Relapsed and refractory classical Hodgkin lymphoma
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.
Overview
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.
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.
Red cards
From the labels and guidelines behind the standard of care. Your team's thresholds win.- Emergency services nowHypophysitis or adrenal crisis
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
- Emergency services nowBleeding or bruising
Bleeding that will not stop, black or bloody stools, or unexplained bruising when platelets are expected to be low.
- Emergency services nowSkin reaction
Blisters, peeling, or sores in the mouth or eyes with a rash. Enfortumab vedotin carries a boxed warning for Stevens-Johnson syndrome and toxic epidermal necrolysis, mostly in the first cycle.
- Check before combiningFood and drink: Everolimus
Avoid grapefruit. Live vaccines are contraindicated.
- Check before combiningFood and drink: Pembrolizumab
No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.
- Check before combiningLiver: Everolimus
7.5 mg (mild), 5 mg (moderate), 2.5 mg (severe).
See all on the product pages:Brentuximab vedotinEverolimusGemcitabineNivolumabPembrolizumabPenpulimab·Printable cards in the navigator
Anatomy and lymph node drainage
- Bone marrow (leukaemia, MDS, MPN, myeloma)
- Lymph node germinal centre (lymphomas)
- Spleen
- Blood (leukaemic phase)
- Lytic bone lesions (myeloma)
- Skin and extranodal sites
- Nodes: cervical
- Nodes: axillary
- Nodes: mediastinal
- Nodes: para-aortic and mesenteric
- Nodes: inguinal
Leukaemias, myeloma and MDS live in the marrow and blood; lymphomas grow in lymph nodes and spleen. The node stations are the disease map, not a route of spread, and staging counts them.
- Bone marrow (leukaemia, MDS, MPN, myeloma)Primary refractory classical Hodgkin lymphoma (no complete response to first line) · Relapsed classical Hodgkin lymphoma after autologous transplantation (brentuximab vedotin, PD-1 antibodies, allogeneic transplant)
- Lymph node germinal centre (lymphomas)Primary refractory classical Hodgkin lymphoma (no complete response to first line) · Relapsed classical Hodgkin lymphoma after autologous transplantation (brentuximab vedotin, PD-1 antibodies, allogeneic transplant) · Multiply relapsed classical Hodgkin lymphoma (CAR T and bispecific trials)
- Spleen
- Blood (leukaemic phase)
- Lytic bone lesions (myeloma)
- Skin and extranodal sites
- cervical
- axillary
- mediastinal
- para-aortic and mesenteric
- inguinal
In lymphoma the node stations are the disease itself; staging (Ann Arbor / Lugano) counts how many regions and sides of the diaphragm are involved.
Same organ: Marginal zone lymphoma, Cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome), Primary mediastinal (thymic) large B-cell lymphoma, Leukaemia (all types), Acute myeloid leukaemia, Acute lymphoblastic leukaemia, Chronic lymphocytic leukaemia, Chronic myeloid leukaemia (CML), Diffuse large B-cell lymphoma, Follicular lymphoma, Hodgkin lymphoma, Mantle cell lymphoma, Multiple myeloma, Non-Hodgkin lymphoma (all types), Myelodysplastic syndromes / neoplasms (MDS), Myeloproliferative neoplasms (PV, ET, myelofibrosis), Polycythaemia vera (PV), Essential thrombocythaemia (ET), Waldenström macroglobulinaemia, Hairy cell leukaemia, Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma), Blastic plasmacytoid dendritic cell neoplasm (BPDCN), Burkitt lymphoma, HIV-associated (AIDS-related) lymphomas, Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms, Systemic mastocytosis, Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms, Langerhans cell histiocytosis (LCH), Post-transplant lymphoproliferative disorder (PTLD), FLT3-mutated acute myeloid leukaemia, IDH1- and IDH2-mutated acute myeloid leukaemia, NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia, Secondary and therapy-related acute myeloid leukaemia, Acute promyelocytic leukaemia, Acute myeloid leukaemia in older or unfit patients, Smouldering multiple myeloma, Newly diagnosed multiple myeloma, transplant-eligible, Newly diagnosed multiple myeloma, transplant-ineligible, Relapsed or refractory multiple myeloma, Plasma cell leukaemia, Lower-risk myelodysplastic syndromes, Higher-risk myelodysplastic syndromes, Chronic lymphocytic leukaemia, first treatment, Relapsed or refractory chronic lymphocytic leukaemia, Richter transformation of chronic lymphocytic leukaemia, Chronic myeloid