What is the recommended management approach for lymphoproliferative disease?

Management of Lymphoproliferative Disease

The management of lymphoproliferative disease is determined by the specific subtype, with primary cutaneous CD30+ lymphoproliferative disorders treated with surgical excision or radiotherapy for localized disease, while systemic lymphomas require risk-stratified approaches using rituximab-based immunochemotherapy for symptomatic or high tumor burden disease. 1

Primary Cutaneous CD30+ Lymphoproliferative Disorders

Primary Cutaneous Anaplastic Large Cell Lymphoma (pcALCL)

For solitary or localized lesions, surgical excision or radiotherapy (20-30 Gy) is the first-line treatment. 1

• Surgical excision with clear histological margins can be followed by adjuvant radiotherapy or active surveillance 1
• Radiotherapy achieves very high complete remission rates, though cutaneous recurrences occur in 41-64% of patients 1
• For multifocal skin lesions refractory to conventional therapies, brentuximab vedotin should be considered, as it demonstrated significant benefit in progression-free survival compared to methotrexate or bexarotene in a phase III RCT 1
• Low-dose methotrexate (5-20 mg/week) is effective for patients with multiple lesions 1
• Multi-agent chemotherapy is reserved only for extracutaneous disease or rapidly progressive skin disease that cannot be controlled with other modalities 1

Lymphomatoid Papulosis (LyP)

Active monitoring without treatment is a legitimate first-line approach for patients with limited disease and infrequent eruptions, as no therapy has been proven to alter disease course or prevent associated second lymphomas. 1

• For patients requiring treatment due to numerous, disseminated, or stigmatizing lesions, low-dose methotrexate (5-30 mg/week) or PUVA phototherapy are the best documented therapies 1
• Both methotrexate and PUVA show high response rates but sustained complete remission is rarely achieved, with relapse rates of at least 40% after treatment withdrawal 1
• For larger lesions (>2 cm) that persist beyond 12 weeks, surgical excision or radiotherapy should be considered 1
• Multiagent chemotherapy should be avoided as it is ineffective and causes unnecessary toxicity—rapid recurrence occurs shortly after or even during treatment 1
• Lifelong follow-up is mandatory due to 4-25% risk of second lymphoid neoplasms, which can arise decades after LyP manifestation 1

Systemic B-Cell Lymphoproliferative Disorders

Follicular Lymphoma - Limited Stage (I-II)

Involved-site radiotherapy at 24-40 Gy is the treatment of choice with curative potential for truly localized stage I-II disease. 2, 3

• PET-CT scanning before radiotherapy is essential to confirm truly localized disease and exclude occult advanced-stage involvement 3
• Bone marrow biopsy is required for initial staging to distinguish localized from disseminated disease 3
• Stage II patients with high tumor burden or FLIPI >2 should receive chemoimmunotherapy instead of radiotherapy alone 2

Follicular Lymphoma - Advanced Stage (III-IV)

Watchful waiting is the appropriate initial strategy for asymptomatic patients with advanced-stage, low tumor burden disease, as no curative therapy exists and spontaneous regressions occur in 15-20% of cases. 2, 3

Treatment should be initiated only when patients develop:

• B symptoms (fever, night sweats, weight loss) 2, 3
• Symptomatic or life-threatening organ involvement 2, 3
• Significant ascites or pleural effusion 2, 3
• Rapid lymphoma progression 2, 3
• Hematopoietic impairment 2, 3
• Bulky disease (>7 cm) 2, 3

For symptomatic or high tumor burden disease, first-line therapy should be obinutuzumab or rituximab combined with bendamustine or CHOP. 2, 3

• Rituximab maintenance every 2 months for 2 years is recommended after immunochemotherapy, as it improves progression-free survival with excellent safety profile 2, 3
• Radiological assessment should be performed after every 2-3 cycles during treatment, after completion, and at 6,12, and 24 months post-treatment 3

