What is the recommended treatment for a patient with Hodgkin lymphoma, Grade 2 modular sclerosis?

Treatment for Hodgkin Lymphoma Grade 2 Nodular Sclerosis

The recommended treatment depends entirely on the Ann Arbor stage and risk stratification, not the histologic subtype (nodular sclerosis Grade 2), as nodular sclerosis is treated identically to other classical Hodgkin lymphoma subtypes using stage-based and risk-adapted protocols. 1

Risk Stratification Framework

Before selecting treatment, patients must be categorized into one of three risk groups based on stage and specific adverse features 1:

• Early favorable: Stage I-II with ≤3 nodal areas, age <50 years, no B symptoms (or ESR <50 with A symptoms, <30 with B symptoms), and no bulky disease (mediastinal mass <1/3 chest diameter)
• Early unfavorable: Stage I-II with ≥4 nodal areas, age ≥50 years, ESR ≥50 (A symptoms) or ≥30 (B symptoms), bulky disease, or extranodal involvement
• Advanced stage: Stage III-IV or stage IIB with bulky mediastinal mass or extranodal involvement

Treatment by Risk Category

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

Standard treatment is 2 cycles of ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) followed by 30 Gy involved-field radiotherapy. 1

• This regimen is based on German Hodgkin Study Group HD7/HD10 trials and EORTC H7F/H8F trials 1
• Two cycles of ABVD is non-inferior to four cycles when combined with 30 Gy radiotherapy 1
• Chemotherapy alone (4-6 cycles of ABVD) is an alternative but has limited prospective randomized trial support 1

Early Unfavorable Disease (Stage I-II with Risk Factors)

Standard treatment is 4 cycles of ABVD followed by 30 Gy involved-field radiotherapy, achieving tumor control and overall survival exceeding 85-90% at 5 years. 1

• Extended-field radiotherapy or 6 cycles of chemotherapy alone are similarly effective but more toxic 1
• Four cycles of ABVD with radiotherapy is equally effective as 6 cycles for disease control, even in bulky disease 2
• More aggressive chemotherapy (BEACOPP escalated) or chemotherapy-only approaches remain experimental 1

Advanced Stage Disease (Stage III-IV)

For patients ≤60 years, either 6-8 cycles of ABVD or 6 cycles of escalated BEACOPP should be used, with BEACOPP providing superior outcomes (96% overall response, 88% disease-free survival, 92% overall survival at 5 years) but significantly higher acute toxicity. 1, 3

• ABVD achieves long-term cure rates of 50-60% in advanced disease 1, 3
• BEACOPP escalated provides a 10% absolute survival advantage at 5 years compared to COPP/ABVD (87% vs 69% freedom from treatment failure) 3
• For patients >60 years, 6-8 cycles of ABVD is standard; BEACOPP should not be given due to excessive toxicity 1
• Bleomycin should be discontinued after the second cycle in elderly patients 1

Radiotherapy in advanced disease is limited to specific scenarios: 1, 3

• Localized radiotherapy (30 Gy) to residual lymphoma >1.5-2.5 cm after chemotherapy 1, 3
• Radiotherapy may be omitted if residual disease is PET-negative after chemotherapy 3
• Routine consolidation radiotherapy to bulky sites or residual disease <2.5 cm is not recommended 1

PET-Adapted Treatment Considerations

Interim PET scanning after 2-4 cycles allows treatment optimization, though treatment stratification based on interim PET cannot yet be considered standard practice. 3

• PET-positive patients after 2 cycles of BEACOPP escalated require 4 additional cycles, while PET-negative patients need only 2 more cycles 1
• Radiotherapy can be restricted to patients with PET-positive residual lymphoma ≥2.5 cm after chemotherapy 1
• Achieving negative PET should be the goal regardless of protocol used 1

Critical Toxicity Monitoring

Mandatory baseline assessments include: 3

• Left ventricular ejection fraction (LVEF) evaluation for doxorubicin cardiotoxicity 3
• Baseline pulmonary function testing for bleomycin pulmonary toxicity 3
• Bleomycin pulmonary toxicity occurs in 20-31% of patients, with higher rates after 6 cycles versus 4 cycles 2

BEACOPP escalated requires: 3

• G-CSF support for significant hematological toxicity 3
• Appropriate surveillance and supportive care infrastructure 3

Common Pitfalls to Avoid

• Do not use MOPP-based regimens as first-line therapy, especially with radiation, due to significantly higher risk of secondary hematologic malignancies (18% 10-year actuarial risk) compared to ABVD-based regimens 4
• Do not administer G-CSF during concurrent chest radiotherapy due to severe complications; G-CSF should only be given 24-72 hours after chemotherapy completion 5
• Do not routinely use extended-field radiotherapy, which increases toxicity without improving outcomes compared to involved-field approaches 5
• Do not assume 6 cycles of chemotherapy is superior to 4 cycles for early unfavorable disease, as outcomes are equivalent even with bulky disease when combined with radiotherapy 2

Relapsed/Refractory Disease

High-dose chemotherapy followed by autologous stem cell transplantation (HDCT/ASCT) is the treatment of choice for most patients with refractory or relapsed disease. 1

• Salvage regimens include DHAP, IGEV, or ICE before HDCT/ASCT 1
• Consolidating treatment with brentuximab vedotin following HDCT/ASCT is recommended in patients with defined poor-risk factors 1
• Single-agent brentuximab vedotin may be sufficient as salvage therapy before HDCT/ASCT in some patients 1
• Nivolumab and pembrolizumab are approved for patients with disease recurrence after HDCT/ASCT and brentuximab vedotin therapy 1