leukaemia, chronic phase, Chronic myeloid leukaemia, accelerated and blast phase, Primary myelofibrosis, Standard-risk B-cell acute lymphoblastic leukaemia in children, High-risk acute lymphoblastic leukaemia in children (high-risk B-ALL and T-ALL), Philadelphia chromosome-positive acute lymphoblastic leukaemia in children (Ph-positive ALL), Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like or BCR::ABL1-like ALL), Infant acute lymphoblastic leukaemia (KMT2A-rearranged, under one year), Relapsed and refractory acute lymphoblastic leukaemia in children, Acute myeloid leukaemia in children, Erdheim-Chester disease, Rosai-Dorfman-Destombes disease, Single-system Langerhans cell histiocytosis (bone, skin or one other organ), Multisystem Langerhans cell histiocytosis (with or without risk-organ involvement), Indolent and smouldering systemic mastocytosis, Advanced systemic mastocytosis (aggressive SM, SM with an associated haematological neoplasm, mast cell leukaemia), Early-stage classical Hodgkin lymphoma (stage I to II), Advanced-stage classical Hodgkin lymphoma (stage III to IV), Nodular lymphocyte-predominant Hodgkin lymphoma (nodular lymphocyte-predominant B-cell lymphoma)
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.
Cases by country
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
Platinum-based chemotherapy (ICE, DHAP, GVD) increasingly combined with brentuximab vedotin or pembrolizumab, or brentuximab vedotin with nivolumab, to reach PET-negative remission.
High-dose chemotherapy with autologous stem cell transplantation for chemosensitive relapse; brentuximab vedotin maintenance for a year in high-risk patients (AETHERA).
Pembrolizumab (KEYNOTE-204) or nivolumab (CheckMate 205); brentuximab vedotin if not previously given; PD-1 antibodies in China include penpulimab and others.
Allogeneic transplantation for fit patients; bendamustine, gemcitabine or everolimus; CD30 CAR T cells and bispecific antibodies in trials.
PD-1 antibody with or without brentuximab vedotin as ongoing therapy; palliative radiotherapy for symptomatic sites.
Subtypes & biomarkers
top- 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)
- 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)
How often this target appears
- 1993Randomised trial confirms autologous transplantation improves outcomes in relapsed Hodgkin lymphoma
- 2011Brentuximab vedotin approved for relapsed Hodgkin lymphoma after transplant
- 2015AETHERA: brentuximab vedotin consolidation after transplant lengthens progression-free survival
- 2016Nivolumab approved after CheckMate 205
- 2017Pembrolizumab approved after KEYNOTE-087
- 2021KEYNOTE-204: pembrolizumab beats brentuximab vedotin in relapsed disease
Dated changes read from the records linked to this cancer: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.
All 12 changes by month →- 2026-09-18This recordRelapsed and refractory classical Hodgkin lymphomaFacts on this page last checked
When this page itself was last checked or edited.
- 2021MilestoneKEYNOTE-204KEYNOTE-204: pembrolizumab beats brentuximab vedotin in relapsed disease
A milestone in how this cancer is treated.
- 2020Trial resultKEYNOTE-204KEYNOTE-204 reported
PFS 13.
- 2017MilestonePembrolizumabPembrolizumab approved after KEYNOTE-087
A milestone in how this cancer is treated.
- 2016Trial resultCheckMate 205CheckMate 205 reported
ORR 69%.
- 2016MilestoneNivolumabNivolumab approved after CheckMate 205
A milestone in how this cancer is treated.
What is in development for Relapsed and refractory classical Hodgkin lymphoma, drawn from the whole corpus: 6 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.
Technologies being tested · 1
Trials under way · 1
- Phase 2 Study Evaluating Autologous CD30.CAR-T Cells in Patients With Relapsed/Refractory Hodgkin Lymphoma (CHARIOT) · phase 2 · Tessa Therapeutics
Trials reported · 3
- AETHERA · phase 3 · 2015 · positive
- CheckMate 205 · phase 2 · 2016 · positive
- KEYNOTE-204 · phase 3 · 2020 · positive
Ideas not yet in a trial · 1
Open problems and what is being done
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.
and how the field plans to fix it →What is being done about thisSide effects and quality of lifeAvailable now- Allogeneic stem cell transplantationStandard of care
- Antibody-drug conjugate (ADC)Approved
- Immune checkpoint inhibitorsStandard of care
- IMRT / IGRT (modern external beam)Standard of care
In trialsNothing recorded yet.
