What is the recommended relapse protocol for an adolescent with stage III Hodgkin lymphoma who has relapsed after frontline therapy?

Relapse Protocol for Adolescent Stage III Hodgkin Lymphoma

Primary Treatment Recommendation

For an adolescent with relapsed stage III Hodgkin lymphoma after frontline therapy, proceed immediately with platinum-based salvage chemotherapy (DHAP, ICE, or IGEV for 2-3 cycles) followed by high-dose chemotherapy with autologous stem cell transplantation (HDCT/ASCT), which represents the standard of care for achieving cure in this population. 1

Step 1: Confirm Relapse and Assess Disease Status

• Obtain PET-CT imaging immediately to confirm metabolically active disease, as achieving PET negativity after salvage therapy is the single most important predictor of post-transplant outcomes 2
• Perform tissue biopsy if there is any uncertainty about true relapse versus residual fibrosis, particularly important to exclude transformation to aggressive NHL in nodular lymphocyte-predominant HL 1
• Stage III disease at relapse requires aggressive salvage therapy regardless of timing, though early relapse (<12 months) carries worse prognosis than late relapse 2

Step 2: Salvage Chemotherapy Selection

Choose one of these platinum-based regimens (administered for 2-3 cycles):

• DHAP (dexamethasone/high-dose cytarabine/cisplatin) - preferred if prior ABVD or BEACOPP with mediastinal radiotherapy due to cardiac toxicity concerns 1, 3
• ICE (ifosfamide/carboplatin/etoposide) - equally effective alternative 1, 3
• IGEV (ifosfamide/gemcitabine/vinorelbine) - demonstrates good activity with favorable toxicity profile 1, 3

Alternative for select patients:

• Single-agent brentuximab vedotin may be sufficient as salvage therapy before HDCT/ASCT in some patients, though this is less established in adolescents 1

Critical goal: Achieve PET-negative status after salvage therapy, which defines chemosensitivity and dramatically impacts post-ASCT outcomes 1, 3

Step 3: Response Assessment After Salvage

• Perform PET-CT after 2-3 cycles of salvage chemotherapy to evaluate metabolic response 2, 3
• If PET-negative: Proceed immediately to HDCT/ASCT 1
• If single PET-positive lymph node remains: Consider radiotherapy to that site before proceeding to HDCT/ASCT 1
• If PET-positive with multiple sites: May give additional salvage cycle or consider alternative salvage regimen before transplant 3

Step 4: High-Dose Chemotherapy with ASCT

For chemosensitive disease (responding to salvage):

• Proceed to HDCT (typically BEAM regimen) followed by ASCT - this is the treatment of choice for most patients with relapsed/refractory HL and offers the best chance for cure 1, 2
• Adolescents tolerate this approach well and should not be excluded based on age 2
• High-risk patients may benefit from tandem ASCT (two sequential transplants) 1

Post-ASCT consolidation:

• Brentuximab vedotin consolidation is recommended following HDCT/ASCT in patients with defined poor-risk factors (such as early relapse, refractory disease, or extranodal involvement) 1

Step 5: Management of ASCT Failure or Ineligibility

If disease relapses after ASCT or patient fails to achieve transplant:

• First option: Single-agent brentuximab vedotin - achieves 75% overall response rate in post-ASCT relapse 1, 2
• Second option: PD-1 inhibitors (nivolumab or pembrolizumab) - approved for disease recurrence after HDCT/ASCT and brentuximab vedotin therapy 1, 2
• Third option: Allogeneic stem cell transplantation - represents potentially curative option for young, chemosensitive patients in good general condition after careful risk-benefit evaluation 1, 2
• Palliative option: Gemcitabine-based chemotherapy and/or regional radiotherapy - for patients with multiple relapses who have exhausted other options 1

Pediatric-Specific Considerations

Risk-adapted approach in adolescents:

• Pediatric practice adopts a more individualized risk-stratified approach compared to adult protocols, with greater use of non-transplant salvage in favorable-risk relapses 4, 5
• However, for stage III disease at relapse, HDCT/ASCT remains the standard approach given the advanced stage 4, 5
• Important prognostic factors include time to relapse, stage at relapse, B symptoms, and extranodal disease 4, 5

Critical Pitfalls to Avoid

• Do NOT use Mini-BEAM or Dexa-BEAM due to significant toxic mortality 3
• Do NOT use escalated BEACOPP as second-line due to risk of exceeding critical cumulative anthracycline dose and impaired stem cell mobilization 3
• Do NOT delay salvage therapy - early aggressive intervention improves outcomes 2
• Do NOT proceed to ASCT without achieving chemosensitive disease - patients with refractory disease have poor post-transplant outcomes 1

Regimens NOT Recommended

• Dose-intensive sequential chemotherapy does not improve prognosis compared to standard DHAP-based salvage 3
• BEACOPPescalated as salvage may be considered only in highly selected low-risk patients who relapsed after minimal frontline therapy (2 cycles chemotherapy + radiotherapy only) 1, 3