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PubMed This is a summary of 18 peer-reviewed journal articles Updated
Oncology

When the Cancer Returns: Relapsed and Refractory Disease

At a Glance

If classic Hodgkin lymphoma relapses or resists initial treatment, highly effective curative options remain. Salvage therapies like targeted drugs and immunotherapy are used to achieve remission, often acting as a bridge to an autologous stem cell transplant to provide a long-term cure.

If your cancer does not respond to the first line of treatment (meaning it is refractory) or returns after a period of remission (meaning it has relapsed), it is important to know that there are still many effective, curative-intent options available [1][2]. The treatment for relapsed or refractory (R/R) classic Hodgkin Lymphoma has been transformed by the development of targeted and immune-based therapies [3][4].

Why Immunotherapy Works Best in Hodgkin

Classic Hodgkin Lymphoma is uniquely “addicted” to a specific survival pathway [5]. Almost all cases of cHL have a genetic change in a region called 9p24.1 [6]. This genetic quirk causes the cancer cells to overproduce a protein called PD-L1, which acts like a “cloaking device” that makes the cancer invisible to your immune system [6][7].

PD-1 inhibitors (such as nivolumab or pembrolizumab) work by stripping away this cloak. Because cHL cells rely so heavily on this specific defense, these drugs are more effective in this disease than in almost any other type of cancer [5][8]. They “re-awaken” your body’s exhausted T cells so they can find and destroy the lymphoma [9][10].

Salvage and Bridging Strategies

When the cancer returns, the first goal is to get it back into a complete remission using salvage therapy [11].

  • Targeted Therapy: Brentuximab vedotin (BV) is a common salvage agent. It is an antibody-drug conjugate that acts like a “smart bomb,” delivering chemotherapy directly to cells that carry the CD30 marker (found on Hodgkin cells) while sparing most healthy cells [12][13].
  • Bridging to Transplant: These treatments are often used as a “bridge.” The goal is to reach a PET-negative status (no active cancer visible on scans) before moving on to more intensive treatment [11][14].

The Role of Stem Cell Transplant

For many patients, the goal of salvage therapy is to prepare for an autologous stem cell transplant (ASCT) [1].

  • How it works: First, your own healthy stem cells are collected and frozen. Then, you receive a very high dose of chemotherapy designed to kill any remaining cancer cells [15]. Finally, your stem cells are returned to your body to help your bone marrow recover and begin producing healthy blood cells again [1].
  • Curative Intent: ASCT remains the standard of care for achieving a long-term cure in the relapsed setting [2].
  • Maintenance: In some cases, doctors may recommend “maintenance” therapy with brentuximab vedotin after the transplant to further reduce the risk of the cancer coming back [16][17].

Evolving Options

For patients who cannot undergo a transplant or for whom these therapies are not successful, researchers are investigating even newer options, such as CAR-T cell therapy, which involves genetically engineering your own immune cells to specifically target the CD30 protein on the lymphoma cells [18]. While the road may be more complex, the number of tools available to fight R/R cHL continues to grow [3].

Common questions in this guide

What happens if my classic Hodgkin lymphoma comes back?
If your cancer returns after a period of remission, it is called relapsed disease. There are still many highly effective, curative-intent treatment options available, including targeted therapies, immunotherapy, and stem cell transplants.
Why is immunotherapy so effective for relapsed Hodgkin lymphoma?
Classic Hodgkin lymphoma cells often overproduce a protein called PD-L1 to hide from the immune system. Immunotherapy drugs like nivolumab and pembrolizumab strip away this cloak, allowing your body's exhausted immune cells to find and destroy the cancer.
What is the goal of salvage therapy?
Salvage therapy is the treatment used to get relapsed cancer back into complete remission. The primary goal is often to clear all active cancer visible on a PET scan as a bridge to a more intensive treatment, such as a stem cell transplant.
Am I a candidate for a stem cell transplant for relapsed Hodgkin lymphoma?
An autologous stem cell transplant (ASCT) is the standard of care for achieving a long-term cure in relapsed Hodgkin lymphoma. Your doctor will evaluate your overall health, response to salvage therapy, and other criteria to determine if you are a candidate.
What is brentuximab vedotin and how does it work?
Brentuximab vedotin is a targeted therapy commonly used as a salvage treatment. It acts like a smart bomb by delivering chemotherapy directly to cells that carry the CD30 marker, which destroys Hodgkin cells while sparing most healthy tissue.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Am I a candidate for an autologous stem cell transplant (ASCT), and what are the specific criteria for moving forward?
  2. 2.How will we use immunotherapy (like nivolumab or pembrolizumab) to 'bridge' me to a transplant?
  3. 3.Based on my previous treatments, are there any unique long-term risks I should be aware of with these new salvage options?
  4. 4.If we use brentuximab vedotin, what is the plan for monitoring and managing peripheral neuropathy?
  5. 5.Would a clinical trial for newer therapies like CAR-T cell therapy be appropriate for my situation?

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 (18)
  1. 1

    Current Status of Stem Cell Transplant in Treatment of Testicular Germ Cell Tumors.