Ideas and roadmapsNothing recorded yet.
Also on OnCo: Side effects by symptom · Immune-related side effects · Toxicity compare · Survivorship planner.
Trials
topTrials recruiting now
Country and place are remembered in this browser only. A postcode is sent to OpenStreetMap's Nominatim service to find coordinates when you press the button; nothing else leaves your device.
Landmark trials
Expert centres
topExpert centres
Baltimore · cancer center | United States | 0 | 2,955 | 41,449 | #10 | ||
Amsterdam · cancer center | Netherlands | none recorded | 0 | 1,451 | 25,873 | #45 | |
Wuhan · hospital | China | none recorded | 0 | 2,478 | 31,527 | - | |
Utrecht · cancer center | Netherlands | none recorded | 0 | 1,422 | 20,323 | - | |
Beijing · cancer center | China | none recorded | 0 | 1,344 | 18,195 | - | |
Leiden · university | Netherlands | none recorded | 0 | 1,245 | 16,125 | - | |
Tianjin · cancer center | China | none recorded | 0 | 1,219 | 11,455 | - | |
Hangzhou · cancer center | China | none recorded | 0 | 1,219 | 17,635 | - | |
Lyon · cancer center | France | none recorded | 0 | 1,071 | 14,301 | - | |
Rozzano (Milan) · hospital | Italy | none recorded | 0 | 1,031 | 10,720 | - | |
Zhengzhou · cancer center | China | none recorded | 0 | 970 | 12,409 | - | |
Padua · cancer center | Italy | none recorded | 0 | 962 | 12,326 | - | |
Naples · cancer center | Italy | none recorded | 0 | 961 | 15,028 | - | |
Changsha · cancer center | China | none recorded | 0 | 930 | 14,477 | - | |
Jinan · cancer center | China | none recorded | 0 | 920 | 7,804 | - |
These are the things we can measure; they are not a ranking of quality. Each column is a field on the institution record or a count over what OnCo has linked; a centre that treats many patients with Relapsed and refractory classical Hodgkin lymphoma but is thinly recorded here will look small.
Not known: OnCo holds no case-volume or outcome figures for centres, so none are shown. Where a national audit or registry publishes them, the centre's page links to it. Default order: Newsweek rank, then trials for this cancer, then research output.
Questions to ask
topQuestions to ask your oncologist about Relapsed and refractory classical Hodgkin lymphoma
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example PET-negative remission before transplant, Time to relapseand primary refractory status, Extranodal disease, B symptoms and prior lines, CD30 expression, 9p24.1 amplification and PD-L1 expression), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include Primary refractory classical Hodgkin lymphoma, Early relapse within twelve months of first-line therapy, Late relapse after twelve months.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Salvage before transplant
- For my situation (salvage before transplant), which of the standard options do you recommend and why?Why: Guideline options include: Platinum-based chemotherapy (ICE, DHAP, GVD) increasingly combined with brentuximab vedotin or pembrolizumab, or brentuximab vedotin with nivolumab, to reach PET-negative remission.
- Am I a candidate for Brentuximab vedotin, Nivolumab, Pembrolizumab or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Consolidation
- For my situation (consolidation), which of the standard options do you recommend and why?Why: Guideline options include: High-dose chemotherapy with autologous stem cell transplantation for chemosensitive relapse; brentuximab vedotin maintenance for a year in high-risk patients (AETHERA).
- Am I a candidate for Brentuximab vedotin, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of AETHERA apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Relapse after transplant
- For my situation (relapse after transplant), which of the standard options do you recommend and why?Why: Guideline options include: Pembrolizumab (KEYNOTE-204) or nivolumab (CheckMate 205); brentuximab vedotin if not previously given; PD-1 antibodies in China include penpulimab and others.
- Am I a candidate for Pembrolizumab, Nivolumab, Brentuximab vedotin or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of KEYNOTE-204 and CheckMate 205 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Failure of PD-1 antibodies and brentuximab
- For my situation (failure of pd-1 antibodies and brentuximab), which of the standard options do you recommend and why?Why: Guideline options include: Allogeneic transplantation for fit patients; bendamustine, gemcitabine or everolimus; CD30 CAR T cells and bispecific antibodies in trials.
