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Observational Study
. 2025 Aug 26;15(1):144.
doi: 10.1038/s41408-025-01338-1.

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

Michael Winkelmann #  1   2 , Sandeep S Raj #  3 , Michael D Jain  4 , Gloria Iacoboni  5   6 , Fabian Müller  7   8 , Leo Hansmann  9 , Magdalena Corona  3 , Alejandro Luna  3 , Khushali Jhaveri  10 , Gunjan L Shah  3   11 , Michael Scordo  3   11 , Turab Mohammad  4   12 , Erin A Dean  13 , Gabriel T Sheikh  14 , Wolfgang G Kunz  1   2 , Tobias Tix  15 , Veit L Bücklein  7   15 , Akshay Bedmutha  16 , Doris Leithner  16 , Michael von Bergwelt-Baildon  15 , Alexander P Boardman  17 , M Lia Palomba  11   17 , Jae H Park  11   18 , Gilles Salles  11   17 , Miguel-Angel Perales  3   11 , Heiko Schöder  16 , Marion Subklewe  2   7   15 , Pere Barba  5   6 , Frederick L Locke  4 , Roni Shouval  3   11 , Kai Rejeski  19   20   21
Affiliations
Observational Study

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

Michael Winkelmann et al. Blood Cancer J. .

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.

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Conflict of interest statement

Competing interests: M.D.J.: Consultancy/Advisory for Kite/Gilead, Novartis, and Myeloid Therapeutics. Research funding by Incyte, Kite/Gilead, and Loxo@Lilly. G.I.: Honoraria from AbbVie, AstraZeneca, Bristol Myers Squibb, Janssen, Kite, a Gilead Company, Miltenyi Biotec, Novartis, and Roche; consulting/advisory role for Autolus Therapeutics, Bristol Myers Squibb, Kite, Miltenyi Biotec, and Novartis; and travel support from AbbVie, AstraZeneca, Kite and Miltenyi Biotec. F.M.: ArgoBIO Consulting; AstraZeneca Honoraria, Consulting, Research grant; BMS Honoraria, Consulting, Research Grant, CRISPR Therapeutics Consulting, EcoR1 Consulting, Janssen Honoraria, Consulting, Kite/Gilead, Honoraria, Consulting, Research Grant, Abbvie Honoraria, Incayte Honoraria, Miltenyi medicine Honoraria, MSD Honoraria, Novartis Honoraria, Consulting, Pfizer Honoraria, Sobi Honorarai, Takeda Honoraria. L.H.: Advisory Committees: Bristol Myers Squibb, Gilead, Johnson&Johnson, Pierre-Fabre, Sanofi; travel support: Amgen, Gilead, Johnson&Johnson. G.L.S.: has research funding to the institution from Janssen, Amgen, BMS, Beyond Spring, and GPCR, and is on the DSMB for ArcellX. Mi.S.: served as a paid consultant for McKinsey & Company, Angiocrine Bioscience, and Omeros; has received research funding from Angiocrine Bioscience and Omeros; has served on ad hoc advisory boards for Kite Pharma; and has received honoraria from i3Health and Medscape for CME related activity. W.G.K.: Bristol Myers Squibb: Advisor. The remaining authors declare no competing financial interests. None of the mentioned conflicts of interest were related to financing of the content of this manuscript. A.P.B.: received compensation for participating in consulting activities with Bristol Myers Squibb. M.A.P.: honoraria from Adicet, Allogene, Caribou Biosciences, Celgene, Bristol-Myers Squibb, Equilium, Exevir, ImmPACT Bio, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Nektar Therapeutics, Novartis, Omeros, OrcaBio, Pierre Fabre, Sanofi, Syncopation, Takeda, VectivBio AG, and Vor Biopharma. He serves on DSMBs for Cidara Therapeutics and Sellas Life Sciences. He has ownership interests in Omeros and OrcaBio. He has received institutional research support for clinical trials from Allogene, Genmab, Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis. M.S.: Amgen: Research Funding, Speakers Bureau; Astra Zeneca: Speakers Bureau; Aven Cell: Consultancy, BMS/Celgene: Research Funding, Speakers Bureau; CDR-Life: Consultancy, Gilead: Research Funding, Speakers Bureau; GSK: Speakers Bureau; Ichnos Sciences: Consultancy; Incyte Biosciences: Consultancy; Janssen: Research Funding, Consultancy, Speakers Bureau; Miltenyi Biotec: Research Funding, Consultancy; Morphosys: Research Funding; Molecular Partners: Consultancy; Novartis: Research Funding, Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Roche: Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Takeda: Research Funding, Consultancy, Speakers Bureau. P.B.: Allogene, Amgen, Autolus, BMS/Celgene, Kite/Gilead, Incyte, Miltenyi Biomedicine, Novartis, Pfizer and Pierre Fabre: Honoraria, travel support and consultancy. F.L.L.: Consulting or Advisory Role: Novartis, Celgene, Calibr, Alimera Sciences, Gerson Lehrman Group, EcoR1 Capital, Amgen, Bluebird Bio, Bristol Myers Squibb, Iovance Biotherapeutics, Legend Biotech, Cowen, Kite, a Gilead company, Umoja Biopharma, Takeda, Sana Biotechnology, Daiichi Sankyo/UCB Japan, Bristol Myers Squibb/Celgene, Janssen, A2 Biotherapeutics, Miltenyi Biotec, Caribou Biosciences. Research Funding: Kite, a Gilead company (Inst), Alimera Sciences (Inst), Novartis (Inst), Bluebird Bio (Inst), Bristol Myers Squibb/Celgene (Inst). Patents, Royalties, Other Intellectual Property: Double Mutant Survivin Vaccine. US010414810B2 (Inst), CAR T Cells with Enhanced Metabolic Fitness. Serial Number: 62/939,727 (Inst), Methods of Enhancing CAR T Cell Therapies. Serial Number: 62/892,292 (Inst), Evolutionary Dynamics of Non-Hodgkin Lymphoma CAR-T cell therapy. Serial Number: 62/879,534 (Inst). Travel, Accommodations, Expenses: Kite, a Gilead company, A2 Biotherapeutics. R.S: Honoraria from Sanofi and Incyte. K.R.: Kite/Gilead: Research Funding, Consultancy, Honoraria and travel support; Novartis: Honoraria; BMS/Celgene: Consultancy, Honoraria; Pierre-Fabre: travel support. CSL Baehring: Consultancy. Ethics approval, consent to participate and Publication: All medical records and imaging studies were reviewed and approved by the appropriate Institutional Review Boards of each participating institution. Written informed consent was obtained from all individual participants included in the study. All procedures were conducted in accordance with relevant guidelines and regulations, and in compliance with the Declaration of Helsinki.

