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PubMed This is a summary of 15 peer-reviewed journal articles Updated
Oncology · Relapsed or Refractory Diffuse Large B-cell Lymphoma

When the First Treatment Doesn't Work

At a Glance

If DLBCL returns or does not respond to initial treatment, powerful second-line options exist. CAR-T cell therapy engineers your own immune cells to attack the cancer, while off-the-shelf bispecific antibodies bring immune cells and lymphoma cells together for destruction.

If your first treatment didn’t work or your lymphoma has returned, it is normal to feel a sense of fear or frustration. However, the landscape for “relapsed or refractory” DLBCL has undergone a revolution. Today, there are powerful new options that offer a genuine chance for long-term remission [1][2].

Defining the Challenge

Doctors use specific terms to describe how the lymphoma is behaving:

  • Primary Refractory: The lymphoma did not respond to the first treatment or began growing again within six months of finishing it [3].
  • Early Relapse: The cancer returned within 12 months of finishing treatment [3][4].
  • Late Relapse: The cancer returned more than 12 months after the end of treatment.

CAR-T Cell Therapy: Engineering Your Immune System

CAR-T cell therapy (Chimeric Antigen Receptor T-cell therapy) is a breakthrough “living drug” [1]. Instead of using chemicals to kill cancer, it uses your own immune cells [5].

  1. Collection: Your T-cells (a type of white blood cell) are collected from your blood [5].
  2. Engineering: In a lab, these cells are genetically modified to grow “sensors” (CARs) that allow them to recognize and attach to a specific protein on your lymphoma cells [5].
  3. Infusion: Once grown into an army of millions, the engineered cells are infused back into your body to destroy the cancer [5].

Manufacturing Timeline: Unlike off-the-shelf treatments, this custom manufacturing process typically takes 3 to 4 weeks (often called “vein-to-vein” time) [5].

For patients with early relapse or refractory disease, CAR-T has now replaced the older standard of Autologous Stem Cell Transplant (ASCT) because it has been shown to be more effective at keeping the cancer away for a longer period [1][2].

Managing CAR-T Side Effects

Because CAR-T cells are so active, they can trigger intense immune reactions that require specialized hospital monitoring:

  • Cytokine Release Syndrome (CRS): As the CAR-T cells attack the cancer, they release “cytokines” that can cause high fevers, low blood pressure, and flu-like symptoms [6][7].
  • ICANS (Neurotoxicity): This involves temporary inflammation in the brain that can cause confusion, difficulty speaking, or tremors [6][8].

Bispecific Antibodies: The “Off-the-Shelf” Option

If CAR-T cell therapy is not an option—or if the lymphoma returns after CAR-T—a new class of drugs called bispecific antibodies (such as epcoritamab or glofitamab) is now available [9][10].

  • How They Work: These drugs act like a “matchmaker.” One arm of the antibody grabs a lymphoma cell, and the other arm grabs a nearby T-cell, pulling them together so the immune cell can destroy the cancer [11][12].
  • The Advantage: Unlike CAR-T, bispecific antibodies are “off-the-shelf” and can be started almost immediately [13][14].

While a relapse is a serious hurdle, these innovative therapies mean that a “second-line” treatment today is often more targeted and powerful than the first-line treatments used just a few years ago [1][15]. For life beyond treatment, review Life After DLBCL Treatment.

Common questions in this guide

What is the difference between primary refractory and early relapse DLBCL?
Primary refractory means the lymphoma did not respond to your first treatment or started growing again within six months. Early relapse means the cancer returned within 12 months after finishing treatment. Knowing which type you have helps your doctor choose the most effective next step for your care.
How does CAR-T cell therapy work for returning lymphoma?
CAR-T cell therapy is a treatment that uses your own immune system to fight the cancer. Your T-cells are collected from your blood, genetically modified in a laboratory to recognize lymphoma cells, and then infused back into your body to hunt down and destroy the disease.
What are the side effects of CAR-T cell therapy?
Because CAR-T cells trigger a very strong immune response, they can cause Cytokine Release Syndrome (CRS), which leads to high fevers and low blood pressure. They can also cause ICANS, a temporary neurological condition resulting in confusion, tremors, or difficulty speaking. Patients require specialized hospital monitoring to manage these risks.
What are bispecific antibodies and how do they treat DLBCL?
Bispecific antibodies are off-the-shelf drugs that act like a matchmaker between your immune system and the cancer. One part of the medication attaches to a lymphoma cell, and the other part attaches to one of your T-cells, pulling them together so your immune system can destroy the cancer.
Why might I receive bispecific antibodies instead of CAR-T cell therapy?
Bispecific antibodies are readily available off-the-shelf and can be started almost immediately, avoiding the 3-to-4 week manufacturing wait time required for CAR-T therapy. They are often used if you are not a candidate for CAR-T or if your lymphoma returns after CAR-T treatment.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Am I considered 'primary refractory' or 'early relapse,' and how does that change my treatment options?
  2. 2.Am I a candidate for CAR-T cell therapy, and is it a better choice for me than a stem cell transplant?
  3. 3.What is the process for collecting and engineering my T-cells, and how long will the 'wait time' be for manufacturing?
  4. 4.What specific steps does your center take to monitor and manage CRS and ICANS during CAR-T therapy?
  5. 5.If CAR-T isn't the right fit for me, are bispecific antibodies like epcoritamab or glofitamab an option?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (15)
  1. 1

    Second-Line Chimeric Antigen Receptor T-Cell Therapy in Diffuse Large B-Cell Lymphoma : A Cost-Effectiveness Analysis.

