ludwig Maximilian University (LMU) Munich and the Bavarian Cancer Research Center (BZKF) to MW. KR acknowledges funding from the Else Kröner Forschungskolleg (EKFK) within the Munich Clinician Scientist Program (MCSP), the Bruno and Helene Jöster Foundation, and the “CAR-T Control” translational group within the Bavarian Center for Cancer Research (BZKF-#TLG-22). All authors from Memorial Sloan Kettering Cancer Center (MSKCC) were supported by a MSKCC Core grant (P30 CA008748) from the National Institutes of Health/National Cancer Institute. RS was supported by an NIH-NCI K-award (K08CA282987) and Comedy vs. Cancer. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Open Access funding enabled and organized by Projekt DEAL.