- Am I a candidate for Gemcitabine, Everolimus, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of Phase 2 Study Evaluating Autologous CD30.CAR-T Cells in Patients With Relapsed/Refractory Hodgkin Lymphoma (CHARIOT) apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Transplant-ineligible patients
- For my situation (transplant-ineligible patients), which of the standard options do you recommend and why?Why: Guideline options include: PD-1 antibody with or without brentuximab vedotin as ongoing therapy; palliative radiotherapy for symptomatic sites.
- Am I a candidate for Nivolumab, Brentuximab vedotin, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Any stage
- Are there clinical trials I could join, for example of Phase 2 Study Evaluating Autologous CD30.CAR-T Cells in Patients With Relapsed/Refractory Hodgkin Lymphoma (CHARIOT), CD30 CAR-T for multiply relapsed Hodgkin lymphoma, Brentuximab vedotin, Pembrolizumab?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “Which patients in complete remission after immunotherapy salvage can safely skip transplantation is unproven”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “Salvage for patients already exposed to brentuximab and PD-1 antibodies in first line is undefined”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
Newly diagnosed? Read the first 60 days with Relapsed and refractory classical Hodgkin lymphoma, then print the one-page appointment sheet with room for the answers.
Print this page for your appointment (your browser's print command). These prompts are for discussion; your clinical team knows your case.
Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
11targets
5drugs
6companies
7terms
3trials
4ideas
1key papers
3PD-1 blockade is the standard for classical Hodgkin lymphoma that has relapsed after or is unsuitable for autologous transplant, ahead of brentuximab vedotin in most patients.
Nivolumab, like pembrolizumab, is a standard for relapsed Hodgkin lymphoma after transplant, and the activity seen here led to its testing in first-line therapy (S1826).
Patients at high risk of relapse after autologous transplant are offered brentuximab vedotin consolidation; the benefit is largest in those with two or more risk factors.
Latest papers
topQuery for this cancer: (TITLE:"Relapsed and refractory classical Hodgkin lymphoma" OR ABSTRACT:"Relapsed and refractory classical Hodgkin lymphoma" OR TITLE:"Relapsed Hodgkin lymphoma" OR ABSTRACT:"Relapsed Hodgkin lymphoma" OR TITLE:"Refractory Hodgkin lymphoma" OR ABSTRACT:"Refractory Hodgkin lymphoma" OR TITLE:"R/R cHL" OR ABSTRACT:"R/R cHL" OR TITLE:"Hodgkin lymphoma after first-line failure" OR ABSTRACT:"Hodgkin lymphoma after first-line failure") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Relapsed and refractory classical Hodgkin lymphoma, not a curated reading list.
Similar pages
not linked directly; found by shared links- CancerNodular lymphocyte-predominant Hodgkin lymphoma (nodular lymphocyte-predominant B-cell lymphoma)
Shares Early-stage classical Hodgkin lymphoma (stage I to II), Advanced-stage classical Hodgkin lymphoma (stage III to IV), FDG PET, Autologous stem cell transplant (high-dose therapy) and the tags subtype-page, haematologic.
- CancerRosai-Dorfman-Destombes disease
Shares FDG PET, IMRT / IGRT (modern external beam) and the tags subtype-page, haematologic.
- CancerErdheim-Chester disease
Shares FDG PET and the tags subtype-page, haematologic.
- CancerAdvanced systemic mastocytosis (aggressive SM, SM with an associated haematological neoplasm, mast cell leukaemia)
Shares Allogeneic stem cell transplantation and the tags subtype-page, haematologic.
- CancerIndolent and smouldering systemic mastocytosis
Shares the tags subtype-page, haematologic.
- CancerPrimary mediastinal (thymic) large B-cell lymphoma
Shares Deauville five-point scale, ctDNA monitoring in lymphoma (PhasED-seq, clonoSEQ), CD30, Early-stage classical Hodgkin lymphoma (stage I to II) and the tag subtype-page.
- CancerAdvanced cutaneous squamous cell carcinoma
Shares Everolimus, PD-L1, PD-1, IMRT / IGRT (modern external beam) and the tag subtype-page.
- CancerAngiosarcoma
Shares Gemcitabine, Nivolumab, IMRT / IGRT (modern external beam), Immune checkpoint inhibitors and the tag subtype-page.