What are the recommended salvage chemotherapy regimens for patients with relapsed or refractory Classical Hodgkin Lymphoma (CHL)?

Salvage Chemotherapy for Relapsed/Refractory Classical Hodgkin Lymphoma

Primary Recommendation

For patients with relapsed or refractory classical Hodgkin lymphoma eligible for transplant, use platinum-based salvage chemotherapy regimens—specifically DHAP (dexamethasone, high-dose cytarabine, cisplatin) or ICE (ifosfamide, carboplatin, etoposide)—administered for 2-3 cycles to achieve tumor reduction and mobilize stem cells prior to autologous stem cell transplantation. 1

Recommended Salvage Regimens

First-Choice Platinum-Based Regimens

DHAP (Dexamethasone, High-Dose Cytarabine, Cisplatin):

• Standard dosing: Dexamethasone 40 mg IV days 1-4, cisplatin 100 mg/m² as 24-hour continuous infusion day 1, cytarabine 2 g/m² IV every 12 hours day 2 1, 2
• Recycling interval: Can be given every 3-4 weeks, but time-intensified DHAP with 15-day (median 16-day) recycling has been shown to be effective and well-tolerated while maintaining stem cell harvest capability 1, 2
• Response rate: 89% overall response (21% CR, 68% PR) in relapsed/refractory patients 2
• 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 1

ICE (Ifosfamide, Carboplatin, Etoposide):

• Standard dosing: Ifosfamide 5 g/m² (fractionated over days 1-3), carboplatin AUC 5 day 1, etoposide 100 mg/m² days 1-3 1, 3
• Response rate: 85-89% overall response in lymphoma patients 3
• Can be administered on 2-week intervals, though frequently delayed beyond two weeks due to scheduling or thrombocytopenia 1
• Advantage: Can be given as outpatient therapy 3

Alternative Platinum-Based Options

Modified DHAP regimens for specific situations:

• DHAOx (dexamethasone, high-dose cytarabine, oxaliplatin): Preferred in patients at risk for renal insufficiency or when allogeneic SCT is planned; oxaliplatin dose 130 mg/m² 1
• DHAC (dexamethasone, high-dose cytarabine, carboplatin): Carboplatin AUC 5; same indications as DHAOx 1

GDP (Gemcitabine, Cisplatin, Dexamethasone):

• Gemcitabine 1,000 mg/m² day 1, cisplatin 33 mg/m²/day for 3 days (or 75 mg/m² day 1), dexamethasone (maximum total dose 800 mg) 1

IGEV (Ifosfamide, Gemcitabine, Vinorelbine):

• Demonstrated activity with low toxicity profile and good mobilizing potential 1
• Widely utilized in Italian guidelines 1

IVOx (Ifosfamide, Etoposide, Oxaliplatin):

• Potential outpatient option with good response rate, no cardiac toxicity, without compromising stem cell mobilization 1

Treatment Duration and Monitoring

Number of cycles:

• Give 2-3 cycles of salvage regimen before evaluating response 1
• A fourth cycle may be given to maintain response if transplantation must be delayed, considering risk/benefit ratio 1

Hematologic recovery thresholds:

• Withhold chemotherapy until recovery to at least 0.8 × 10⁹/L neutrophils and at least 80 × 10⁹/L platelets (adapt to individual situations when appropriate) 1

Goal of salvage therapy:

• Achievement of FDG-PET negativity defines chemosensitivity and should be the goal, as this has major impact on post-ASCT outcome 1

Regimens NOT Recommended

Mini-BEAM or Dexa-BEAM:

• No consensus among experts; these display significant toxic mortality, though still used by some as bridge to transplantation 1

Dose-intensive sequential chemotherapy:

• Does not improve prognosis compared to standard DHAP-based salvage; not recommended 1

Escalated BEACOPP as second-line:

• Not recommended due to risk of exceeding critical cumulative anthracycline dose and significant hematologic toxicity with potential impairment of stem cell mobilization 1
• Exception: May be considered in low-risk patients relapsing after primary treatment with only 2 cycles of chemotherapy followed by radiotherapy 1

Third-Line Regimens

For patients failing after two cycles of second-line therapy:

• Give 2-3 cycles of chemotherapy containing non-cross-resistant drugs to obtain tumor reduction and achieve chemosensitivity 1

Novel Agent-Based Salvage (FDA-Approved)

Brentuximab vedotin combinations:

• BV-ICE (dose-dense brentuximab vedotin plus ICE): Brentuximab vedotin 1.5 mg/kg days 1 and 8 (capped at 150 mg) with standard ICE dosing days 1-3, every 21 days for two cycles 4
• Response rate: 74% complete response after two cycles 4
• FDA-approved indication: Brentuximab vedotin is approved for classical Hodgkin lymphoma after failure of auto-HSCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates 5
• Toxicity: Grade 3-4 neutropenia (73%), thrombocytopenia (80%), febrile neutropenia (9%), sepsis (13%) 4

Common Pitfalls and Caveats

Cardiac toxicity:

• Always evaluate cardiac function before salvage therapy 1
• Avoid anthracycline-containing regimens if cumulative doxorubicin dose has reached 300-400 mg/m² 1

Renal protection:

• Use oxaliplatin or carboplatin instead of cisplatin in patients at risk for renal insufficiency 1

Stem cell mobilization:

• All recommended platinum-based regimens maintain the possibility of harvesting stem cells 1, 2, 3
• Median time to PBSC harvest with ICE is 14 days 3
• With time-intensified DHAP, hematopoietic progenitors show rapid increase from day 10 with peak on day 12; mean 6.1 × 10⁶/kg CD34+ cells collected per apheresis 2

Pulmonary toxicity:

• Evaluate pulmonary function prior to treatment 1

Fertility preservation:

• Reproductive counseling should be proposed prior to treatment 1

Subsequent Management

After salvage chemotherapy:

• Patients with chemosensitive disease (achieving at least partial response) should proceed to high-dose chemotherapy with autologous stem cell transplantation 1
• Radiotherapy (30-36 Gy) to residual nodal disease may be recommended in patients with residual disease after salvage therapy 1