Overview of Hodgkin Lymphoma Treatment

Hodgkin lymphoma is one of the most curable malignancies, with overall cure rates exceeding 80% even in advanced stages. Classical Hodgkin lymphoma accounts for 95% of cases and is characterized by Reed-Sternberg cells in a background of inflammatory cells. Treatment involves risk-adapted chemotherapy regimens, often combined with radiation therapy in early-stage disease. For relapsed/refractory disease, salvage chemotherapy followed by autologous stem cell transplant is standard, with checkpoint inhibitors and antibody-drug conjugates providing important options for patients who fail transplant.

Treatment Approach by Stage

Early-Stage Favorable (Stage I-II, No Risk Factors)

  • 2-4 cycles ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)
  • Involved-site radiation therapy (ISRT) 20-30 Gy
  • PET-adapted approach to minimize therapy

Early-Stage Unfavorable / Advanced Stage (Stage III-IV)

  • 6 cycles ABVD or escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone)
  • PET-directed therapy escalation or de-escalation
  • Consider radiation to bulky sites or residual PET-positive disease

Relapsed/Refractory Disease

  • Salvage chemotherapy (ICE, DHAP, GDP, etc.) followed by autologous SCT
  • Brentuximab vedotin post-auto SCT consolidation or for transplant-ineligible patients
  • PD-1 inhibitors (nivolumab, pembrolizumab) for post-transplant relapse
  • Allogeneic SCT for multiply relapsed disease

Epidemiology & Impact

Hodgkin lymphoma has approximately 8,360 new cases expected in 2025 with a distinctive bimodal age distribution peaking in young adults (15-35) and again after 55. HL is one of the most curable cancers, with 5-year survival exceeding 90% and cure rates of 80-90% even in advanced-stage disease. Classic HL (95% of cases) is characterized by Reed-Sternberg cells embedded in an extensive inflammatory microenvironment. The major challenge has shifted to minimizing long-term treatment toxicity, including secondary cancers, cardiovascular disease, and infertility.

Molecular Biology & Biomarkers

The hallmark Reed-Sternberg cells harbor amplification of chromosome 9p24.1 containing PD-L1, PD-L2, and JAK2 genes, leading to constitutive PD-L1 overexpression. This provides the molecular basis for HL's exceptional sensitivity to PD-1 blockade — the highest response rates to checkpoint immunotherapy in any cancer. Additional features include NF-kappaB pathway activation and JAK-STAT dependence.

Evolving Treatment Landscape

The ECHELON-1 trial established brentuximab vedotin plus AVD (A+AVD) as preferred first-line for advanced-stage HL, improving overall survival while eliminating bleomycin toxicity. For early-stage favorable HL, abbreviated chemotherapy (2 cycles ABVD) plus involved-site radiation achieves cure rates exceeding 95%. PET-adapted strategies de-escalate therapy in good responders. For relapsed disease, PD-1 inhibitors achieve 65-70% response rates.

Approved Hodgkin Lymphoma Therapies

Adcetris
brentuximab vedotin
FDA Approved 2011 Multiple Settings
Approved Indications (US/FDA)
Treatment of adult patients with previously untreated Stage III or IV classical Hodgkin lymphoma in combination with chemotherapy; Consolidation treatment post-auto SCT in patients at high risk of relapse or progression; Treatment of classical Hodgkin lymphoma after failure of auto SCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto SCT candidates.
Dosing Schedule
Frontline (with AVD): 1.2 mg/kg IV (max 120 mg) every 2 weeks on Days 1 and 15 of each 28-day cycle for up to 6 cycles
Post-auto SCT Consolidation: 1.8 mg/kg IV (max 180 mg) every 3 weeks starting 4-6 weeks post-transplant or upon recovery, for up to 16 cycles
Relapsed/Refractory: 1.8 mg/kg IV (max 180 mg) every 3 weeks until disease progression or unacceptable toxicity (max 16 cycles)
Clinical Evidence
ECHELON-1 trial: A-AVD (brentuximab + doxorubicin, vinblastine, dacarbazine) improved PFS vs ABVD (82.1% vs 77.2% at 2 years) in frontline advanced Hodgkin lymphoma. AETHERA trial: Post-auto SCT consolidation improved PFS (59% vs 41% at 3 years) in high-risk patients. Brentuximab vedotin is an antibody-drug conjugate targeting CD30, which is expressed on Reed-Sternberg cells. The conjugated MMAE causes microtubule disruption. Main adverse events include peripheral neuropathy (often reversible), neutropenia, and pulmonary toxicity (avoid concurrent bleomycin).
Manufacturer
Seagen
Approval Year
2011
Pivotal Trial
NCT01712490 ↗
Key Publication
Moskowitz et al. JCO 2015 ↗
Opdivo
nivolumab
FDA Approved 2016 Post-SCT Relapse
Approved Indications (US/FDA)
Treatment of adult and pediatric (12 years and older) patients with classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin.
Dosing Schedule
3 mg/kg IV over 60 minutes every 2 weeks OR 240 mg IV every 2 weeks OR 480 mg IV every 4 weeks. Continue until disease progression or unacceptable toxicity.
Clinical Evidence
CheckMate 205 trial: Nivolumab monotherapy achieved 69% overall response rate (8% CR) in heavily pretreated relapsed/refractory classical Hodgkin lymphoma after auto SCT and brentuximab vedotin failure. Median PFS was 14.7 months. Nivolumab is a PD-1 checkpoint inhibitor particularly effective in Hodgkin lymphoma due to genetic alterations on chromosome 9p24.1 leading to high PD-L1/PD-L2 expression. Main adverse events include immune-related toxicities (pneumonitis, colitis, hepatitis, endocrinopathies) and increased risk of GVHD if used before allogeneic SCT.
Manufacturer
Bristol Myers Squibb
Approval Year
2016
Pivotal Trial
NCT02181738 ↗
Key Publication
Younes et al. Lancet Oncol 2016 ↗
Keytruda
pembrolizumab
FDA Approved 2017 R/R After SCT
Approved Indications (US/FDA)
Treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma, or who have relapsed after 3 or more prior lines of therapy.
Dosing Schedule
Adults: 200 mg IV over 30 minutes every 3 weeks OR 400 mg IV every 6 weeks
Pediatric: 2 mg/kg (up to 200 mg) IV every 3 weeks
Continue until disease progression, unacceptable toxicity, or up to 24 months
Clinical Evidence
KEYNOTE-087 trial: Pembrolizumab monotherapy demonstrated 69% overall response rate (22% CR) in multiply relapsed/refractory classical Hodgkin lymphoma across three cohorts (post-auto SCT with brentuximab failure, post-brentuximab without auto SCT, and post-auto SCT without brentuximab). Median duration of response was 16.5 months. Similar to nivolumab, pembrolizumab targets PD-1 and shows high activity in Hodgkin lymphoma due to the unique biology of Reed-Sternberg cells. Immune-related adverse events and increased GVHD risk before allogeneic transplant are key considerations.
Manufacturer
Merck
Approval Year
2017
Pivotal Trial
NCT02453594 ↗
Key Publication
Chen et al. JCO 2017 ↗