Management of Cytokine Release Syndrome (CRS) following CAR T-cell therapy: a comprehensive review

Abstract

Chimeric antigen receptor T-cell (CAR T-cell) therapy represents a paradigm shift in treating refractory hematological malignancies. Despite its transformative potential, clinical application is frequently complicated by severe, potentially life-threatening toxicities, with cytokine release syndrome (CRS) being the most prominent. This comprehensive review synthesizes current therapeutic strategies for CRS, integrating recent advancements in multidisciplinary care models, refined risk stratification, and evolving prophylactic protocols. Furthermore, this paper contextualizes CRS management within the broader landscape of CAR T-cell-related adverse event (AE) mitigation, highlighting established best practices and exploring future directions aimed at enhancing the safety profile and optimizing the therapeutic index of CAR T-cell therapies.

Keywords

Chimeric antigen receptor T-cell (CAR T-cell) therapy / Cytokine release syndrome (CRS) / Adverse event management / Risk stratification / Biomarker-guided intervention

References

[1] MaudeSL, LaetschTW, BuechnerJ, RivesS, BoyerM, BittencourtH, et al.. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med, 2018, 378(5): 439-448

[2] NeelapuSS, LockeFL, BartlettNL, LekakisLJ, MiklosDB, JacobsonCA, et al.. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med, 2017, 377(26): 2531-2544

[3] SchusterSJ, SvobodaJ, ChongEA, NastaSD, MatoAR, AnakO, et al.. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med, 2017, 377(26): 2545-2554

[4] MunshiNC, AndersonLD Jr, ShahN, MadduriD, BerdejaJ, LonialS, et al.. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med, 2021, 384(8): 705-716

[5] KochenderferJN, RosenbergSA. Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol, 2013, 10(5): 267-276

[6] TurtleCJ, HanafiLA, BergerC, GooleyTA, CherianS, HudecekM, et al.. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest, 2016, 126(6): 2123-2138

[7] LeeDW, GardnerR, PorterDL, LouisCU, AhmedN, JensenM, et al.. Current concepts in the diagnosis and management of cytokine release syndrome. Blood, 2014, 124(2): 188-195

[8] BrudnoJN, KochenderferJN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood, 2016, 127(26): 3321-3330

[9] NeelapuSS, TummalaS, KebriaeiP, WierdaW, GutierrezC, LockeFL, et al.. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol, 2018, 15(1): 47-62

[10] TeacheyDT, LaceySF, ShawPA, MelenhorstJJ, MaudeSL, FreyN, et al.. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov, 2016, 6(6): 664-679

[11] HayKA, HanafiLA, LiD, GustJ, LilesWC, WurfelMM, et al.. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood, 2017, 130(21): 2295-2306

[12] GustJ, HayKA, HanafiLA, LiD, MyersonD, Gonzalez-CuyarLF, et al.. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov, 2017, 7(12): 1404-1419

[13] SantomassoBD, ParkJH, SalloumD, RiviereI, FlynnJ, MeadE, et al.. Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov, 2018, 8(8): 958-971

[14] MaudeSL, FreyN, ShawPA, AplencR, BarrettDM, BuninNJ, et al.. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med, 2014, 371(16): 1507-1517

[15] TurtleCJ, HayKA, HanafiLA, LiD, CherianS, ChenX, et al.. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor-modified T cells after failure of ibrutinib. J Clin Oncol, 2017, 35(26): 3010-3020

[16] DavilaML, RiviereI, WangX, BartidoS, ParkJ, CurranK, et al.. Efficacy and toxicity management of 19–28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med, 2014, 6(224): 224ra25

[17] PorterDL, HwangWT, FreyNV, LaceySF, ShawPA, LorenAW, et al.. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med, 2015, 7(303): 303ra139

[18] LeeDW, SantomassoBD, LockeFL, GhobadiA, TurtleCJ, BrudnoJN, 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

[19] WangZ, HanW. Biomarkers of cytokine release syndrome and neurotoxicity related to CAR-T cell therapy. Biomark Res, 2018, 6: 4

[20] LichtensteinDA, SchischlikF, ShaoL, SteinbergSM, YatesB, WangHW, et al.. Characterization of HLH-like manifestations as a CRS variant in patients receiving CD22 CAR T cells. Blood, 2021, 138(24): 2469-2484

[21] BrudnoJN, NatrakulD, LamN, Dulau-FloreaA, YuanCM, KochenderferJN. Acute and delayed cytopenias following CAR T-cell therapy: an investigation of risk factors and mechanisms. Leuk Lymphoma, 2022, 63(8): 1849-1860

