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. 2025 Jul;31(7):419-433.
doi: 10.1016/j.jtct.2025.03.011. Epub 2025 Apr 25.

Cytokine Release Syndrome and Neurotoxicity Following CD19 CAR-T in B-Cell Lymphoma

Roni Shouval  1 , Christopher Strouse  2 , Soyoung Kim  3 , Temitope Oloyede  4 , Sairah Ahmed  5 , Farrukh T Awan  6 , Danny Luan  7 , Veronika Bachanova  8 , Talha Badar  9 , Merav Bar  10 , Pere Barba  11 , Amer M Beitinjaneh  12 , Amanda Cashen  13 , Bhagirathbhai Dholaria  14 , Mahmoud Elsawy  15 , Siddhartha Ganguly  16 , Praveen Ramakrishnan Geethakumari  6 , Uri Greenbaum  17 , Hamza Hashmi  18 , LaQuisa C Hill  19 , Michael D Jain  20 , Tania Jain  21 , Partow Kebriaei  22 , Adam S Kittai  23 , Frederick L Locke  20 , Premal D Lulla  19 , Elena Mead  24 , Joseph P McGuirk  25 , Alberto Mussetti  26 , Taiga Nishihori  20 , Amanda L Olson  22 , Martina Pennisi  27 , Miguel-Angel Perales  1 , Peter A Riedell  28 , Wael Saber  4 , Abu-Sayeef Mirza  20 , Margarida Magalhaes-Silverman  29 , Elizabeth J Shpall  22 , Mohamed Sorror  30 , Kitsada Wudhikarn  31 , Cameron J Turtle  32 , Amy Moskop  33 , Marcelo C Pasquini  34
Affiliations

Cytokine Release Syndrome and Neurotoxicity Following CD19 CAR-T in B-Cell Lymphoma

Roni Shouval et al. Transplant Cell Ther. 2025 Jul.

Abstract

Chimeric antigen receptor T cell (CAR-T) therapy is an effective treatment for relapsed-refractory large B-cell lymphoma (LBCL). However, toxicities, particularly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), remain significant concerns. Analyze temporal trends, risk factors, and associations between these toxicities and their severity. In this registry study by the Center for International Blood and Marrow Transplant Research, we studied CRS and ICANS in 1916 LBCL patients treated with commercial CAR-T therapies (axicabtagene ciloleucel 74.9%, tisagenlecleucel 25.1%) between 2018 and 2020. Outcomes include development of CRS/ICANS, timing and severity according to ASTC grading, overall survival (OS). Risk factors were assessed using Cox proportional hazards model. Among patients developing CRS (75.2%), 11.3% had grade ≥3 CRS. Among patients developing ICANS (43.5%), 47.7% had grade ≥3 ICANS. Among patients developing CRS, severe CRS rates decreased from 14.0% in 2018 to 9.2% in 2020 (P< .01). However, the proportion of severe ICANS in patients who developed ICANS remained statistically unchanged (41.5% in 2018 to 53.7% in 2020, P= .10). CRS and ICANS were correlated: 57.1% of patients with CRS also experienced ICANS, and CRS was reported in 97.5% of ICANS cases, suggesting a potential continuum between toxicities. Axicabtagene ciloleucel was associated with higher risk of any grade CRS (OR, 4.6; 95% CI, 3.65 to 5.81) and ICANS (OR, 5.85; 95% CI, 4.48 to 7.64) as well as early and severe forms of both complications. Older age, lower performance status, and elevated lactate dehydrogenase levels prior to infusion also variably predicted these toxicities. In a landmark analysis starting 30 days postinfusion, patients with severe CRS or severe ICANS had shorter OS compared to those without these toxicities. High grades of CRS improved over time likely related to earlier intervention, development of ICANS is intrinsically related with CRS. These findings underscore the need for effective strategies to mitigate these toxicities and improve CAR-T safety.

Keywords: CAR T Cell toxicities; Cytokine release syndrome; Large B-cell lymphoma.

