Residency · Residency · Hematology Thrombosis

Hodgkin Lymphoma

Introduction

Hodgkin lymphoma is a B-cell-derived lymphoma distinguished by the presence of the pathognomonic Reed-Sternberg cells within a characteristically abundant reactive inflammatory background. The disease demonstrates a bimodal age distribution, with the first peak occurring in young adults aged 20 to 30 years and a second peak in adults over 55. The incidence is approximately 2.6 per 100,000 per year, with roughly 8,500 new cases diagnosed annually in the United States. Hodgkin lymphoma is one of the most curable cancers, with an overall cure rate exceeding 85% with modern therapy. The major ongoing challenge in Hodgkin lymphoma management is the mitigation of long-term treatment-related toxicity in the growing population of cured survivors, including secondary malignancies and cardiovascular disease.

Pathology and Classification

Classical Hodgkin Lymphoma (cHL) - 95%

Classical Hodgkin lymphoma is defined by the presence of Reed-Sternberg cells, large binucleated cells with prominent eosinophilic nucleoli producing the characteristic "owl-eye" appearance, set against a background of reactive lymphocytes, histiocytes, eosinophils, and plasma cells. The immunophenotype of Reed-Sternberg cells is distinctive: CD30-positive, CD15-positive, PAX5-positive (weak), CD20-negative (or weakly positive in a minority), and CD45-negative.

Four histologic subtypes are recognized. Nodular sclerosis is the most common (approximately 70%), characterized by collagen bands and lacunar cells, frequently presenting with a mediastinal mass in young adults. Mixed cellularity (20 to 25%) features a heterogeneous inflammatory infiltrate with prominent Reed-Sternberg cells, is associated with EBV infection in approximately 75% of cases, and is more commonly seen in older adults and HIV-positive patients. Lymphocyte-rich cHL (approximately 5%) carries a favorable prognosis. Lymphocyte-depleted cHL (fewer than 5%) typically presents at an advanced stage with aggressive behavior and is associated with HIV infection and elderly populations. Overall, EBV is associated with approximately 40% of cHL cases, with a higher prevalence in mixed cellularity subtype, immunocompromised hosts, and populations in developing countries.

Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL) - 5%

Nodular lymphocyte-predominant Hodgkin lymphoma is a biologically distinct entity characterized by "LP cells" (formerly known as "popcorn cells") that express a B-cell immunophenotype fundamentally different from classical Reed-Sternberg cells: CD20-positive, CD45-positive, BCL6-positive, EMA-positive, and characteristically CD30-negative and CD15-negative. NLPHL follows an indolent clinical course with an excellent prognosis, though late relapses are common. Transformation to aggressive B-cell lymphoma occurs in approximately 10 to 15% of cases. The WHO 5th Edition and ICC 2022 have reclassified this entity as "Nodular Lymphocyte-Predominant B-cell Lymphoma," reflecting its distinct biology.

Staging (Lugano Classification)

PET-CT Based Staging

PET-CT is the standard staging modality for Hodgkin lymphoma, given the consistently high FDG avidity of the disease. Stage I involves a single nodal region. Stage II involves two or more nodal regions on the same side of the diaphragm. Stage III involves nodal regions on both sides of the diaphragm. Stage IV indicates extranodal involvement of sites such as the liver, bone marrow, or lung parenchyma. The suffix "A" denotes the absence of B symptoms, while "B" indicates the presence of fever above 38 degrees Celsius, drenching night sweats, or unintentional weight loss exceeding 10% of body weight over 6 months. Bulky disease is defined as any mass measuring 10 cm or greater, or a mediastinal mass occupying more than one-third of the thoracic diameter on CT.

Risk Stratification

Early-Stage Favorable (Stage I-II without risk factors)

Risk factors defining unfavorable early-stage disease vary by cooperative group. The German Hodgkin Study Group (GHSG) criteria include involvement of 3 or more nodal areas, elevated ESR (50 or greater without B symptoms, 30 or greater with B symptoms), mediastinal bulk, and extranodal disease. The EORTC criteria include age 50 or older, elevated ESR (50 or greater without B symptoms, 30 or greater with B symptoms), 4 or more involved nodal areas, and a mediastinal mass ratio of 0.35 or greater.

Early-Stage Unfavorable (Stage I-II with one or more risk factors)

This category encompasses patients with limited-stage disease who have one or more adverse risk factors as defined above, necessitating more intensive therapy than early-stage favorable disease.

