Background:

Sarcopenia is a hallmark of cachexia commonly found in cancer patients that is caused by immune and metabolic mediators of catabolism. Chimeric antigen receptor (CAR) T-cell therapy is used to treat cancer and is characterized by the release of inflammatory cytokines and other potentially catabolic mediators. Previously, we showed that baseline sarcopenia and other immuno-nutritional scores were associated with poor outcomes after CD19-directed CAR T-cell therapies in patients with R/R LBCL (Rejeski et al. Cancer Immunol. Res. 2023). Here we examined the relationship between body composition and serum metabolite levels over time after CAR T-cell infusion.

Methods: This is a single-center retrospective study of N=83 patients with R/R LBCL who received CAR T-cell therapy. The median clinical follow-up was 18.4 months. Muscle and adipose tissue distribution were calculated from clinical pre-lymphodepletion, day (d) 30, and day (d) 90 CT imaging using Slice-O-Matic software (v5.0, Tomovision). Baseline sarcopenia status was determined using established criteria (SMI 52.4 cm2/m2 for Males and 38.5 cm2/m2 for Females) . Immuno-nutritional scores included: GPS Score: CRP ≤ 10 mg/L = 0; CRP > 10 mg/L and albumin > 3.5 g/dL = 1; CRP > 10 mg/L and albumin < 3.5 g/dL = 2. PNI Score: Albumin (g/L) + 5 × total lymphocyte count (10^9/L). Muscle loss at d30 or d90 after CAR T-cell therapy was defined by a decrease of > 10% in their skeletal muscle index (SMI) from baseline. Patients who had relapsed, died or had missing scans were censored during the analysis. Univariate and multivariable Cox regression models using LASSO regularization assessed the association between various factors and survival outcomes. Serum metabolites were profiled at baseline and at regular time points up to 4 weeks after CAR T cell therapy (n=55) as previously described (Fahrmann et al. Cell Rep. Medicine 2022).

Results:

Patients with baseline sarcopenia (n=44) had worse progression-free (PFS) and overall survival (OS) after CD19 CAR T cell therapy for R/R LBCL compared to non-sarcopenic patients (n=39) (OS: HR=2.5, 95% CI: 1.3-4.9, P=0.008; PFS: HR=1.8, 95% CI: 1.0-3.2, P=0.037). In multivariable Cox fits (MVA) for OS, male gender (HR=3.3, 95% CI: 1.3-8.8, P=0.014), and GPS score of 2 (HR=3.8, 95% CI: 1.4-10.6, P=0.011) were associated with worse OS. On MVA for PFS, a lower PNI score was mildly associated with worse outcomes (HR=0.9, 95% CI: 0.8-1.0, P=0.039).

Muscle loss occurred between baseline and d30 and d90 after CAR T-cell therapy in 34% and 32% of patients, respectively. Muscle loss correlated with concurrent adipose tissue loss and overall weight loss. Patients who had baseline sarcopenia had more pronounced muscle loss at d30 and d90 compared to patients who were non-sarcopenic at baseline. Associations with d30 muscle loss included ICANS grade 2 or higher (P=0.046) and baseline LDH (P=0.033). Further, patients with ICANS grade 2 or higher had a significantly higher d30 median muscle loss compared to patients with grade 0-1 ICANS (9.1% versus 6.4%; p=0.049). However, whether landmarked at d30 or d90, muscle loss after CAR T-cell therapy did not significantly associate with the risk of subsequent progression or death.

Individual serum metabolites that significantly decreased between pre-infusion and after CAR T-cell infusion included those potentially associated with gut microbiome alterations (indole-3-acetate and xanthosine). Pathway analysis revealed changes in purine and pyrimidine metabolism over time after CAR T-cell therapy. Subgroup analyses comparing metabolites over time in sarcopenia versus non-sarcopenia, as well as based on muscle loss are in progress.

Conclusions: Sarcopenia is highly prevalent (53%) in R/R DLBCL patients presenting for CAR-T and approximately 1/3 of patients lose muscle mass during the course of therapy, with the greatest risk noted in those with baseline sarcopenia. High immuno-nutritional scores are associated with inferior outcomes. Muscle loss was associated with a higher disease burden and higher-grade toxicities. Further study is needed to understand the association between antibiotics use and clinical factors for microbiome-related metabolites that change over time after CAR T-cell infusion. Interventional approaches to improve functional and nutritional reserve to optimize outcomes are warranted.

