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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.
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.
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.
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.
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: High-grade B-cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma), Mediastinal grey zone lymphoma, Primary effusion lymphoma, Plasmablastic lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, EBV-positive diffuse large B-cell lymphoma, Primary large B-cell lymphoma of the testis, Gastric MALT lymphoma, Ocular adnexal MALT lymphoma, Extranodal NK/T-cell lymphoma, Adult T-cell leukaemia/lymphoma, ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma, Breast implant-associated anaplastic large cell lymphoma, Primary cutaneous anaplastic large cell lymphoma, Lymphomatoid papulosis, Mycosis fungoides, Enteropathy-associated T-cell lymphoma, Monomorphic epitheliotropic intestinal T-cell lymphoma, Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), Splenic marginal zone lymphoma, Nodal marginal zone lymphoma, Primary cutaneous marginal zone lymphoma, Primary cutaneous follicle centre lymphoma, Sezary syndrome, Nodal T-follicular helper cell lymphoma, angioimmunoblastic type (angioimmunoblastic T-cell lymphoma), Hepatosplenic T-cell lymphoma, Intravascular large B-cell lymphoma, Lymphomatoid granulomatosis, T-cell prolymphocytic leukaemia, Splenic B-cell lymphoma/leukaemia with prominent nucleoli (formerly B-cell prolymphocytic leukaemia and hairy cell leukaemia variant), T-cell large granular lymphocytic leukaemia, Mixed-phenotype acute leukaemia, Myeloid leukaemia of Down syndrome, Burkitt leukaemia, 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)
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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.
The aim of salvage treatment is not a response but a negative PET, because the proportion of patients cured by the transplant that follows depends more on the depth of the remission before it than on which salvage regimen produced it. Salvage regimens in use: brentuximab vedotin with bendamustine; brentuximab vedotin with nivolumab, which produces high complete response rates without chemotherapy; ICE or IGEV or DHAP or ESHAP. There is no randomised trial ranking them, and the choice is made on toxicity, on stem cell mobilisation and on what the patient has already had. Two to three cycles, then a PET; if it is negative, proceed to BEAM conditioning and autologous transplant; if it is positive, change salvage rather than proceeding. Consolidation after transplant with brentuximab vedotin is standard for patients at high risk of relapse, on the strength of AETHERA, which randomised 329 such patients to brentuximab vedotin or placebo and gave median progression-free survival of 42.9 against 24.1 months (hazard ratio 0.57). High risk means primary refractory disease, relapse within twelve months, or extranodal disease at relapse. Patients who received brentuximab vedotin in first-line treatment are a group in whom this is less clear.
Classical Hodgkin lymphoma has amplification of chromosome 9p24.1, which drives expression of PD-L1 and PD-L2, and it is the disease in which PD-1 blockade works best of all. Nivolumab. CheckMate 205 treated 243 patients after autologous transplant failure and reported an objective response of 69 per cent, with responses lasting in many. It is also active after both autologous transplant and brentuximab vedotin have failed. Pembrolizumab. KEYNOTE-204 randomised 304 patients with relapsed or refractory classical Hodgkin lymphoma to pembrolizumab or brentuximab vedotin and gave median progression-free survival of 13.2 against 8.3 months (hazard ratio 0.65), which established PD-1 blockade as preferred over brentuximab vedotin at this point for patients who have had one or the other. Combinations of brentuximab vedotin with nivolumab are used as a bridge to transplant and in later lines. Where a response is achieved in a fit younger patient who has already had an autologous transplant, an allogeneic transplant with reduced-intensity conditioning is considered, although PD-1 blockade before allogeneic transplant increases the risk of severe graft-versus-host disease and the timing has to be planned with the transplant team.
This is a small group and there is no standard. Options, roughly in the order they are usually considered: re-treatment with a PD-1 antibody after a chemotherapy-induced response, because chemotherapy can restore sensitivity; an allogeneic transplant with reduced-intensity conditioning in a fit younger patient, which is the only treatment with curative potential; anti-CD30 CAR-T, which has produced responses in phase 1 and 2 studies and is not approved; gemcitabine-based or single-agent chemotherapy for control; involved-site radiotherapy for a symptomatic site, which is highly effective in a radiosensitive disease; and a clinical trial, which at this point is often the best available treatment. The conversation about aim belongs here explicitly. Palliative radiotherapy and low-intensity chemotherapy can give good quality of life for a long time in Hodgkin lymphoma, and early involvement of a palliative care team alongside oncology is recommended rather than deferred.
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PD-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.
Query 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.
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Bleeding that does not stop by itself, bleeding from more than one site, or new bruising in several places or one large area.
Breathing very fast, confusion or slurred speech, blue, pale or blotchy skin, a very high or very low temperature, shivering, or a rash that does not fade when pressed: the NHS says call 999 or go to A and E, and do not drive yourself.
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
Any new neurological symptom that is not explained. Brentuximab vedotin carries a boxed warning for progressive multifocal leukoencephalopathy, a brain infection; the label says to hold the drug and investigate at the first suspicion.
Macmillan lists difficulty passing urine, loss of bladder or bowel control and constipation among the signs of spinal cord compression and says to contact the hospital straight away. If you cannot reach anyone, go to A and E and say you have lymphoma and symptoms of spinal cord compression.
These are the signs that the airway or the brain is being affected rather than only the veins. The triage standard sends shortness of breath at rest and any altered level of consciousness straight to 999.
See all on the product pages:BendamustineBrentuximab vedotinCarboplatinCarmustineCentral venous access (port, PICC line)CisplatinCytarabineEtoposideFebrile neutropeniaGemcitabineHypogammaglobulinaemia and infection risk after B-cell therapiesIfosfamideMelphalan (including hepatic delivery system)Metastatic spinal cord compression (MSCC)NeutropeniaNivolumabPembrolizumabPenpulimabSuperior vena cava obstruction·Printable cards in the navigator
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