Advanced-Stage (Stage III-IV)

The International Prognostic Score (IPS) for advanced-stage Hodgkin lymphoma incorporates seven adverse prognostic factors: age 45 or older, male sex, stage IV disease, hemoglobin below 10.5 g/dL, white blood cell count of 15,000 or greater, lymphocyte count below 600 or below 8%, and serum albumin below 4.0 g/dL. Each factor scores 1 point, with 0 to 1 factors indicating favorable risk and 4 or more factors indicating adverse risk. The 7-year freedom from progression ranges from 84% with 0 factors to 42% with 5 or more factors.

Treatment - Classical HL

Early-Stage Favorable

The standard treatment for early-stage favorable cHL is ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) for 2 cycles followed by 20 Gy involved-site radiation therapy (ISRT). This approach was established by the GHSG HD10 trial, which demonstrated non-inferiority of 2 cycles versus 4 cycles and 20 Gy versus 30 Gy, establishing the less intensive regimen as standard. A PET-adapted approach uses interim PET after 2 cycles to guide further management: a PET-negative result (Deauville score 1-3) may allow omission of radiation therapy (as demonstrated in the RAPID trial, where 3-year PFS was 95.1% with RT versus 90.8% without). The slight PFS decrement without radiation must be weighed against the long-term toxicity of radiation, particularly in young patients, and patient preference plays an important role in this decision.

Early-Stage Unfavorable

The standard treatment is ABVD for 4 cycles followed by 30 Gy ISRT, as established by the GHSG HD11 trial. PET-adapted strategies are also employed, with completion of ABVD for a total of 4 cycles with or without radiation if the interim PET is negative, and escalation to BEACOPPesc (escalated BEACOPP) for patients with a positive interim PET. BV-AVD (brentuximab vedotin plus AVD) is an emerging option supported by subgroup data from the ECHELON-1 trial.

Advanced-Stage

BV-AVD (brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine) for 6 cycles is now the standard first-line treatment for advanced-stage cHL based on the ECHELON-1 trial, which demonstrated a 6-year PFS of 82.3% compared to 74.5% with ABVD (hazard ratio 0.68), with a significant overall survival benefit in stage IV disease (hazard ratio 0.59). BV-AVD is now the NCCN-preferred regimen for advanced-stage disease. G-CSF support is mandatory with BV-AVD due to the high rate of febrile neutropenia without growth factor support. Notably, BV-AVD does not include bleomycin, eliminating the risk of pulmonary toxicity.

ABVD for 6 cycles remains a valid standard alternative. A PET-adapted de-escalation strategy, as demonstrated in the RATHL trial, allows omission of bleomycin after a PET-negative result at cycle 2, reducing pulmonary toxicity while maintaining efficacy. Escalated BEACOPP (BEACOPPesc) is a more intensive regimen that achieves higher PFS but at the cost of substantially greater toxicity, including gonadal failure in approximately 50% of females and an increased risk of secondary leukemia, and is used primarily by GHSG and other European centers. Consolidation radiation therapy has no established role in advanced-stage HL that achieves a PET-negative complete metabolic response.

Interim PET Response Assessment (Deauville Score)

The Deauville scoring system provides a standardized framework for interpreting PET-CT in Hodgkin lymphoma. Score 1 indicates no FDG uptake. Score 2 indicates uptake at or below the level of mediastinal blood pool. Score 3 indicates uptake above mediastinal blood pool but at or below liver uptake. Score 4 indicates uptake moderately above liver. Score 5 indicates uptake markedly above liver or the presence of new lesions. For end-of-treatment assessment, Deauville scores 1 through 3 constitute a complete metabolic response (CMR).

<image>A treatment algorithm for classical Hodgkin lymphoma divided into three columns: Early Favorable, Early Unfavorable, and Advanced Stage. For Early Favorable: ABVD x 2 + 20 Gy ISRT (standard) OR PET-adapted approach (ABVD x 2 → PET: if Deauville 1-3, ABVD x 1-2 more without RT; if Deauville 4-5, escalate to BEACOPPesc + RT). For Early Unfavorable: ABVD x 4 + 30 Gy ISRT or PET-adapted with escalation for PET-positive. For Advanced Stage: BV-AVD x 6 (ECHELON-1, preferred) with G-CSF, or ABVD x 6 with PET-adapted bleomycin omission (RATHL). Show interim PET assessment at cycle 2 as a key decision point with the Deauville scoring scale (1-5) displayed as a visual reference. Include response-adapted pathways. At the bottom, show the relapsed/refractory pathway: salvage chemotherapy → auto-HSCT → brentuximab vedotin maintenance. Clean clinical algorithm style with trial names annotated at each decision point.</image>

Relapsed/Refractory HL

Salvage Chemotherapy + Auto-HSCT

The standard approach for relapsed or refractory Hodgkin lymphoma is salvage chemotherapy followed by autologous HSCT. Commonly used salvage regimens include ICE, DHAP, GVD, GemOx, and BeGEV. A PET-negative status before HSCT is a strong predictor of superior post-transplant outcomes. Autologous HSCT achieves long-term cure in approximately 50% of patients with chemosensitive relapse.