Figures

Fig. 1
Fig. 1. Linear Spline with one knot.
Depicted are the results of a linear spline model with one knot for the CAR-T cell-specific metabolic tumor volume (MTV) threshold determined in the development cohort. MTV is plotted on the x-axis and the log-transformed hazard ratio (HR) on the y-axis.
Fig. 2
Fig. 2. Survival Analysis stratified by Median CAR-IMPI and Transfer to the Validation Cohort.
The upper panel shows the Kaplan-Meier curves for progression-free survival (PFS; A and overall survival (OS; B for development cohort stratified by median CAR-IMPI. The lower part of the figure displays PFS (C) and OS (D) survival curves for validation cohort using the same CAR-IMPI cut-off established in the development cohort. The low risk group is marked in yellow and the high risk group in blue. The hazard ratio (HR) with 95% confidence interval (CI) from the univariate Cox regression using the low-risk group as reference is provided.
Fig. 3
Fig. 3. Frequency and Severity of CRS and ICANS by CAR-IMPI Risk Group.
Depicted are with severity of cytokine release syndrome (CRS; A and Immune effector cell-associated neurotoxicity syndrome (ICANS; B and the probability of ICU admission (C) by median CAR-IMPI. The stacked bar plots show the total number of patients. The p-values indicate the results of the Chi-Square and Fisher’s exact test.
Fig. 4
Fig. 4. Modification of CAR-IMPI with CAR-HEMATOTOX and InflaMix Cluster Assignment.
Illustrated are Kaplan-Meier survival curves for CAR-IMPI risk groups modified by CAR-HEMATOTOX and InflaMix. A Schema showing the combination of CAR-IMPI (stratified by median) and inflammation-based risk scores. CAR-HEMATOTOX high is defined for patients with values ≥ 3 and low with values ≤ 2. B, C Estimated progression-free (PFS, B) and overall survival (OS, C) by CAR-IMPI with CAR-HEMATOTOX. D, E Estimated progression-free (PFS, D) and overall survival (OS, E) by CAR-IMPI with Inflamix cluster assignment. Patients with low values in both parameters are marked in yellow, with high values in both parameters in red, the CAR-IMPI high and CAR-HEMATOTOX/InflaMix low-risk group in blue and CAR-IMPI low and CAR-HEMATOTOX/InflaMix high-risk group in gray. P-values by logrank test are provided in the graph inset. Median PFS or OS in months with the 95% confidence intervals are depicted above the Kaplan-Meier graph together with the results of the univariate Cox regression using the lowest-risk group as reference.
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