Saini:Panbela Theraputics: Research Funding; GSK: Research Funding. Hanash:Abbott: Honoraria; Cosmos Wisdom: Research Funding; BMS: Honoraria; Dynex: Research Funding. Jenq:Prolacta: Membership on an entity's Board of Directors or advisory committees; Da Volterra: Consultancy; Kaleido: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Seres: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; LISCure: Membership on an entity's Board of Directors or advisory committees; MaaT Pharma: Membership on an entity's Board of Directors or advisory committees; Karius: Membership on an entity's Board of Directors or advisory committees; Microbiome DX: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees. Chavez:Adaptive: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Cellectar: Membership on an entity's Board of Directors or advisory committees; Epizyme: Speakers Bureau; Genmab: Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Lilly: Honoraria; Merck: Research Funding; Morphosys: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Shah:Moffitt Cancer Center: Current Employment; Pharmacyclics/Janssen, Spectrum/Acrotech, BeiGene, Gilead Sciences: Honoraria; Incyte, Jazz Pharmaceuticals, Kite/Gilead, SERVIER: Research Funding; Celgene, Novartis, Pfizer, Janssen, Seattle Genetics, AstraZeneca, Stemline Therapeutics, Kite/Gilead: Other: Travel, Accommodations, Expenses; DSMC, Pepromene Bio: Membership on an entity's Board of Directors or advisory committees; Takeda, AstraZeneca, Adaptive Biotechnologies, BMS/Celgene, Novartis, Pfizer, Amgen, Precision Biosciences, Kite/Gilead, Jazz Pharmaceuticals, Century Therapeutics, Deciphera, Autolus Therapeutics, Lilly, Pepromene: Consultancy. Nishihori:Medexus: Speakers Bureau; Moffitt Cancer Center: Other: Personal fees from Karyopharm and Novartis outside the submitted work. Lazaryan:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bachmeier:Kite Pharma: Consultancy. Davila:Synthekine: Consultancy; Syncopation Life Sciences: Consultancy; Precision Biosciences: Other: Ownership interest (stock, stock options in a publicly owned company); Legend Biotech: Consultancy; Kite Pharma Inc.: Other: Teaching and Speaking; Caribou Biosciences: Consultancy; Capstan: Other: Advisor or review panel participant; CRISPR (CRSP): Patents & Royalties: Intellectual property rights (Royalties or patent sales); Bellicum Pharmaceuticals, Inc.: Other: Advisor or review panel participant; Ownership interest (stock, stock options in a publicly owned company); Atara Biotherapeutics: Consultancy; Adicet: Consultancy; Adaptive Biotechnologies: Other: Ownership interest (stock, stock options in a publicly owned company). Rejeski:Kite/Gilead: Other: Travel Support, Research Funding; Novartis: Honoraria; BMS/CELGENE: Consultancy, Honoraria; Pierre-Fabre: Other: Travel Support. Subklewe:Amgen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Other: Travel Support, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seagen: Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel Support, Speakers Bureau; Incyte Biosciences: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding; Ichnos Sciences: Consultancy, Honoraria; AvenCell: Consultancy, Honoraria; AstraZeneca: Speakers Bureau; Gilead/Kite: Consultancy, Honoraria, Other: Travel Support, Research Funding, Speakers Bureau; Molecular Partners: Consultancy, Honoraria, Research Funding; GSK: Speakers Bureau; LAWG: Speakers Bureau; Springer Healthcare: Speakers Bureau; AbbVie: Consultancy, Honoraria; Autolus: Consultancy, Honoraria; advesya (CanCell Therapeutics): Consultancy, Honoraria; Genmab US: Consultancy, Honoraria; Interius BioTherapeutics: Consultancy, Honoraria; Nektar Therapeutics: Consultancy, Honoraria; Orbital Therapeutics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Scare: Consultancy, Honoraria. Locke:Umoja: Consultancy, Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Other; ASH: Other: Travel Support; BioPharma Communications CARE Education: Other: Institutional; Daiichi Sankyo: Consultancy; Cowen: Consultancy; Calibr: Consultancy; National Cancer Institute: Other; Leukemia and Lymphoma Society: Other; Caribou: Consultancy; Aptitude Health: Other: Travel Support; Clinical Care Options Oncology: Other; Cellular Medicine Group: Consultancy; Emerging Therapy Solutions: Consultancy, Other; CERo Therapeutics: Other: (Institutional); Imedex: Other; Wugen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sana: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Iovance: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allogene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional ; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional , Research Funding; Kite, a Gilead Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional , Research Funding; Bristol Myers Squibb/ Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional , Research Funding; Gerson Lehrman Group (GLG): Consultancy; A2 Biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; EcoR1: Consultancy; GammaDelta Therapeutics: Consultancy. Freeman:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; ONK Therapeutics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Jain:Kite/Gilead: Consultancy, Honoraria, Research Funding; Myeloid Therapeutics: Consultancy, Honoraria; Loxo@Lilly: Research Funding; Incyte: Research Funding.

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2023
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