Evaluation of cytokine release syndrome in non-Hodgkin lymphoma therapy with bispecific antibodies: A meta-analysis of clinical trials
DOI:
https://doi.org/10.30968/jhphs.2026.172.1496Abstract
Objectives: To provide a comprehensive analysis regarding the safety profile of bispecific antibodies (BsAbs), focusing on the prevalence of cytokine release syndrome (CRS) in patients with non-Hodgkin lymphoma (NHL). Methods: We performed a meta-analysis of phase 1 to 3 clinical trials with different BsAbs approved for commercialization (mosunetuzumab, glofitamab, odronextamab, and epcoritamab), administered as monotherapy or in combination with other anticancer therapies, both in first-line and in cases of relapsed/refractory disease, as well as in different NHL subtypes. Results: This meta-analysis provides pooled data from 40 clinical trial cohorts totaling information from 3,653 patients and 1,577 events on the safety of BsAbs (anti-CD20/CD3) in the treatment of NHL. The median age of participants was 64.4 years. The pooled prevalence of CRS of all grades and grade ≥3 was 43% and 7%, respectively. Stratification by treatment regimen (monotherapy versus combination therapy) showed that CRS of all grades was estimated at 47% (95% CI: 41–54%) in monotherapy and 35% (95% CI: 27–45%) in combination therapy, based on the included studies. However, the pooled prevalence estimates of severe CRS (grade ≥3) were similar between groups, with 7% (95% CI: 5–9%) in monotherapy and 6% (95% CI: 3–11%) in combination therapy. Conclusion: This meta-analysis provides a comprehensive descriptive synthesis of CRS prevalence among patients with NHL treated with bispecific antibodies (BsAbs). CRS of any grade was frequently reported, whereas severe events (grade ≥3) remained uncommon, particularly in the context of relapsed/refractory disease, which represented 90.61% of the included cohort. Given the clinical and methodological heterogeneity across trials and the non-comparative nature of the pooled estimates, these findings should be interpreted as descriptive evidence rather than direct comparative evidence of safety. Future research should focus on optimizing dosing strategies, incorporating prophylactic measures, standardizing CRS reporting, and improving toxicity management to better balance tolerability and efficacy of BsAbs in patients with NHL.
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1. Damlaj M, El Fakih R, Hashmi SK. Evolution of survivorship in lymphoma, myeloma and leukemia: Metamorphosis of the field into long term follow-up care. Blood Rev. 2019;33:63-73. doi:10.1016/j.blre.2018.07.003
2. Zhang N, Wu J, Wang Q, et al. Global burden of hematologic malignancies and evolution patterns over the past 30 years. Blood Cancer Journal. 2023;5(4):1-13. doi:10.1038/s41408-023-00853-3
3. Al-hamadani M, Habermann TM, Cerhan JR, Macon WR, Maurer MJ, Go RS. Non-Hodgkin lymphoma subtype distribution, geodemographic patterns, and survival in the US: A longitudinal analysis of the National Cancer Data Base from 1998 to 2011. American Journal of Hematology. 2015;90(9):1-6. doi:10.1002/ajh.24086
4. Solomon J, Arcila M. Molecular Diagnostics of Non-Hodgkin Lymphoma. The Cancer Journal. 2020;8(3):186-194.
5. Silkenstedt E, Salles G, Campo E, Dreyling M. B-cell non-Hodgkin lymphomas. Lancet. 2024;403(4):1791-1807. doi:10.1016/S0140-6736(23)02705-8.B-cell
6. Chen H, Zhao J, Zhao D, et al. Lymphoma relapse 1 year or later after immunochemotherapy in DLBCL patients : clinical features and outcome. Clinical and Experimental Medicine. 2024;24(1):1-7. doi:10.1007/s10238-024-01306-2
7. Kahl BS, Yang DT. Follicular lymphoma : evolving therapeutic strategies. Blood. 2016;127(17):2055-2063. doi:10.1182/blood-2015-11-624288
8. Jones BSE, Grozea PN, Miller TP, et al. Chemotherapy With Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Alone or With Levamisole or With Levamisole Plus BCG for Malignant Lymphoma: A Southwest Oncology Group Study. Journal of Clinical Oncology. 1985;3(10):1318-1324.
