What is the management of Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL)?

Management of Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL)

Initial Diagnostic Requirements

Before initiating any treatment for NLPHL, obtain an excisional lymph node biopsy to confirm the diagnosis and distinguish NLPHL from classical Hodgkin lymphoma, as the treatment approaches differ significantly. 1

• Core needle biopsy may be adequate only if diagnostic tissue is obtained and reviewed by an expert hematopathologist 1
• Fine-needle aspiration is insufficient except in unusual circumstances 1
• Immunostaining must demonstrate CD20-positive lymphocyte-predominant ("popcorn") cells that are CD30-negative, distinguishing NLPHL from classical HL 1, 2
• Recognize variant histological patterns, as these carry worse prognosis and may require more aggressive treatment 3, 4

Staging Workup

Complete the following staging evaluation before treatment decisions 1, 5:

• PET-CT scan (skull base to mid-thigh) is preferred for accurate staging 1, 5
• Contrast-enhanced CT of neck, chest, and abdomen if PET-CT unavailable 1
• Complete blood count, ESR, comprehensive metabolic panel including LDH 1, 5
• Bone marrow biopsy is NOT required if PET-CT is performed 1, 5
• Screen for hepatitis B, hepatitis C, and HIV 1, 5
• Document B symptoms (fever >38°C, drenching night sweats, >10% weight loss in 6 months) 1

Stage IA Without Risk Factors

For stage IA NLPHL patients presenting without clinical risk factors, treat with involved-site radiotherapy (ISRT) at 30 Gy alone—this is the ONLY scenario where NLPHL differs from classical HL treatment. 1, 5, 2

• This approach achieves excellent outcomes with minimal toxicity 1
• The ISRT fields in this RT-alone approach are larger than combined-modality ISRT to include potential microscopic regional disease 1
• No chemotherapy is required for this favorable subset 1

All Other Stages (IA with Risk Factors, IB-IV)

For all NLPHL stages beyond IA without risk factors, treat identically to classical Hodgkin lymphoma using combined modality therapy or chemotherapy alone based on stage and risk factors. 1, 2

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

Risk factors include: bulky mediastinal disease (mediastinal mass ratio >0.33), bulky disease >10 cm, B symptoms, ESR >50, or >3 nodal sites 1

Administer 4 cycles of ABVD chemotherapy followed by 30 Gy involved-field radiotherapy. 1, 5

• This combined modality approach balances cure rates with long-term toxicity reduction 1
• PET-guided approaches may allow radiotherapy omission in patients achieving complete metabolic response after chemotherapy, though this remains investigational 1, 5

Advanced-Stage Disease (Stage III-IV)

Treat with 6-8 cycles of ABVD or BEACOPPescalated chemotherapy. 1, 5

• Consider consolidative radiotherapy for sites of initial bulky disease 1, 5
• The International Prognostic Score (IPS) helps determine treatment intensity for advanced disease 1

Rituximab-Based Approaches

Because NLPHL malignant cells consistently express CD20, consider adding rituximab to chemotherapy regimens, particularly R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). 1, 5, 3

• The largest retrospective study showed promising results with R-CHOP for NLPHL 1, 5
• This approach leverages the CD20 positivity unique to NLPHL versus classical HL 1, 3, 2
• Prospective data are still pending, but retrospective evidence supports this strategy 1

Critical Pitfall: Transformation Risk

Always obtain a new tissue biopsy before initiating salvage therapy for suspected relapse, as NLPHL can transform to aggressive diffuse large B-cell lymphoma. 1, 6, 3

• Transformation occurs more frequently than previously recognized 6
• Clinical features alone cannot distinguish relapsed NLPHL from transformed disease 6
• Transformed disease requires immediate aggressive B-cell NHL protocols, not indolent lymphoma approaches 6
• Watch-and-wait is inappropriate once transformation is confirmed 6

Relapsed/Refractory Disease Management

First Relapse

For first relapse, treatment intensity depends on timing and extent of recurrence. 2, 7

• Late relapses (>12 months) can be treated with less intensive approaches: rituximab monotherapy, limited radiotherapy, or single-agent chemotherapy 2, 7
• Early relapses (<12 months) or aggressive presentations require salvage chemotherapy (DHAP, IGEV, or ICE) followed by high-dose chemotherapy with autologous stem cell transplantation 1, 5, 2

Multiple Relapses

For patients failing autologous stem cell transplantation, use brentuximab vedotin or anti-PD-1 antibodies (nivolumab or pembrolizumab). 1, 5

• These agents are FDA and EMA approved for multiply relapsed disease after ASCT failure 1
• Anti-PD-1 antibodies show high response rates and durable remissions in heavily pretreated patients 1

Response Assessment and Follow-Up

During Treatment

• Perform interim PET-CT after 2 cycles of chemotherapy if using PET-guided treatment strategies 1
• Use Deauville 5-point scale for PET response assessment 1
• Conduct final staging with PET-CT after treatment completion 1, 5

Long-Term Surveillance

Follow patients every 3 months for 6 months, then every 6 months until year 4, then annually thereafter with history, physical examination, and laboratory tests. 1, 5

• Obtain CT scan once to confirm remission status, then only for clinical symptoms—routine surveillance imaging is NOT indicated 1, 5
• Monitor thyroid function annually if neck was irradiated 1, 5
• Screen for second malignancies and cardiovascular disease given long-term survival 1
• Remain vigilant for late relapses, which are characteristic of NLPHL 3, 8, 2

Special Considerations for Treatment Selection

Given the excellent overall survival of NLPHL (80-90% achieve permanent remission), prioritize treatment strategies that minimize long-term toxicity, particularly in young patients. 1, 3

• Avoid overtreatment in early-stage disease where radiotherapy alone suffices 1
• Consider rituximab-based regimens to potentially reduce chemotherapy intensity 1, 3
• Balance cure rates against risks of secondary malignancies, cardiovascular disease, and infertility 1, 3, 8
• The indolent natural history and propensity for late relapses means treatment decisions should account for decades of survivorship 3, 8, 2