Bortezomib in Classical Hodgkin Lymphoma
Bortezomib is NOT recommended for use in classical Hodgkin lymphoma, as it has demonstrated no single-agent activity in relapsed/refractory disease and is more toxic and less effective than standard salvage regimens.
Evidence Against Bortezomib Use
Clinical Trial Results
A multi-institutional phase II trial (CALGB 50206) evaluated bortezomib 1.3 mg/m² on days 1,4,8,11 every 21 days in 30 heavily pretreated patients (median 4 prior therapies, 83% previously transplanted) and found zero responses, with median progression-free survival of only 1.4 months 1
When combined with gemcitabine, the overall response rate was only 22% with increased hepatotoxicity (grade III transaminase elevation in 3 patients), making it less active and more toxic than other available treatments 2
Preclinical studies suggest the microenvironment protects Hodgkin lymphoma cells from bortezomib activity, explaining the poor clinical efficacy despite in vitro activity 3
Important Distinction: Wrong Disease
The evidence provided regarding bortezomib efficacy pertains to Waldenström macroglobulinemia/lymphoplasmacytic lymphoma, not classical Hodgkin lymphoma 4. In Waldenström macroglobulinemia, bortezomib/dexamethasone/rituximab achieves 70-80% response rates and is a preferred regimen 4. This should not be confused with its lack of activity in Hodgkin lymphoma.
Recommended Salvage Therapies for Classical Hodgkin Lymphoma
Standard Platinum-Based Regimens
For relapsed/refractory classical Hodgkin lymphoma eligible for transplant, use platinum-based salvage chemotherapy (DHAP, ICE, or IGEV) for 2-3 cycles prior to autologous stem cell transplantation 5, 4
DHAP (dexamethasone, high-dose cytarabine, cisplatin): Preferred for patients previously treated with ABVD or BEACOPP, especially if mediastinal radiotherapy was delivered, due to cardiac toxicity risk if cumulative doxorubicin exceeds 300-400 mg/m² 4, 5
ICE (ifosfamide, carboplatin, etoposide): Widely utilized with good stem cell mobilization potential 4, 6
IGEV (ifosfamide, gemcitabine, vinorelbine): Demonstrates activity with low toxicity profile and good mobilizing potential 4, 5
Novel Agent-Based Salvage
Brentuximab vedotin-containing regimens (BV-ICE, BV-DHAP): Increase complete metabolic response rates to 75-90% before transplant, which is the strongest predictor of favorable post-transplant outcomes 6
These combinations are intended specifically to raise the proportion of PET-negative responses prior to autologous stem cell transplantation 6
Definitive Treatment Algorithm
Administer 2-3 cycles of platinum-based salvage chemotherapy to achieve maximum tumor reduction and mobilize peripheral blood progenitor cells 5, 7
Assess response using FDG-PET with Deauville scoring after 2-3 cycles, where PET negativity defines optimal chemosensitivity 5, 7
For chemosensitive patients: Proceed to high-dose chemotherapy with BEAM conditioning followed by autologous stem cell transplantation 4, 7
Post-transplant: Administer brentuximab vedotin consolidation for up to 16 cycles in high-risk patients including those with primary refractory disease 7
For chemoresistant patients: Attempt third-line salvage or consider novel agents such as brentuximab vedotin plus nivolumab 7
Critical Pitfalls to Avoid
Do not use bortezomib as salvage therapy in classical Hodgkin lymphoma based on the definitive negative phase II trial showing zero responses 1
Avoid mini-BEAM or dexa-BEAM due to significant toxic mortality, though some centers still use them as a bridge to transplantation 5
Do not use dose-intensive sequential chemotherapy, as it does not improve prognosis compared to standard DHAP-based salvage 5
Avoid escalated BEACOPP as second-line due to risk of exceeding critical cumulative anthracycline dose and significant hematologic toxicity that impairs stem cell mobilization 5
Do not use more than two salvage chemotherapy lines before proceeding to definitive therapy, as this risks selecting highly chemoresistant clones without improving outcomes 7