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Conflict of interest statement

Conflict of Interest Statement: Dr. Strouse reports advisory board: Pfizer. Dr. Ahmed receives research support from Nektar, Merck, Xencor, Chimagen, Genmab, Kite/Gilead, Janssen, and Caribou. She is a member of the scientific advisory board for Chimagen, serves as a member of a data and safety monitoring board for Myeloid Therapeutics, and is a consultant for ADC Therapeutics and Kite/Gilead. Dr. Awan reports consultancy to: Loxo Oncology, BeiGene, Dava Oncology, AstraZeneca, Genmab, Adaptive Biotechnologies, BMS, AbbVie, Incyte, Kite Pharma, Caribou Biosciences, ADCT therapeutics, and received research funding from AbbVie/Pharmacyclics. Dr. Bachanova reports research funding from Citius, Incyte, and Gamida Cell; advisory board: ADC, Astra Zeneca, and CRIPSR, and DSMB Member: Miltenyi Biotech. Dr. Badar reports advisory board for MorphoSys, Takeda, and Pfizer. Dr. Bar is an employee of Bristol Myers Squibb. Dr. Barba reports advisory board and consultancy: Allogene, Amgen, Autolus, BMS/Celgene, Kite/Gilead, Incyte, Miltenyi Biomedicine, Novartis, Nektar, Pfizer, and Pierre Fabre. Dr. Beitinjaneh reports advisory board consultation: 2022–Kite Pharm and 2023 Autolus. Dr. Cashen reports being a member of an advisory board of Kite Pharma. Dr. Dholaria reports institutional research funding: Janssen, Angiocrine, Pfizer, Poseida, MEI, OrcaBio, Wugen, AlloVir, Adicet, BMS, Molecular template, Atara; Consultancy/Advisor: MJH BioScience, AriVan Research, Janssen, ADC Therapeutics, Gilead, GSK, Caribou, Roche, Autolus. Dr. Elsawy reports honoraria and Consultancy from Kite/Gilead, BMS, Novartis. Dr. Ganguly reports Ad Board: Pfizer, BMS, Sanofi Genzyme. Dr. Locke Frederick L. Locke reports scientific advisory roles/consulting fees from A2, Allogene, Amgen, Bluebird Bio, BMS, Calibr, Caribou, Cowen, EcoR1, Gerson Lehrman Group (GLG), Iovance, Kite Pharma, Janssen, Legend Biotech, Novartis, Sana, Umoja, and Pfizer. He serves on the data and safety monitoring board for the NCI Safety Oversight CAR-T-cell Therapies Committee. He has research contracts or grants to his institution for service from Kite Pharma, Allogene, CERo Therapeutics, Novartis, bluebird bio, 2seventy bio, BMS, and the National Cancer Institute (R01CA244328 MPI: Locke; P30CA076292 PI: Cleveland), as well as support from the Leukemia and Lymphoma Society (Scholar in Clinical Research PI: Locke). He holds several patents in the field of cellular immunotherapy. He has education or editorial activities with Aptitude Health, ASH, BioPharma Communications CARE Education, Clinical Care Options Oncology, Imedex, and the Society for Immunotherapy of Cancer. Dr. Ramakrishnan Geethakumari reports consultancy services/served on advisory boards of Kite Pharma, Bristol Myers Squibb (BMS), ADC Therapeutics, Cellectar Biosciences, Ono Pharma, Ipsen Biopharma, and Regeneron Pharma. Dr. Greenbaum reports honoraria: Novartis; advisory board: Gilead. Dr. Hashmi reports advisory board: Janssen; honoraria: Amgen, Karyopharm. Dr. Hill reports advisory board–March Biosciences; Kite/Gilead–Speaker’s Bureau. Dr. Jain reports institutional research support from CTI Biopharma, Kartos Therapeutics, Incyte, Bristol Myers Squibb, Tscan; Advisory board participation with Bristol Myers Squibb, Incyte, AbbVie, CTI, Kite, Cogent Biosciences, Blueprint Medicine, Telios Pharma, Protagonist Therapeutics, Galapagos, Tscan Therapeutics, Karyopharm, MorphoSys, In8Bio. Dr. Kittai reports research funding from AstraZeneca and BeiGene, has performed speaking engagements for AstraZeneca, BeiGene, and Eli-Lilly, and has participated in advisory boards for AbbVie, AstraZeneca, BeiGene, and BMS. Dr. McGuirk reports consulting for the following: Kite, Novartis, BMS, AlloVir, Nektar, Sana, CRISPR Therapeutics. Dr. Mussetti reports honoraria for lectures: Takeda, BMS, Gilead, Sanofi; honoraria for advisory board activities: Merck, Jazz Pharma; Participation in clinical trials (PI): Atara, Takeda; research funding: Gilead. Dr. Mirza reports BMS, consultant, speakers bureau. Dr. Pasquini report research support from Novartis, Kite Pharma, a Gilead Company, BMS, Janssen. Consultant and honoraria: Novartis, BMS and Kite Pharma. Dr. Perales reports receiving honoraria from Adicet, Allogene, AlloVir, Caribou Biosciences, Celgene, Bristol Myers Squibb, Equilium, ExeVir, ImmPACT Bio, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Nektar Therapeutics, Novartis, Omeros, OrcaBio, Sanofi, Syncopation, VectivBio AG, and Vor Biopharma. He serves on DSMBs for Cidara Therapeutics and Sellas Life Sciences, and the scientific advisory board of NexImmune. He has ownership interests in NexImmune, Omeros, and OrcaBio. He has received institutional research support for clinical trials from Allogene, Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis. Dr. Shpall reports Scientific Advising: Axio Research, Zelluna Immunotherapy, FibroBiologics, and Adaptimmune Limited; License Agreement: Affimed, Takeda, and RegeNexus; Board of Directors/Management: NMDP. Mohamed Sorror reports consulting and receiving honoraria from Jazz Pharmaceuticals and research funding from MGH and BlueNote. Dr. Turtle reports research funding: Juno Therapeutics/BMS, Nektar Therapeutics, 10X Genomics; Scientific Advisory Boards: Caribou Biosciences, T-CURX, Myeloid Therapeutics, Arsenal Bio, Cargo Therapeutics, Celgene/BMS Cell Therapy, Differentia Bio, eGlint, Advesya; DSMB member: Kyverna; Ad hoc advisory roles/consulting (last 12 months): Prescient Therapeutics, Century Therapeutics, IGM Biosciences, AbbVie, Boxer Capital, Novartis, Merck; Stock options: Eureka Therapeutics, Caribou Biosciences, Myeloid Therapeutics, Arsenal Bio, Cargo Therapeutics, eGlint; Speaker engagement (last 12 months): Pfizer, Novartis; Patents: CJT is an inventor on patents related to CAR-T cell therapy. All other co-authors report no conflict of interest.

