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. 2025 Apr 21;26(8):3904.
doi: 10.3390/ijms26083904.

Intravenous Immunoglobulin (IVIG) for Patients with Severe Neurotoxicity Associated with Chimeric Antigen Receptor T-Cell (CAR-T) Therapy

Sepideh Mokhtari  1 , Justin M Asquith  2 , Syeda Saba Kareem  3 , Christina A Bachmeier  1 , Yolanda Pina  1 , Rawan G Faramand  3 , Youngchul Kim  4 , Edwin N Peguero  1 , Solmaz Sahebjam  5 , Mohammad H Jaffer  1 , David P Iacono  1 , Michael D Jain  2 , Michael A Vogelbaum  1 , Marco L Davila  6 , Peter A Forsyth  1 , Frederick L Locke  2 , Aleksandr Lazaryan  2
Affiliations

Intravenous Immunoglobulin (IVIG) for Patients with Severe Neurotoxicity Associated with Chimeric Antigen Receptor T-Cell (CAR-T) Therapy

Sepideh Mokhtari et al. Int J Mol Sci. .

Abstract

Severe immune effector cell-associated neurotoxicity syndrome (ICANS) occurs in about 30% of all patients with large B-cell lymphoma (LBCL) who are treated with axicabtagene ciloleucel (axi-cel). There are currently limited treatment strategies other than the standard corticosteroids, and it is essential to find additional therapies to manage severe ICANS. We conducted a retrospective study of neurologic outcomes among patients who received axi-cel for LBCL from May 2015 to February 2019. We identified patients who developed severe ICANS and were treated with glucocorticoids followed by intravenous immunoglobulin (IVIG) (n = 9) or glucocorticoids alone (n = 10). There was no statistically significant difference in the time to resolution (TTR) of severe ICANS between groups; however, patients in the IVIG had more severe grades of ICANS with a lower performance status at baseline. The cumulative steroid days were 11.2 in the IVIG arm and 13.5 in the glucocorticoids-only arm. The use of IVIG for severe ICANS after axi-cel therapy was tolerable and safe and is generally recommended in the CAR-T setting in patients with hypogammaglobinemia. The use of IVIG as a potential therapeutic agent for severe ICANS can be further explored in future prospective studies.

Keywords: CAR-T; CAR-T-related encephalopathy syndrome; CRES; ICANS; IVIG; axicabtagene ciloleucel; neurotoxicity.

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Conflict of interest statement

Sepideh Mokhtari, Michael D. Jain: Kite Pharma consultancy. Frederick L. Locke: Kite/Gilead: scientific advisor, research support; Celgene/BMS: scientific advisor, travel and lodging support; Novartis: scientific advisor; Allogene: scientific advisor; Wugen: scientific advisor; Calibr: scientific advisor; GammaDelta Therapeutics: scientific advisor; Cellular BioMedicine Group Inc: consultant, travel and lodging support. Moffitt Cancer Center holds patents in Frederick Locke’s name in the field of cellular immunotherapy, including CAR-T-cell therapy. Aleksandr Lazaryan: Sanofi: scientific advisor/consultant.

Figures

Figure 1
Figure 1
(A): Kaplan–Meier curve of time to resolution of severe ICANS. Abbreviations: ICANS, immune effector cell-associated neurotoxicity syndrome; IVIG, intravenous immunoglobulin. (B): Change in neurotoxicity grade over time. Glucocorticoids-alone group: change in ICANS grade for patients after receiving glucocorticoids alone. Steroid + IVIG: change in ICANS grade for patients who received IVIG + glucocorticoids after the initiation of glucocorticoids and before the administration of IVIG. Abbreviations: CAR-T, chimeric antigen receptor T-cell; CI, confidence interval; ICANS, immune effector cell-associated neurotoxicity syndrome; IVIG, intravenous immunoglobulin.
Figure 2
Figure 2
Clinical outcomes and medical interventions after CAR-T therapy in patients over time. Patients 1 through 9 received IVIG + glucocorticoids and patients 10 through 19 received glucocorticoids alone. The top bar represents the ICANS profile, and the lower bar represents the CRS profile. The grading of each type of toxicity is labeled with a different color, as demonstrated in the legend. Each intervention, such as tocilizumab, dexamethasone, methylprednisolone, or IVIG, is labeled with a different symbol, as demonstrated in the legend. Abbreviations: CAR-T, chimeric antigen receptor T-cell; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; IVIG, intravenous immunoglobulin; NT, neurotoxicity.
Figure 3
Figure 3
Comparison of median cytokine levels in each group. Serum cytokine data were available for 7 patients who received IVIG + glucocorticoids and 4 patients who received glucocorticoids alone. Dashed lines represent the median day each intervention was given after CAR-T therapy. Green dashed line: tocilizumab (day 4). Red dashed line: glucocorticoids (day 7). Blue dashed line: IVIG (day 8). * trend, but not significantly different (p < 0.1); ** significant difference (p < 0.05). Abbreviations: CAR-T, chimeric antigen receptor T-cell; IVIG, intravenous immunoglobulin.
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