    Kelkar AH, Cliff ERS, Jacobson CA, et al.

    Annals of internal medicine 2023; (176(12)):1625-1637 doi:10.7326/M22-2276.

    PMID: 38048587
  2. 2

    Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma.

    Westin JR, Oluwole OO, Kersten MJ, et al.

    The New England journal of medicine 2023; (389(2)):148-157 doi:10.1056/NEJMoa2301665.

    PMID: 37272527
  3. 3

    Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial.

    Kamdar M, Solomon SR, Arnason J, et al.

    Lancet (London, England) 2022; (399(10343)):2294-2308 doi:10.1016/S0140-6736(22)00662-6.

    PMID: 35717989
  4. 4

    Outcome of patients with primary refractory diffuse large B cell lymphoma after R-CHOP treatment.

    Hitz F, Connors JM, Gascoyne RD, et al.

    Annals of hematology 2015; (94(11)):1839-43 doi:10.1007/s00277-015-2467-z.

    PMID: 26246466
  5. 5

    Safety of Axicabtagene Ciloleucel for the Treatment of Relapsed or Refractory Large B-Cell Lymphoma.

    Grana A, Gut N, Williams K, et al.

    Clinical lymphoma, myeloma & leukemia 2021; (21(4)):238-245 doi:10.1016/j.clml.2020.10.005.

    PMID: 33132101
  6. 6

    Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy.

    Morris EC, Neelapu SS, Giavridis T, Sadelain M

    Nature reviews. Immunology 2022; (22(2)):85-96 doi:10.1038/s41577-021-00547-6.

    PMID: 34002066
  7. 7

    Glial injury in neurotoxicity after pediatric CD19-directed chimeric antigen receptor T cell therapy.

    Gust J, Finney OC, Li D, et al.

    Annals of neurology 2019; (86(1)):42-54 doi:10.1002/ana.25502.

    PMID: 31074527
  8. 8

    Cytokine release syndrome: grading, modeling, and new therapy.

    Liu D, Zhao J

    Journal of hematology & oncology 2018; (11(1)):121 doi:10.1186/s13045-018-0653-x.

    PMID: 30249264
  9. 9

    Challenges and solutions to superior chimeric antigen receptor-T design and deployment for B-cell lymphomas.

    Gao J, Dahiya S, Patel SA

    British journal of haematology 2023; (203(2)):161-168 doi:10.1111/bjh.19001.

    PMID: 37488074
  10. 10

    Update on bi-specific monoclonal antibodies for blood cancers.

    Shouse G

    Current opinion in oncology 2023; (35(5)):441-445 doi:10.1097/CCO.0000000000000966.

    PMID: 37551951
  11. 11

    Clinical Development and Therapeutic Applications of Bispecific Antibodies for Hematologic Malignancies.

    Hays P

    Cancer treatment and research 2022; (183()):287-315 doi:10.1007/978-3-030-96376-7_11.

    PMID: 35551665
  12. 12

    The value of bispecific antibodies in relapsed and refractory DLBCL.

    Lewis KL, Cheah CY

    Leukemia & lymphoma 2024; (65(6)):720-735 doi:10.1080/10428194.2024.2323085.

    PMID: 38454535
  13. 13

    Mosunetuzumab and the emerging role of T-cell-engaging therapy in follicular lymphoma.

    Matarasso S, Assouline S

    Future oncology (London, England) 2023; (19(31)):2083-2101 doi:10.2217/fon-2023-0274.

    PMID: 37882361
  14. 14

    Novel Bispecific T-Cell Engagers for the Treatment of Relapsed B Cell Non-Hodgkin Lymphomas: Current Knowledge and Treatment Considerations.

    Varon B, Horowitz NA, Khatib H

    Patient preference and adherence 2024; (18()):2159-2167 doi:10.2147/PPA.S485838.

    PMID: 39479221
  15. 15

    CD20×CD3 bispecific antibody achieved significant efficacy in patients with large B-cell lymphoma relapsing after or refractory to CAR-T therapy: a systematic review and meta-analysis.

    Shen J, Zhang J, Zhu Z, et al.

    Frontiers in oncology 2025; (15()):1641769 doi:10.3389/fonc.2025.1641769.

    PMID: 40919147

This page provides educational information about treatments for relapsed or refractory DLBCL. It does not replace professional medical advice. Always discuss your specific treatment options and clinical trial eligibility with your hematologist or oncologist.

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