9. Feugier P, Van Hoof A, Sebban C, et al. Long-Term Results of the R-CHOP Study in the Treatment of Elderly Patients With Diffuse Large B-Cell Lymphoma : A Study by the Groupe d’Etude des Lymphomes de l’ Adulte. Journal of Clinical Oncology. 2005;23(18):4117-4126. doi:10.1200/JCO.2005.09.131
10. Klener P, Klanova M. Drug Resistance in Non-Hodgkin Lymphomas. Int J Mol Sci. 2020;21(6):2081. doi:10.3390/ijms21062081
11. Herrera M, Pretelli G, Desai J, et al. Bispecific antibodies: advancing precision oncology. Trends Cancer. 2024;10(10):893-919. doi:10.1016/j.trecan.2024.07.002
12. Huang S, van Duijnhoven SMJ, Sijts AJAM, van Elsas A. Bispecific antibodies targeting dual tumor-associated antigens in cancer therapy. J Cancer Res Clin Oncol. 2020;146(12):3111-3122. doi:10.1007/s00432-020-03404-6
13. Wei J, Yang Y, Wang G, Liu M. Current landscape and future directions of bispecific antibodies in cancer immunotherapy. Front Immunol. 2022;13:1035276. doi:10.3389/fimmu.2022.1035276
14. Salvaris R, Ong J, Gregory GP. Bispecific Antibodies: A Review of Development, Clinical Efficacy and Toxicity in B-Cell Lymphomas. J Pers Med. 2021;11(5):355. doi:10.3390/jpm11050355
15. Omer MH, Shafqat A, Ahmad O, Alkattan K, Yaqinuddin A, Damlaj M. Bispecific Antibodies in Hematological Malignancies: A Scoping Review. Cancers (Basel). 2023;15(18):4550. doi:10.3390/cancers15184550
16. 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. doi:10.1038/s41577-021-00547-6
17. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, et al. Cytokine release syndrome. J Immunother Cancer. 2018;6(1):56. doi:10.1186/s40425-018-0343-9
18. Basch E, Reeve BB, Mitchell SA, et al. Development of the National Cancer Institute’s patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). J Natl Cancer Inst. 2014;106(9):dju244. doi:10.1093/jnci/dju244
19. Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. Glofitamab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2022;387(24):2220-2231. doi:10.1056/NEJMoa2206913
20. Kim WS, Kim TM, Cho SG, et al. Odronextamab monotherapy in patients with relapsed/refractory diffuse large B cell lymphoma: primary efficacy and safety analysis in phase 2 ELM-2 trial. Nat Cancer. 2025;6(3):528-539. doi:10.1038/s43018-025-00921-6
21. Matasar M, Bartlett NL, Shadman M, et al. Mosunetuzumab Safety Profile in Patients With Relapsed/Refractory B-cell Non-Hodgkin Lymphoma: Clinical Management Experience From a Pivotal Phase I/II Trial. Clin Lymphoma Myeloma Leuk. 2024;24(4):240-253. doi:10.1016/j.clml.2023.12.005
22. Thieblemont C, Karimi YH, Ghesquieres H, et al. Epcoritamab in relapsed/refractory large B-cell lymphoma: 2-year follow-up from the pivotal EPCORE NHL-1 trial. Leukemia. 2024;38(12):2653-2662. doi:10.1038/s41375-024-02410-8
23. Zhang M-Y, Cai Y-M, Zhu X-Q, Lu K-J, Shen L-J, Du J. Meta-analysis of comparing CAR-T and bispecific antibody therapy in relapsed/refractory indolent B-cell non-Hodgkin’s lymphomas. Journal of Translational Medicine. 2025;24(3):1-12. doi:10.1186/s12967-025-07571-3
24. Crombie JL, Graff T, Falchi L, et al. Consensus recommendations on the management of toxicity associated with CD3×CD20 bispecific antibody therapy. Blood. 2024;143(16):1565-1575. doi:10.1182/blood.2023022432
25. Schmidt C, Leclerq G, Gaillard B, et al. Understanding and mitigating the cytokine release syndrome (CRS) mediated by T cell biespecific antibody (TCB) treatment. Journal for ImmunoTherapy of Cancer. 2024;12(2):1-2. doi: 10.1136/jitc-2024-SITC2024.1171 Nascimento RG, et al. Evaluation of cytokine release syndrome in non-Hodgkin lymphoma therapy with bispecific antibodies: A meta-analysis of clinical trials. J Hosp Pharm Health Serv. 2026;17(2):e1496. DOI:10.30968/jhphs.2026.172.1496. JHPHSJournal of Hospital Pharmacy and Health Services
26. Leclercq-Cohen G, Steinhoff N, Servera LA, et al. Dissecting the Mechanisms Underlying the Cytokine Release Syndrome (CRS) Mediated by T-Cell Bispecific Antibodies. Clinical Cancer Research. 2023;29(21):4449-4463. doi:10.1158/1078-0432.CCR-22-3667
27. Zhu M, Olson K, Kirshner JR, et al. Translational findings for odronextamab: From preclinical research to a first-in-human study in patients with CD20+ B-cell malignancies. Clinical and Translational Science. 2022;15(4):954-966. doi:10.1111/cts.13212
28. Shumilov E, Wurm-Kuczera R, Kerkhoff A, et al. Safety and efficacy of glofitamab for relapsed/refractory large B-cell lymphoma in a multinational real-world study. Blood Advances. 2025;9(15):3865-3877. doi:10.1182/bloodadvances.2024014903
29. Radtke KK, Bender BC, Li Z, et al. Clinical Pharmacology of Cytokine Release Syndrome with T-Cell-Engaging Bispecific Antibodies: Current Insights and Drug Development Strategies. Clinical Cancer Research. 2025;31(2):245-257. doi:10.1158/1078-0432.CCR-24-2247
30. Falchi L, Hutchings M, Carlo-Stella C, et al. Dexamethasone is associated with reduced frequency and intensity of cytokine release syndrome compared with alternative corticosteroid regimens as premedication for glofitamab in patients with relapsed/refractory large B-cell lymphoma. Haematologica. 2025;110(4):999-1004. doi:10.3324/haematol.2024.286257
31. Le RQ, Li L, Yuan W, et al. FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell-Induced Severe or Life-Threatening Cytokine Release Syndrome. The Oncologist. 2018;23(8):943-947. doi:10.1634/theoncologist.2018-0028
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