    King J, Adra N

    Current oncology reports 2022; (24(3)):303-310 doi:10.1007/s11912-022-01204-4.

    PMID: 35113353
  2. 2

    CD34+ cell mobilization, blood graft composition, and posttransplant recovery in myeloma patients compared to non-Hodgkin's lymphoma patients: results of the prospective multicenter GOA study.

    Turunen A, Partanen A, Valtola J, et al.

    Transfusion 2020; (60(7)):1519-1528 doi:10.1111/trf.15820.

    PMID: 32333404
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    Novel agents and immune invasion in Hodgkin lymphoma.

    Merryman RW, LaCasce A

    Hematology. American Society of Hematology. Education Program 2019; (2019(1)):243-248 doi:10.1182/hematology.2019000029.

    PMID: 31808827
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    Has PD-1 blockade changed the standard of care for cHL?

    Kuczmarski TM, Lynch RC

    Hematology. American Society of Hematology. Education Program 2024; (2024(1)):505-510 doi:10.1182/hematology.2024000574.

    PMID: 39643988
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    PD-1/PD-L1 Pathway and Its Blockade in Patients with Classic Hodgkin Lymphoma and Non-Hodgkin Large-Cell Lymphomas.

    Xie W, Medeiros LJ, Li S, et al.

    Current hematologic malignancy reports 2020; (15(4)):372-381 doi:10.1007/s11899-020-00589-y.

    PMID: 32394185
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    9p24.1 alterations and programmed cell death 1 ligand 1 expression in early stage unfavourable classical Hodgkin lymphoma: an analysis from the German Hodgkin Study Group NIVAHL trial.

    Gerhard-Hartmann E, Goergen H, Bröckelmann PJ, et al.

    British journal of haematology 2022; (196(1)):116-126 doi:10.1111/bjh.17793.

    PMID: 34520052
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    Genetic alterations of 9p24 in lymphomas and their impact for cancer (immuno-)therapy.

    Menter T, Tzankov A

    Virchows Archiv : an international journal of pathology 2019; (474(4)):497-509 doi:10.1007/s00428-018-2438-6.

    PMID: 30132131
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    Immune checkpoint inhibitors in malignant lymphoma: Advances and perspectives.

    Lin N, Song Y, Zhu J

    Chinese journal of cancer research = Chung-kuo yen cheng yen chiu 2020; (32(3)):303-318 doi:10.21147/j.issn.1000-9604.2020.03.03.

    PMID: 32694896
  9. 9

    Title not available

    Gilardin L, Amorim S, Bernard S, et al.

    Bulletin du cancer 2018; (105 Suppl 1()):S50-S58 doi:10.1016/S0007-4551(18)30390-4.

    PMID: 30595199
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    CD4+ T cells in classical Hodgkin lymphoma express exhaustion associated transcription factors TOX and TOX2: Characterizing CD4+ T cells in Hodgkin lymphoma.

    Veldman J, Rodrigues Plaça J, Chong L, et al.

    Oncoimmunology 2022; (11(1)):2033433 doi:10.1080/2162402X.2022.2033433.

    PMID: 35111387
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    Brentuximab vedotin and bendamustine: an effective salvage therapy for relapsed or refractory Hodgkin lymphoma patients.

    Uncu Ulu B, Dal MS, Yönal Hindilerden İ, et al.

    Journal of chemotherapy (Florence, Italy) 2022; (34(3)):190-198 doi:10.1080/1120009X.2021.1976912.

    PMID: 34514960
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    Brentuximab vedotin and its use in the treatment of advanced Hodgkin's lymphoma.

    Nikolaenko L, Nademanee A

    Future oncology (London, England) 2020; (16(29)):2273-2282 doi:10.2217/fon-2020-0026.

    PMID: 32677451
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    Brentuximab vedotin in Hodgkin lymphoma and anaplastic large-cell lymphoma: an evidence-based review.

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    Treatment with brentuximab vedotin plus bendamustine in unselected patients with CD30-positive aggressive lymphomas.

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    European journal of haematology 2020; (104(3)):251-258 doi:10.1111/ejh.13368.

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    Long-term outcomes among 2-year survivors of autologous hematopoietic cell transplantation for Hodgkin and diffuse large b-cell lymphoma.

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    Impact of pre- and/or post-autologous stem cell transplantation exposure to brentuximab vedotin on survival outcomes in patients with high-risk Hodgkin lymphoma.

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    Annals of hematology 2023; (102(2)):429-437 doi:10.1007/s00277-022-05011-6.

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    Brentuximab vedotin consolidation therapy after autologous stem-cell transplantation in patients with high-risk Hodgkin lymphoma: Multicenter retrospective study.

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    Safety and efficacy of anti-CD30 CAR-T cell therapy in relapsed/refractory classic Hodgkin lymphoma: a systematic review and meta-analysis.

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    PMID: 39806291

This page provides educational information about treatment options for relapsed or refractory classic Hodgkin lymphoma. Always consult your oncologist to determine the best and safest treatment plan for your specific diagnosis.

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