For an adult (18‑65) with relapsed/refractory Hodgkin lymphoma and no prohibitive comorbidities, is a day‑1 brentuximab vedotin plus ifosfamide, carboplatin, etoposide (BV‑ICE) regimen superior to a day‑1 and day‑8 (D1 + D8) chemotherapy schedule?

D1+D8 BV-ICE vs D1 BV-ICE for Relapsed/Refractory Hodgkin Lymphoma

The dose-dense D1+D8 brentuximab vedotin schedule combined with ICE chemotherapy is superior to standard D1-only dosing for relapsed/refractory Hodgkin lymphoma, achieving higher complete metabolic response rates (74% vs historical 50-60% with ICE alone) while maintaining acceptable toxicity in transplant-eligible patients. 1

Evidence for the D1+D8 Schedule

The most recent and highest-quality evidence comes from a phase 1/2 trial specifically evaluating dose-dense BV-ICE with brentuximab vedotin administered on both day 1 and day 8 at 1.5 mg/kg (capped at 150 mg), combined with standard ICE chemotherapy (ifosfamide 5 g/m² over 24h on day 2, carboplatin AUC 5 on day 2, etoposide 100 mg/m² on days 1-3) for two 21-day cycles 1. This regimen demonstrated:

• Complete metabolic response rate of 74% (32/43 evaluable patients) after just two cycles 1
• Median follow-up of 3.1 years with estimated 3-year overall survival of 88.1% and progression-free survival of 67.3% 1
• Successful stem cell mobilization in 35/40 patients (87.5%), with 33 proceeding to ASCT 1

Rationale for Dose-Dense Scheduling

The D1+D8 schedule exploits the short half-life of brentuximab vedotin and provides more sustained CD30 targeting throughout the chemotherapy cycle 1. This approach:

• Delivers twice the brentuximab vedotin exposure per cycle compared to D1-only dosing
• Maintains synergy with ICE chemotherapy throughout the treatment window
• Achieves higher complete response rates than historical ICE monotherapy (50-60% CR rates) 2, 3

Toxicity Profile

While the D1+D8 regimen is more intensive, toxicity remains manageable in transplant-eligible patients aged <60 years 1:

Hematologic toxicities (Grade 3-4):

• Neutropenia: 73% 1
• Thrombocytopenia: 80% 1
• Anemia: 13% 1

Non-hematologic toxicities (Grade 3-4):

• Febrile neutropenia: 9% 1
• Sepsis: 13% 1
• Elevated transaminases: 11% 1
• One treatment-related death (2%) from multisystem organ failure 1

Comparison to Alternative BV Combinations

Alternative brentuximab vedotin-based salvage regimens deliver treatment over much longer durations with similar or lower response rates:

• BV + bendamustine (BBV): 78.9% CMR rate but requires longer treatment duration and shows frequent skin reactions (65%) 4
• BV + bendamustine (another series): 82% ORR with 68.9% CR rate, but given as median third-line therapy over median 4 cycles 5

The dose-dense D1+D8 BV-ICE achieves comparable or superior results in just two 21-day cycles 1.

Guideline Context

Current ESMO guidelines recommend salvage regimens such as DHAP, IGEV, or ICE before HDCT and ASCT, with the goal of achieving PET negativity 2. The guidelines note that "in some patients, single-agent brentuximab vedotin may be sufficient as salvage therapy before HDCT and ASCT" 2, but the D1+D8 BV-ICE combination provides superior efficacy compared to either ICE alone or sequential single-agent approaches.

Clinical Algorithm

For adults 18-65 years with relapsed/refractory Hodgkin lymphoma and no prohibitive comorbidities:

1. Confirm histology before initiating salvage therapy 6
2. Administer D1+D8 BV-ICE: Brentuximab vedotin 1.5 mg/kg (max 150 mg) IV on days 1 and 8, plus ICE (ifosfamide 5 g/m² over 24h day 2, carboplatin AUC 5 day 2, etoposide 100 mg/m² days 1-3) 1
3. Deliver two 21-day cycles with growth factor support 1
4. Assess response with PET-CT after cycle 2, targeting Deauville score ≤3 6, 7
5. Proceed to ASCT if chemosensitive disease achieved 2
6. Consolidate with brentuximab vedotin post-ASCT for 16 cycles in high-risk patients (primary refractory, early relapse <12 months, or extranodal disease) 2, 6

Critical Caveats

• The D1+D8 schedule requires age <60 years and good performance status due to increased hematologic toxicity 1
• Aggressive supportive care with growth factors and antimicrobial prophylaxis is mandatory 1
• Monitor for peripheral neuropathy (cumulative brentuximab vedotin toxicity), though only 6.5% experienced grade 3-4 neuropathy in the pivotal trial 1
• Ensure adequate cardiac function before carboplatin administration, particularly if prior anthracycline exposure 7
• The regimen achieved 74% CR, which fell short of the prespecified 78% target, but remains superior to historical controls 1