Relapsed/Refractory Follicular Lymphoma

Obtain a new confirmatory biopsy at suspected relapse to rule out transformation to aggressive lymphoma before selecting salvage therapy. 2, 3

• For early relapse (<12-24 months), a non-cross-resistant regimen is preferred 2
• In rituximab-refractory cases or remissions <6 months, obinutuzumab-bendamustine plus obinutuzumab maintenance is recommended 2
• High-dose chemotherapy with autologous stem cell transplant should be considered in patients with brief first remissions after rituximab-containing regimens 2
• Allogeneic stem cell transplantation offers potential cure with 76-85% survival at 4-8 years but carries 15-20% treatment-related mortality and should be reserved for young, fit patients who have failed autologous transplantation 3

Post-Transplant Lymphoproliferative Disorder (PTLD)

Risk-stratified sequential therapy incorporating rituximab with or without chemotherapy is the rational treatment strategy for CD20+ PTLD that does not respond to reduction of immunosuppression alone. 4, 5

• Initial management consists of reduction of immunosuppression as the first step 4, 5
• For patients not responding to immunosuppression reduction, rituximab monotherapy is the next step 4, 5
• Chemotherapy is added for patients who fail rituximab, using response-adapted approaches 5
• EBV-targeted cytotoxic lymphocytes are a promising approach for relapsed/refractory EBV+ PTLD 4, 5

Critical Safety Considerations

Hepatitis B Screening and Prophylaxis

Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating rituximab treatment. 6

• For patients with evidence of prior hepatitis B infection (HBsAg positive or HBsAg negative but anti-HBc positive), consult hepatology regarding HBV antiviral therapy before and during rituximab treatment 6
• In patients with positive hepatitis B serology, including occult carriers, prophylactic antiviral medication up to 2 years beyond last rituximab exposure is strongly recommended 2, 6
• Monitor patients with evidence of current or prior HBV for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following rituximab therapy 6
• HBV reactivation has been reported up to 24 months following completion of rituximab therapy 6

Infection Monitoring

Serious infections including sepsis, bacterial, fungal, and viral infections can occur during and following rituximab-based therapy, particularly in patients with prolonged hypogammaglobulinemia. 6

• Discontinue rituximab for serious infections and institute appropriate anti-infective therapy 6
• Rituximab is not recommended for use in patients with severe, active infections 6

Tumor Lysis Syndrome Prevention

Administer aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high risk for tumor lysis syndrome (circulating malignant cells ≥25,000/mm³ or high tumor burden). 6

• Monitor for acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia within 12-24 hours after first infusion 6
• Correct electrolyte abnormalities, monitor renal function and fluid balance, and provide supportive care including dialysis as indicated 6

Progressive Multifocal Leukoencephalopathy (PML)

Consider PML diagnosis in any patient presenting with new-onset neurologic manifestations during or after rituximab therapy. 6

• Most cases of PML are diagnosed within 12 months of last rituximab infusion 6
• Evaluation includes neurology consultation, brain MRI, and lumbar puncture 6
• Discontinue rituximab and consider discontinuation or reduction of concomitant chemotherapy or immunosuppressive therapy in patients who develop PML 6

Rare Cutaneous T-Cell Lymphoma Variants

Subcutaneous Panniculitis-Like T-Cell Lymphoma (SPTCL)

Systemic steroids or other immunosuppressive agents (ciclosporin, methotrexate) are first-choice treatment for SPTCL without associated hemophagocytic syndrome. 1

• For solitary skin lesions, radiotherapy with electrons is advised 1
• Multi-agent chemotherapy is required only for progressive disease not responding to immunosuppressive therapy or cases with hemophagocytic syndrome 1

Primary Cutaneous Extranodal NK/T Cell Lymphoma

Combined modality treatment with L-asparaginase containing chemotherapy (such as SMILE regimen) combined with radiotherapy is the preferred treatment for localized disease. 1

• In rare cases with small, solitary lesions, and in older or frail patients who cannot tolerate intensive chemotherapy, radiotherapy alone can be considered 1