# Relapsed and refractory classical Hodgkin lymphoma

Source: https://onco.cc/cancers/relapsed-refractory-hodgkin-lymphoma/  
OnCo record `relapsed-refractory-hodgkin-lymphoma` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Relapsed or refractory classical Hodgkin lymphoma is Hodgkin lymphoma that comes back or does not respond after first-line chemotherapy. The standard path is salvage chemotherapy, often with brentuximab vedotin or a PD-1 antibody, then high-dose chemotherapy with an autologous stem cell transplant; for those who relapse again, nivolumab and pembrolizumab give lasting control in many.

## Summary

Classical Hodgkin lymphoma that relapses after or is refractory to first-line therapy has been treated since the 1990s with salvage chemotherapy (ICE, DHAP, GVD, bendamustine-based regimens) followed by high-dose chemotherapy with autologous stem cell transplantation, which cures about half of patients; achieving a PET-negative remission before transplant is the strongest predictor of cure. Two classes of drug then transformed the field. Brentuximab vedotin, an antibody-drug conjugate against CD30, produced responses in three quarters of patients relapsing after transplant in its pivotal trial and was approved in 2011, and the AETHERA trial (Lancet 2015) showed that giving it as consolidation after transplant to high-risk patients lengthened progression-free survival from 24.1 to 42.9 months. PD-1 antibodies exploit the near-universal 9p24.1 amplification of PD-L1 in Reed-Sternberg cells: nivolumab (CheckMate 205) and pembrolizumab (KEYNOTE-087) produced responses in about two thirds of heavily pretreated patients and were approved in 2016 and 2017, and KEYNOTE-204 (Lancet Oncology 2021) showed pembrolizumab beat brentuximab vedotin in relapsed disease with progression-free survival of 13.2 against 8.3 months.

These agents have moved earlier. Salvage regimens now combine brentuximab vedotin or a PD-1 antibody with chemotherapy or with each other (brentuximab-nivolumab, pembrolizumab-GVD) to reach PET-negative remission in more patients before transplant, and trials ask whether some patients with a complete response to immunotherapy-based salvage can skip transplantation altogether. After failure of transplant, brentuximab vedotin and a PD-1 antibody, allogeneic transplantation, which can cure a minority with acceptable risk after PD-1 blockade with careful management, and clinical trials of CD30-directed CAR T cells (CHARIOT), bispecific antibodies and novel combinations are the options; older agents such as bendamustine, gemcitabine and everolimus retain a role. Because first-line nivolumab-AVD and brentuximab-AVD are now standard, the definition of relapse after these regimens and the best salvage for patients already exposed to both classes is the open question, and cardiac, pulmonary and second-cancer late effects of cumulative therapy need lifelong attention.

## Fields

- Kind: Cancer
- Last checked: 2026-09-18
- Also known as: Relapsed Hodgkin lymphoma; Refractory Hodgkin lymphoma; R/R cHL; Hodgkin lymphoma after first-line failure
- Tags: subtype-page; haematologic
- Group: haematologic
- Burden: A tenth to a quarter of classical Hodgkin lymphoma relapses or fails to respond to first-line treatment; most of these patients are still cured with salvage chemotherapy and transplantation, and immunotherapy has changed the outlook for the rest.
- Subtypes: Primary refractory classical Hodgkin lymphoma (no complete response to first line); Early relapse within twelve months of first-line therapy; Late relapse after twelve months (favourable, may be retreated with less); Relapsed classical Hodgkin lymphoma after autologous transplantation (brentuximab vedotin, PD-1 antibodies, allogeneic transplant); Relapse after first-line brentuximab-AVD or nivolumab-AVD; Multiply relapsed classical Hodgkin lymphoma (CAR T and bispecific trials)
- Biomarkers: PET-negative remission before transplant (Deauville 1 to 3; strongest predictor of cure); Time to relapse (under or over twelve months) and primary refractory status; Extranodal disease, B symptoms and prior lines (AETHERA high-risk criteria); CD30 expression (brentuximab target); 9p24.1 amplification and PD-L1 expression (PD-1 responsiveness); Circulating tumour DNA (research)

