CAR T-Cell Therapy in Non-Hodgkin Lymphoma 

Clinical Practice Guidelines

The 2025 US National Comprehensive Cancer Network (NCCN) [3] and European Society for Medical Oncology (ESMO) [4] clinical practice guidelines recognize CAR T-cell therapy as a standard and increasingly preferred treatment option for selected patients with relapsed or refractory B-cell Non-Hodgkin Lymphomas, particularly Diffuse Large B-Cell Lymphoma. Both guidelines also emphasize important nuances in CAR T-cell therapy management, including confirmation of CD19 expression before treatment, careful patient selection and bridging therapy, toxicity monitoring for cytokine release syndrome (CRS) and neurotoxicity, infection prophylaxis, and the evolving integration of bispecific antibodies and other immunotherapies in sequencing strategies for relapsed disease.

There are currently four FDA-approved CAR T-cell-based therapies for NHL indicated for the following:

Kymriah® Tisagenlecleucel [5]

• Children and young adults ≤25 y with  B-cell acute leukemia (B-ALL) that is refractory or in second or later relapse.

• Adults with relapsed or refractory large B-Cell lymphoma (R/R LBCL), including diffuse diffuse LBCL (DLBCL) not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (FL) after 2 or more treatment lines.

• Adults with R/R FL after 2 or more treatment lines

Yescarta® Axicabtagene ciloleucel [5]

• Adults with LBCL refractory to first line chemoimmunotherapy or relapse within 1 y

• Adults with R/R LBCL, including DLBCL not otherwise specified, primary high mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from FL after 2 or more treatment lines

• Adults with R/R FL after 2 or more treatment lines

Tecartus® Brexucabtagene autoleucel [5]

• Adults with R/R mantle cell lymphoma (MCL)

• Adults ≥26 y with R/R B-ALL 

Breyanzi® Lisocabtagene maraleucel [5]

• Adults with LBCL, including DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade large B-cell lymphoma, primary mediastinal LBCL, and FL refractory to first line chemoimmunotherapy or relapsed within 12 months

• Adults with R/R LBCL after 1 treatment line in transplant-ineligible patients

• Adults with R/R LBCL after 2 or more treatment lines

• Adults with R/R chronic- or small- lymphocytic leukemia after 2 or more treatment lines which have included a BTK inhibitor and a BCL-2 inhibitor

Meta-analysis

• In a meta-analytic study, Cao and colleagues have reviewed and analyzed available clinical studies to systematically evaluate the efficacy and associated complete-remission rate of CAR-T in relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) which is the most common non-Hodgkin lymphoma (NHL), reporting strong evidence of efficacy in terms of curative effects and remission rates (complete remission rate pooled OR=46.8%; 95% CI: 0.408-0.533 vs. 7% reported in large scale retrospective studies using conventional salvage therapies). [6] [7] 

Landmark Trials

• In ZUMA-2 trial, Brexucabtagene autoleucel achieved an objective response rate (ORR) of 87% (95% CI 75–94) and complete remission rate (CR) of 62%, with median duration of response (DOR) not reached at 8.6 months median follow-up. [8] 

• In ZUMA-7 trial, Axicabtagene ciloleucel significantly improved event-free survival (HR 0.40; 95% CI 0.31–0.51; P<0.0001) with ORR 83% vs 50% and CR 65% vs 32% compared to standard care. [9]

• In the ELARA trial, Tisagenlecleucel produced an ORR of 86% (95% CI 77–92) and CR of 68% (95% CI 57–77), with 75% of responders still in remission at 9 months. [10]

• In  the TRANSCEND-MCL trial, Lisocabtagene maraleucel achieved an ORR of 85.3% (95% CI 74.6–92.7) and CR of 67.6% (95% CI 55.2–78.5), with median DOR of 13.3 months.  [11]

• Cytokine release syndrome (CRS): CRS is the most common toxicity of CAR-T therapy, with grade ≥3 CRS reported in ~5–25% of cases; it is typically managed with tocilizumab and corticosteroids when indicated [5] [12]

• Neurotoxicity / ICANS: Neurologic events, collectively known as ICANS, with grade ≥3 neurotoxicity reported in ~5–30%; these events generally respond to corticosteroid therapy and require close neurologic monitoring [5] [12]

• Cytopenias and infection risk: Prolonged cytopenias, including neutropenia, anemia, and thrombocytopenia, often accompanied by hypogammaglobulinemia, which together increase the risk of infections; supportive care with transfusions, growth factors, IVIG, and prophylactic antimicrobials is frequently required [5] [12]

• Treatment-related mortality: Deaths directly related to CAR-T therapy are uncommon, occurring in ~1–5% of patients, and are most often due to severe CRS or ICANS despite appropriate interventions [5] [12]

• Allogeneic (“off-the-shelf”) CAR-T aim to reduce manufacturing delays and broaden patient access. Early trials show encouraging activity with manageable safety profiles [13].