[22] StratiP, AhmedS, KebriaeiP, NastoupilLJ, ClaussenCM, WatsonG, et al.. Clinical efficacy of anakinra to mitigate CAR T-cell therapy-associated toxicity in large B-cell lymphoma. Blood Adv, 2020, 4(13): 3123-3127

[23] NorelliM, CamisaB, BarbieraG, FalconeL, PurevdorjA, GenuaM, et al.. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med, 2018, 24(6): 739-748

[24] LinMY, NamE, ShihRM, ShaferA, BourenA, Ayala CejaM, et al.. Self-regulating CAR-T cells modulate cytokine release syndrome in adoptive T-cell therapy. J Exp Med, 2024, 221(6): e20221988

[25] LiuY, JieX, NianL, WangY, WangC, MaJ, et al.. A combination of pre-infusion serum ferritin, CRP and IL-6 predicts outcome in relapsed/refractory multiple myeloma patients treated with CAR-T cells. Front Immunol, 2023, 14: 1169071

[26] SchmidtsA, WehrliM, MausMV. Toward better understanding and management of CAR-T cell-associated toxicity. Annu Rev Med, 2021, 72: 365-382

[27] GiavridisT, van der StegenSJC, EyquemJ, HamiehM, PiersigilliA, SadelainM. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med, 2018, 24(6): 731-738

[28] ShouseG, DanilovAV, ArtzA. CAR T-cell therapy in the older person: indications and risks. Curr Oncol Rep, 2022, 24(9): 1189-1199

[29] CurranKJ, MargossianSP, KernanNA, SilvermanLB, WilliamsDA, ShuklaN, et al.. Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL. Blood, 2019, 134(26): 2361-2368

[30] CrombieJL, NastoupilLJ, ReddR, TangK, ShouseG, HerreraAF, et al.. Real-world outcomes of axicabtagene ciloleucel in adult patients with primary mediastinal B-cell lymphoma. Blood Adv, 2021, 5(18): 3563-3567

[31] FeuchtJ, SunJ, EyquemJ, HoYJ, ZhaoZ, LeiboldJ, et al.. Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency. Nat Med, 2019, 25(1): 82-88

[32] PhilipsonBI, O'ConnorRS, MayMJ, JuneCH, AlbeldaSM, MiloneMC. 4–1BB costimulation promotes CAR T cell survival through noncanonical NF-kappaB signaling. Sci Signal, 2020, 13(625): eaay8248

[33] RotteA, FrigaultMJ, AnsariA, GlinerB, HeeryC, ShahB. Dose-response correlation for CAR-T cells: a systematic review of clinical studies. J Immunother Cancer, 2022, 10(12): e005678

[34] CobbDA, LeeDW. Cytokine release syndrome biology and management. Cancer J, 2021, 27(2): 119-125

[35] DiorioC, ShraimR, MyersR, BehrensEM, CannaS, BassiriH, et al.. Comprehensive serum proteome profiling of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome patients with B-cell all receiving CAR T19. Clin Cancer Res, 2022, 28(17): 3804-3813

[36] Caballero-Bellón M, Bobillo-Perez S, Català A, Alonso-Saladrigues A, Valls A, Rives S, Jordan I. Role of procalcitonin, C-reactive protein and ferritin in cytokine release syndrome after CAR T-cell therapy in children and young adults. Biomarkers. 2025;30(2):115–22.

[37] GreenbaumU, StratiP, SalibaRM, TorresJ, RondonG, NietoY, et al.. CRP and ferritin in addition to the EASIX score predict CAR-T-related toxicity. Blood Adv, 2021, 5(14): 2799-2806

[38] AspuriaPJ, VivonaS, BauerM, SemanaM, RattiN, McCauleyS, et al.. An orthogonal IL-2 and IL-2Rbeta system drives persistence and activation of CAR T cells and clearance of bulky lymphoma. Sci Transl Med, 2021, 13(625): eabg7565

[39] GalliE, SoraF, HohausS, FresaA, PansiniI, AutoreF, et al.. Endothelial activation predicts disseminated intravascular coagulopathy, cytokine release syndrome and prognosis in patients treated with anti-CD19 CAR-T cells. Br J Haematol, 2023, 201(1): 86-94

[40] WeiZ, ZhaoC, ZhangM, XuJ, XuN, WuS, et al.. PrCRS: a prediction model of severe CRS in CAR-T therapy based on transfer learning. BMC Bioinformatics, 2024, 25(1): 197

[41] Paludo J SJ, Contreras Guzman E, Khurana A, Kapoor P, Gertz MA, Wang Y, Lin Y. Machine learning-based prediction of cytokine release syndrome post CAR-T cell therapy. 2025 ASCO Annual Meeting; May 28, 2025: Journal of Clinical Oncology; 2025. p. e13622.