## Standard of care

- Salvage before transplant: Platinum-based chemotherapy (ICE, DHAP, GVD) increasingly combined with brentuximab vedotin or pembrolizumab, or brentuximab vedotin with nivolumab, to reach PET-negative remission. ([Brentuximab vedotin](https://onco.cc/drugs/brentuximab-vedotin/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Gemcitabine](https://onco.cc/drugs/gemcitabine/), [FDG PET](https://onco.cc/technologies/fdg-pet/), [Deauville five-point scale](https://onco.cc/terms/deauville-score/))
- Consolidation: High-dose chemotherapy with autologous stem cell transplantation for chemosensitive relapse; brentuximab vedotin maintenance for a year in high-risk patients (AETHERA). ([Autologous stem cell transplant (high-dose therapy)](https://onco.cc/technologies/autologous-stem-cell-transplant/), [Brentuximab vedotin](https://onco.cc/drugs/brentuximab-vedotin/), [AETHERA](https://onco.cc/trials/aethera/))
- Relapse after transplant: Pembrolizumab (KEYNOTE-204) or nivolumab (CheckMate 205); brentuximab vedotin if not previously given; PD-1 antibodies in China include penpulimab and others. ([Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [KEYNOTE-204](https://onco.cc/trials/keynote-204/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [CheckMate 205](https://onco.cc/trials/checkmate-205/), [Brentuximab vedotin](https://onco.cc/drugs/brentuximab-vedotin/), [Penpulimab](https://onco.cc/drugs/penpulimab/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/))
- Failure of PD-1 antibodies and brentuximab: Allogeneic transplantation for fit patients; bendamustine, gemcitabine or everolimus; CD30 CAR T cells and bispecific antibodies in trials. ([Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/), [Gemcitabine](https://onco.cc/drugs/gemcitabine/), [Everolimus](https://onco.cc/drugs/everolimus/), [Phase 2 Study Evaluating Autologous CD30.CAR-T Cells in Patients With Relapsed/Refractory Hodgkin Lymphoma (CHARIOT)](https://onco.cc/trials/nct04268706/), [CD30 CAR-T for multiply relapsed Hodgkin lymphoma](https://onco.cc/ideas/idea-cd30-car-t-hodgkin/))
- Transplant-ineligible patients: PD-1 antibody with or without brentuximab vedotin as ongoing therapy; palliative radiotherapy for symptomatic sites. ([Nivolumab](https://onco.cc/drugs/nivolumab/), [Brentuximab vedotin](https://onco.cc/drugs/brentuximab-vedotin/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/))

## State of the art

- Immunotherapy-based salvage gets more patients to a PET-negative transplant and may let some skip it.
- PD-1 antibodies give durable control to many patients who relapse after transplant.
- CD30 CAR T cells and bispecific antibodies are the next layer for multiply relapsed disease.

## Open problems

- Which patients in complete remission after immunotherapy salvage can safely skip transplantation is unproven.
- Salvage for patients already exposed to brentuximab and PD-1 antibodies in first line is undefined.
- Allogeneic transplant after PD-1 blockade carries a risk of severe graft-versus-host disease.
- Cumulative cardiac and lung toxicity limits options in multiply treated patients.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Hodgkin_lymphoma
- AETHERA (Lancet 2015): https://doi.org/10.1016/S0140-6736(15)60165-9
- KEYNOTE-204 (Lancet Oncology 2021): https://doi.org/10.1016/S1470-2045(21)00005-X
- Wikipedia: https://en.wikipedia.org/wiki/Hodgkin_lymphoma

## Connected records

- cancers: [Advanced-stage classical Hodgkin lymphoma (stage III to IV)](https://onco.cc/cancers/advanced-stage-classical-hodgkin-lymphoma/), [Diffuse large B-cell lymphoma](https://onco.cc/cancers/dlbcl/), [Early-stage classical Hodgkin lymphoma (stage I to II)](https://onco.cc/cancers/early-stage-classical-hodgkin-lymphoma/), [Hodgkin lymphoma](https://onco.cc/cancers/hodgkin-lymphoma/)
- technologies: [Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/), [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/), [Autologous stem cell transplant (high-dose therapy)](https://onco.cc/technologies/autologous-stem-cell-transplant/), [ctDNA monitoring in lymphoma (PhasED-seq, clonoSEQ)](https://onco.cc/technologies/ctdna-lymphoma-monitoring/), [FDG PET](https://onco.cc/technologies/fdg-pet/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/)
- targets: [CD30](https://onco.cc/targets/cd30/), [PD-1](https://onco.cc/targets/pd1/), [PD-L1](https://onco.cc/targets/pdl1/)
- drugs: [Brentuximab vedotin](https://onco.cc/drugs/brentuximab-vedotin/), [Everolimus](https://onco.cc/drugs/everolimus/), [Gemcitabine](https://onco.cc/drugs/gemcitabine/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Penpulimab](https://onco.cc/drugs/penpulimab/)
- terms: [Deauville five-point scale](https://onco.cc/terms/deauville-score/), [Late effects and survivorship toxicity](https://onco.cc/terms/late-effects/), [Reed-Sternberg cell](https://onco.cc/terms/reed-sternberg-cell/)
- trials: [AETHERA](https://onco.cc/trials/aethera/), [CheckMate 205](https://onco.cc/trials/checkmate-205/), [KEYNOTE-204](https://onco.cc/trials/keynote-204/), [Phase 2 Study Evaluating Autologous CD30.CAR-T Cells in Patients With Relapsed/Refractory Hodgkin Lymphoma (CHARIOT)](https://onco.cc/trials/nct04268706/)
- key papers: [AETHERA: brentuximab vedotin consolidation after autologous stem cell transplantation in Hodgkin lymphoma at risk of relapse](https://onco.cc/key-papers/paper-aethera-brentuximab-consolidation-after-asct-hodgkin-lancet-2015/), [CheckMate 205: nivolumab for relapsed or refractory classical Hodgkin lymphoma after autologous transplant failure, extended follow-up](https://onco.cc/key-papers/paper-checkmate-205-nivolumab-rr-hodgkin-extended-follow-up-jco-2018/), [KEYNOTE-204: pembrolizumab versus brentuximab vedotin in relapsed or refractory classical Hodgkin lymphoma](https://onco.cc/key-papers/paper-keynote-204-pembrolizumab-vs-brentuximab-rr-hodgkin-lancet-oncol-2021/)
- ideas: [CD30 CAR-T for multiply relapsed Hodgkin lymphoma](https://onco.cc/ideas/idea-cd30-car-t-hodgkin/)

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