• Dual-antigen targeting CAR-T: By targeting two antigens, these therapies help prevent tumor escape and improve durability of response. Preclinical studies demonstrate robust anti-tumor activity in B-cell NHL [14]

• Gene-edited CAR-T: Gene editing can reduce rejection and T-cell exhaustion, enhancing persistence. Early clinical data show strong responses with acceptable tolerability [15]

• CAR-T for CNS involvement: Third-generation CAR-T constructs show feasibility in patients with secondary CNS lymphoma. This expands therapeutic potential for patients previously excluded from trials. [16]
  
  

1. Alnefaie A, Albogami S, Asiri Y, et al. Chimeric Antigen Receptor T-Cells: An Overview of Concepts, Applications, Limitations, and Proposed Solutions. Front Bioeng Biotechnol. 2022;10:797440. Published 2022 Jun 22. doi:10.3389/fbioe.2022.797440

2. Chu Y, Liu Y, Fang X, et al. The epidemiological patterns of non-Hodgkin lymphoma: global estimates of disease burden, risk factors, and temporal trends. Front Oncol. 2023;13:1059914. Published 2023 Jun 2. doi:10.3389/fonc.2023.1059914

3. Zelenetz AD, Gordon LI, Abramson JS, et al. NCCN Guidelines® Insights: B-Cell Lymphomas 3.2025. J Natl Compr Canc Netw. 2025;23(10):e250048. doi:10.6004/jnccn.2025.0048

4. Eyre TA, Cwynarski K, d'Amore F, et al. Lymphomas: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2025;36(11):1263-1284. doi:10.1016/j.annonc.2025.07.014

5. Goyco Vera D, Waghela H, Nuh M, Pan J, Lulla P. Approved CAR-T therapies have reproducible efficacy and safety in clinical practice. Hum Vaccin Immunother. 2024;20(1):2378543. doi:10.1080/21645515.2024.2378543

6. Cao HH, Wang LL, Geng CK, et al. Therapeutic effects of chimeric antigen receptor T cells (CAR-T) on relapse/refractory diffuse large B-cell lymphoma (R/R DLBCL): a meta-analysis. Eur Rev Med Pharmacol Sci. 2020;24(9):4921-4930. doi:10.26355/eurrev_202005_21181

7. Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, Link BK, Hay A, Cerhan JR, Zhu L, Boussetta S, Feng L, Maurer MJ, Navale L, Wiezorek J, Go WY, Gisselbrecht C. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017 Oct 19;130(16):1800-1808. doi: 10.1182/blood-2017-03-769620. Epub 2017 Aug 3. Erratum in: Blood. 2018 Feb 1;131(5):587-588. doi: 10.1182/blood-2017-11-817775. PMID: 28774879; PMCID: PMC5649550.

8. US Food and Drug Administration. FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma | FDA. Accessed August 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-brexucabtagene-autoleucel-relapsed-or-refractory-mantle-cell-lymphoma

9. Sharma P, Kasamon YL, Lin X, Xu Z, Theoret MR, Purohit-Sheth T. FDA Approval Summary: Axicabtagene Ciloleucel for Second-Line Treatment of Large B-Cell Lymphoma. Clin Cancer Res. 2023;29(21):4331-4337. doi:10.1158/1078-0432.CCR-23-0568

10. US Food and Drug Administration. FDA approves tisagenlecleucel for relapsed or refractory follicular lymphoma | FDA. Accessed August 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-relapsed-or-refractory-follicular-lymphoma

11. US Food and Drug Administration. FDA approves lisocabtagene maraleucel for relapsed or refractory mantle cell lymphoma | FDA. Accessed August 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lisocabtagene-maraleucel-relapsed-or-refractory-mantle-cell-lymphoma

12. Bhaskar ST, Dholaria B, Savani BN, Sengsayadeth S, Oluwole O. Overview of approved CAR-T products and utility in clinical practice. Clin Hematol Int. 2024;6(4):93-99. Published 2024 Oct 23. doi:10.46989/001c.124277

13. Chen S, Zhang Y, Fang C, et al. Donor-derived and off-the-shelf allogeneic anti-CD19 CAR T-cell therapy for R/R ALL and NHL: A systematic review and meta-analysis. Crit Rev Oncol Hematol. 2022;179:103807. doi:10.1016/j.critrevonc.2022.103807

14. Aranda-Orgilles B, Chion-Sotinel I, Skinner J, et al. Preclinical Evidence of an Allogeneic Dual CD20xCD22 CAR to Target a Broad Spectrum of Patients with B-cell Malignancies. Cancer Immunol Res. 2023;11(7):946-961. doi:10.1158/2326-6066.CIR-22-0910

15. Lonez C, Breman E. Allogeneic CAR-T Therapy Technologies: Has the Promise Been Met?. Cells. 2024;13(2):146. Published 2024 Jan 12. doi:10.3390/cells13020146

16. He B, Lin R, Xu N, et al. Efficacy and safety of third-generation CD19-CAR T cells incorporating CD28 and TLR2 intracellular domains for B-cell malignancies with central nervous system involvement: results of a pivotal trial. J Transl Med. 2025;23(1):594. Published 2025 May 27. doi:10.1186/s12967-025-06608-x