[42] BogatuA, WysockaM, WysockiO, ButterworthH, PillaiM, AllisonJ, et al.. Meta-analysis informed machine learning: supporting cytokine storm detection during CAR-T cell therapy. J Biomed Inform, 2023, 142: 104367

[43] BrudnoJN, KochenderferJN. Recent advances in CAR T-cell toxicity: mechanisms, manifestations and management. Blood Rev, 2019, 34: 45-55

[44] HayKA, TurtleCJ. Chimeric Antigen Receptor (CAR) T cells: lessons learned from targeting of CD19 in B-cell malignancies. Drugs, 2017, 77(3): 237-245

[45] MahadeoKM, KhazalSJ, Abdel-AzimH, FitzgeraldJC, TaraseviciuteA, BollardCM, et al.. Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy. Nat Rev Clin Oncol, 2019, 16(1): 45-63

[46] GustJ, TaraseviciuteA, TurtleCJ. Neurotoxicity associated with CD19-targeted CAR-T cell therapies. CNS Drugs, 2018, 32(12): 1091-1101

[47] GazeauN, LiangEC, WuQV, VoutsinasJM, BarbaP, IacoboniG, et al.. Anakinra for refractory cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome after chimeric antigen receptor T cell therapy. Transplant Cell Ther, 2023, 29(7): 430-437

[48] LockeFL, NeelapuSS, BartlettNL, SiddiqiT, ChavezJC, HosingCM, et al.. Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther, 2017, 25(1): 285-295

[49] TurtleCJ, HanafiLA, BergerC, HudecekM, PenderB, RobinsonE, et al.. Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med, 2016, 8(355): 355ra116

[50] LeeDW, KochenderferJN, Stetler-StevensonM, CuiYK, DelbrookC, FeldmanSA, et al.. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet, 2015, 385(9967): 517-528

[51] MuellerKT, WaldronE, GruppSA, LevineJE, LaetschTW, PulsipherMA, et al.. Clinical pharmacology of tisagenlecleucel in B-cell acute lymphoblastic leukemia. Clin Cancer Res, 2018, 24(24): 6175-6184

[52] BonifantCL, JacksonHJ, BrentjensRJ, CurranKJ. Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics, 2016, 3: 16011

[53] YangY, ZhangY, XingX, XuG, LinX, WangY, et al.. IL-6 translation is a therapeutic target of human cytokine release syndrome. J Exp Med, 2023, 220(11): e20230577

[54] JainT, LitzowMR. Management of toxicities associated with novel immunotherapy agents in acute lymphoblastic leukemia. Ther Adv Hematol, 2020, 11: 2040620719899897

[55] ToppMS, van MeertenT, HouotR, MinnemaMC, BouabdallahK, LugtenburgPJ, et al.. Earlier corticosteroid use for adverse event management in patients receiving axicabtagene ciloleucel for large B-cell lymphoma. Br J Haematol, 2021, 195(3): 388-398

[56] SantomassoBD, NastoupilLJ, AdkinsS, LacchettiC, SchneiderBJ, AnadkatM, et al.. Management of immune-related adverse events in patients treated with chimeric antigen receptor T-cell therapy: ASCO guideline. J Clin Oncol, 2021, 39(35): 3978-3992

[57] Los-Arcos I, Iacoboni G, Aguilar-Guisado M, Alsina-Manrique L, Diaz de Heredia C, Fortuny-Guasch C, et al. Recommendations for screening, monitoring, prevention, and prophylaxis of infections in adult and pediatric patients receiving CAR T-cell therapy: a position paper. Infection. 2021;49(2):215–31.

[58] BailenR, IacoboniG, DelgadoJ, Lopez-CorralL, Hernani-MoralesR, Ortiz-MaldonadoV, et al.. Anti-CD19 CAR-T cell therapy in elderly patients: multicentric real-world experience from GETH-TC/GELTAMO. Transplant Cell Ther, 2024, 30(10): 988 e1-e11

[59] BerningP, ShumilovE, MaulhardtM, BoyadzhievH, KerkhoffA, CallS, et al.. Chimeric antigen receptor-T cell therapy shows similar efficacy and toxicity in patients with diffuse large B-cell lymphoma aged 70 and older compared to younger patients: a multicenter cohort study. Hemasphere, 2024, 8(3): e54

