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10 slides generated from the cancer page, with a quiz from the open benchmark and speaker notes that cite the sources. Arrow keys move between slides; Print gives one slide per page.
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.
| Setting | Approach | Guideline |
|---|---|---|
| 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. | not mapped |
| Consolidation | High-dose chemotherapy with autologous stem cell transplantation for chemosensitive relapse; brentuximab vedotin maintenance for a year in high-risk patients (AETHERA). | not mapped |
| 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. | not mapped |
| 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. | not mapped |
| Transplant-ineligible patients | PD-1 antibody with or without brentuximab vedotin as ongoing therapy; palliative radiotherapy for symptomatic sites. | not mapped |
| First relapse of classical Hodgkin lymphoma: salvage to a negative PET, then autologous transplant | 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. | NCCN Category 1 (brentuximab vedotin consolidation, high-risk) |
| Relapse after autologous transplant, or where transplant is not possible: PD-1 blockade | 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. | NCCN Category 1 |
| After brentuximab vedotin and PD-1 blockade have both failed | 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. | not mapped |