Brentuximab Vedotin (BV)

Brentuximab vedotin is an anti-CD30 antibody-drug conjugate carrying the microtubule-disrupting agent monomethyl auristatin E. The AETHERA trial demonstrated the benefit of BV maintenance therapy following autologous HSCT in patients with high-risk relapse features (primary refractory disease, relapse within 12 months, or extranodal relapse at the time of relapse), with 5-year PFS of 59% compared to 41% with placebo. As monotherapy in relapsed HL, BV achieves an overall response rate of 75% with a complete response rate of 34%. Peripheral neuropathy is the dose-limiting toxicity, and neutropenia is also commonly observed.

Checkpoint Inhibitors

Hodgkin lymphoma is uniquely sensitive to PD-1 checkpoint inhibitor therapy due to the near-universal amplification of the 9p24.1 locus, which contains the PD-L1 and PD-L2 genes, and the additional upregulation of PD-L1 expression driven by EBV infection. Nivolumab, evaluated in the CheckMate 205 study, demonstrated an overall response rate of 69% with a complete response rate of 16% in patients who had relapsed after autologous HSCT and brentuximab vedotin. Pembrolizumab, evaluated in KEYNOTE-087, achieved an overall response rate of 72% with a complete response rate of 28%. These agents are approved for relapse after autologous HSCT and BV, or after 3 or more prior lines of therapy. Immune-related adverse events including thyroiditis, pneumonitis, colitis, and hepatitis require monitoring. An important practical consideration is that PD-1 inhibitors administered before allogeneic HSCT increase the risk of severe graft-versus-host disease, necessitating a washout period of at least 6 weeks before proceeding to allogeneic transplant.

Allogeneic HSCT

Allogeneic HSCT is considered for patients who fail autologous HSCT. Reduced-intensity conditioning is preferred, and the graft-versus-lymphoma effect mediates long-term remission. However, significant risks of GVHD and non-relapse mortality limit its application to multiply relapsed patients.

Long-Term Survivorship

Long-term survivors of Hodgkin lymphoma face significant risks of late treatment-related complications. Secondary malignancies are the most concerning, with breast cancer carrying a cumulative risk of 15 to 25% at 20 years in women who received mantle-field radiation. Lung cancer, thyroid cancer, and therapy-related AML and MDS (related to alkylating agents and topoisomerase II inhibitors) are additional risks. Cardiovascular disease, including accelerated coronary artery disease, valvular heart disease, and anthracycline-related cardiomyopathy compounded by mediastinal radiation, represents another major source of late morbidity and mortality.

Annual screening for long-term survivors should include mammography and breast MRI (beginning 8 years after radiation therapy or at age 25, whichever comes first), thyroid function tests, echocardiography, and lipid screening. Fertility preservation should be discussed before treatment initiation; BEACOPPesc carries the highest risk of gonadal toxicity, while ABVD and BV-AVD are generally fertility-sparing in males.

Key Clinical Pearls

• BV-AVD has replaced ABVD as preferred first-line for advanced-stage cHL based on ECHELON-1 PFS and OS benefit; G-CSF is mandatory
• Interim PET after 2 cycles is the most important prognostic tool during treatment; a negative PET allows de-escalation in favorable disease
• HL has extraordinary sensitivity to PD-1 checkpoint inhibitors (~70% ORR) due to 9p24.1 amplification; reserve for relapsed disease after auto-HSCT
• Long-term survivorship care is critical: secondary breast cancer risk is substantial in women treated with mediastinal radiation; screening should begin 8 years after RT
• Bleomycin pulmonary toxicity: check DLCO before each cycle; discontinue if DLCO drops >25%; avoid high FiO2 during anesthesia in bleomycin-exposed patients
• NLPHL (nodular lymphocyte-predominant) is biologically distinct from classical HL; stage IA may be treated with RT alone or rituximab; advanced disease treated similarly to indolent B-cell lymphoma

References

1. Ansell SM, et al. Hodgkin Lymphoma. N Engl J Med. 2022;387(16):1498-1511.
2. Connors JM, et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin's lymphoma (ECHELON-1). N Engl J Med. 2018;378(4):331-344.
3. Ansell SM, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma (CheckMate 205). J Clin Oncol. 2016;34(2S):6529.
4. Radford J, et al. Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma (RAPID). N Engl J Med. 2015;372(17):1598-1607.
5. Engert A, et al. Reduced treatment intensity in patients with early-stage Hodgkin's lymphoma (GHSG HD10). N Engl J Med. 2010;363(7):640-652.

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