[60] KadaukeS, MyersRM, LiY, AplencR, BaniewiczD, BarrettDM, et al.. Risk-adapted preemptive tocilizumab to prevent severe cytokine release syndrome after CTL019 for pediatric B-cell acute lymphoblastic leukemia: a prospective clinical trial. J Clin Oncol, 2021, 39(8): 920-930

[61] HeczeyA, LouisCU, SavoldoB, DakhovaO, DurettA, GrilleyB, et al.. CAR T cells administered in combination with lymphodepletion and PD-1 Inhibition to patients with neuroblastoma. Mol Ther, 2017, 25(9): 2214-2224

[62] ChenF, TeacheyDT, PequignotE, FreyN, PorterD, MaudeSL, et al.. Measuring IL-6 and sIL-6R in serum from patients treated with tocilizumab and/or siltuximab following CAR T cell therapy. J Immunol Methods, 2016, 434: 1-8

[63] HuY, SunJ, WuZ, YuJ, CuiQ, PuC, et al.. Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy. J Hematol Oncol, 2016, 9(1): 70

[64] O'RourkeK. ASCO releases guideline on CAR T-cell therapy: a multidisciplinary team's recommendations help in the recognition, workup, evaluation, and management of the most common chimeric antigen receptor (CAR) T-cell-related toxicities: a multidisciplinary team's recommendations help in the recognition, workup, evaluation, and management of the most common chimeric antigen receptor (CAR) T-cell-related toxicities. Cancer, 2022, 128(3): 429-430

[65] PonnapalliA, AroraAK, SoubaniAO. Critical care considerations of chimeric antigen receptor (CAR) T-cell therapy. Respir Med, 2025, 238: 107958

[66] Fortin EnsignSP, GaulinC, HrachovaM, RuffM, HarahshehE, VicentiK, et al.. Evaluating the patient with neurotoxicity after chimeric antigen receptor T-cell therapy. Curr Treat Options Oncol, 2022, 23(12): 1845-1860

[67] FischerL, GriebN, BornP, WeissR, SeiffertS, BoldtA, et al.. Cellular dynamics following CAR T cell therapy are associated with response and toxicity in relapsed/refractory myeloma. Leukemia, 2024, 38(2): 372-382

[68] LiuW, LinS, ZhuX, YinL, LiuQ, LeiS, et al.. Safety assessment of anti-B cell maturation antigen chimeric antigen receptor T cell therapy: a real-world study based on the FDA adverse event reporting system database. Front Immunol, 2024, 15: 1433075

[69] RejeskiK, PerezA, SesquesP, HosterE, BergerC, JentzschL, et al.. CAR-HEMATOTOX: a model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Blood, 2021, 138(24): 2499-2513

[70] PanJ, DengB, LingZ, SongW, XuJ, DuanJ, et al.. Ruxolitinib mitigates steroid-refractory CRS during CAR T therapy. J Cell Mol Med, 2021, 25(2): 1089-1099

[71] BajwaA, ZhaoQ, GeerM, LinC, WestholderJ, MaakaronJ, et al.. Siltuximab for chimeric antigen receptor T-cell therapy-related CRS and ICANS: a multicenter retrospective analysis. Blood Adv, 2025, 9(1): 170-175

[72] CuiW, ZhangXY, LiZ, DaiHP, YinJ, CuiQY, et al.. Long-term follow-up of tandem CD19/CD22 CAR T-Cells in r/r B-ALL patients with high-risk features. Am J Hematol, 2023, 98(11): E338-E340

[73] Giordano AttianeseGMP, ShuiS, CribioliE, TribouletM, SchellerL, HafeziM, et al.. Dual ON/OFF-switch chimeric antigen receptor controlled by two clinically approved drugs. Proc Natl Acad Sci U S A, 2024, 121(44): e2405085121

[74] XiaoW, XuL, WangJ, YuK, XuB, QueY, et al.. FGFR4-specific CAR-T cells with inducible caspase-9 suicide gene as an approach to treat rhabdomyosarcoma. Cancer Gene Ther, 2024, 31(10): 1571-1584

[75] ParkS, PascuaE, LindquistKC, KimberlinC, DengX, MakYSL, et al.. Direct control of CAR T cells through small molecule-regulated antibodies. Nat Commun, 2021, 12(1): 710

[76] van der SchansJJ, WangZ, van ArkelJ, van SchaikT, KatsarouA, RuiterR, et al.. Specific targeting of multiple myeloma by dual split-signaling chimeric antigen receptor T cells directed against CD38 and CD138. Clin Cancer Res, 2023, 29(20): 4219-4229

Funding

National Natural Science Foundation of China(82341208)

National Major Science and Technology Projects of China(2023ZD0501303)

RIGHTS & PERMISSIONS

The Author(s)