What is the recommended immunotherapy-based regimen for patients with relapsed Hodgkin's lymphoma?

Immunotherapy-Based Regimens for Relapsed Hodgkin's Lymphoma

For patients with relapsed/refractory classical Hodgkin lymphoma after autologous stem cell transplantation (ASCT) failure, brentuximab vedotin is the first-line immunotherapy option, followed by PD-1 checkpoint inhibitors (nivolumab or pembrolizumab) if disease progresses after brentuximab vedotin. 1, 2

Primary Immunotherapy Sequence

First Immunotherapy: Brentuximab Vedotin

• Brentuximab vedotin (1.8 mg/kg up to maximum 180 mg every 3 weeks) is FDA-approved and recommended as single-agent therapy for patients who have failed ASCT or after at least 2 prior multi-agent chemotherapy regimens in patients who are not ASCT candidates 1, 2
• This CD30-directed antibody-drug conjugate achieved objective response rates of 75% and complete remission rates of 34% in pivotal trials of post-ASCT relapsed patients, with median progression-free survival of 5.6 months 1
• Brentuximab vedotin may also be used as single-agent salvage therapy before high-dose chemotherapy and ASCT in some patients 1

Second Immunotherapy: PD-1 Checkpoint Inhibitors

• Nivolumab and pembrolizumab are FDA-approved and recommended specifically for patients with disease recurrence after both ASCT and brentuximab vedotin therapy 1, 2
• These checkpoint inhibitors exploit the fact that Reed-Sternberg cells have chromosome 9p24.1 alterations that increase PD-L1 and PD-L2 expression, making them particularly vulnerable to PD-1 blockade 3
• Nivolumab demonstrated 87% objective response rate (17% complete response, 70% partial response) with 86% progression-free survival at 24 weeks in heavily pretreated patients 3

Post-ASCT Consolidation Strategy

High-Risk Patients

• Consolidating treatment with brentuximab vedotin (1.8 mg/kg up to maximum 180 mg every 3 weeks for maximum 16 cycles) following ASCT is recommended in patients presenting with defined poor-risk factors 1, 2
• Treatment should be initiated within 4-6 weeks post-ASCT or upon recovery from ASCT 2
• Poor-risk factors include: extranodal sites at relapse, complete remission duration <1 year, primary refractory disease, and B symptoms 1

Salvage Therapy Before ASCT

Chemotherapy-Based Salvage

• Platinum-based salvage chemotherapy regimens (DHAP, ICE, or IGEV) administered for 2-3 cycles remain the standard approach before proceeding to ASCT 1, 4
• The goal is achieving PET-negativity, which should be the objective of salvage therapy irrespective of the applied protocol 1, 4
• DHAP is particularly recommended for patients previously treated with ABVD or BEACOPP, especially if mediastinal radiotherapy was delivered, given cardiac toxicity risk if cumulative doxorubicin dose has reached 300-400 mg/m² 4

Brentuximab Vedotin as Salvage

• In select patients, single-agent brentuximab vedotin may be sufficient as salvage therapy before ASCT 1
• This approach should be considered in patients who need less intensive cytoreduction or have contraindications to platinum-based chemotherapy 1

Combination Immunotherapy Strategies

Emerging Combinations

• Combination of brentuximab vedotin with checkpoint inhibitors (ipilimumab and nivolumab) showed promising early results with 72% overall response rate and 50% complete response rate 1
• Immune checkpoint inhibitors combined with radiotherapy (ICI-RT) achieved 100% overall response rate and 58% complete response rate as bridge treatment to transplant consolidation 5
• These combinations are under active investigation but not yet standard of care 1

Allogeneic Transplantation After Immunotherapy

Post-Immunotherapy Allogeneic SCT

• Allogeneic stem cell transplantation represents a potentially curative treatment option for patients failing ASCT, and should be considered in young, chemosensitive patients in good general condition after careful evaluation of the risk-benefit ratio 1
• Patients receiving checkpoint inhibitors prior to allogeneic transplantation with post-transplantation cyclophosphamide (PTCy) GVHD prophylaxis experienced 3-year overall survival of 94% and progression-free survival of 90%, with no increased GVHD incidence 6
• This approach is safe and may improve post-transplant outcomes compared to chemotherapy alone 6

Critical Safety Considerations

Brentuximab Vedotin Toxicities

• Monitor for peripheral neuropathy and institute dose modifications accordingly; this is the most common dose-limiting toxicity 2
• Contraindicated with concurrent bleomycin due to pulmonary toxicity risk 2
• Progressive multifocal leukoencephalopathy (PML) from JC virus infection can occur and is potentially fatal 2
• Monitor complete blood counts for hematologic toxicities and manage with dose delays and growth factor support 2

Checkpoint Inhibitor Toxicities

• Drug-related adverse events occurred in 78% of patients (22% grade 3) with nivolumab 3
• Immune-related adverse events require prompt recognition and management with corticosteroids or immunosuppression 3

Treatment Algorithm Summary

1. First relapse after initial therapy: Platinum-based salvage chemotherapy (DHAP/ICE/IGEV) → ASCT → Consider brentuximab vedotin consolidation if high-risk factors present 1, 4, 2

2. Relapse after ASCT: Brentuximab vedotin as first immunotherapy option 1, 2

3. Progression after brentuximab vedotin: PD-1 checkpoint inhibitors (nivolumab or pembrolizumab) 1, 2

4. Progression after checkpoint inhibitors: Consider allogeneic stem cell transplantation in eligible patients 1, 6

5. Multiple relapses without transplant options: Gemcitabine-based palliative chemotherapy and/or regional radiotherapy 1