Figures

Figure 1.
Figure 1.. Distribution of CRS and ICANS grades overall and across CAR-T products.
Stacked bar plots show the distribution of grades of (A and B) CRS and (C and D) ICANS across CAR-T products. Panels A and C reflect grades of CRS and ICANS in the complete cohort, while panels B and D show grades of CRS and ICANS among patients developing these conditions, respectively. CRS indicates cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity.
Figure 2.
Figure 2.. Temporal distribution of CRS and ICANS grades over 3 years.
Stacked bar plots show the distribution of grades of (A and B) CRS and (C and D) ICANS across different years. Panels A and C reflect grades of CRS and ICANS in the complete cohort, while panels B and D show grades of CRS and ICANS among patients developing these conditions, respectively. CRS indicates cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity.
Figure 3.
Figure 3.. Relationship between CRS and ICANS.
Alluvial plots demonstrate the relationship between CRS and ICANS. The 2 sets of horizontal stacked bars represent the distribution of CRS and ICANS across the entire population. The shaded areas that connect the 2 horizontal stacked bars indicate the density of patients with the connected CRS/ICANS profile. The plot shows CRS and ICANS grades abbreviated, where grade ≥3 represents grades 3, 4, and 5. CRS indicates cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity.
Figure 4.
Figure 4.. Association between CRS and ICANS grades and overall survival.
Kaplan–Meier overall survival estimates by CRS (A) and ICANS (B) status. In this landmark analysis, follow-up days are measured from 30 days after CAR-T infusion. CRS indicates cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity.
See this image and copyright information in PMC

References

    1. Jain T, Bar M, Kansagra AJ, et al. Use of chimeric antigen receptor T cell therapy in clinical practice for relapsed/refractory aggressive B cell non-Hodgkin lymphoma: an expert panel opinion from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. 2019;25(12):2305–2321. - PubMed
    1. Morris EC, Neelapu SS, Giavridis T, Sadelain M. Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nat Rev Immunol. 2022;22(2):85–96. - PMC - PubMed
    1. Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625–638. - PMC - PubMed
    1. Nastoupil LJ, Jain MD, Feng L, et al. Standard-of-care axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma: results from the US lymphoma CAR T consortium. J Clin Oncol. 2020;38(27):3119–3128. - PMC - PubMed
    1. Iacoboni G, Villacampa G, Martinez-Cibrian N, et al. Real-world evidence of tisagenlecleucel for the treatment of relapsed or refractory large B-cell lymphoma. Cancer Med. 2021;10(10):3214–3223. - PMC - PubMed

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