What is the treatment approach for patients presenting with neurological manifestations of lymphoma?

Treatment Approach for Neurological Manifestations of Lymphoma

Patients with neurological manifestations of lymphoma should be treated with high-dose methotrexate (HD-MTX)-containing regimens as the cornerstone of therapy, with treatment modifications based on specific presentation, patient factors, and disease characteristics. 1

Types of Neurological Involvement in Lymphoma

• Central nervous system (CNS) involvement in lymphoma can present as parenchymal brain lesions, leptomeningeal disease, ocular involvement, or spinal cord lesions 1, 2
• Peripheral nervous system involvement may manifest as neurolymphomatosis with infiltration of peripheral nerves 3
• Neurological symptoms can be the initial presentation of lymphoma, occurring during disease progression, or at relapse 4

Diagnostic Approach

• Comprehensive evaluation should include:
  • MRI of brain and/or spine with contrast 1, 2
  • CSF examination with cytology and flow cytometry to detect occult leptomeningeal disease 1
  • Vitreous fluid examination when ocular involvement is suspected 1
  • Whole-body FDG-PET to evaluate for systemic disease 3
  • Tissue biopsy when possible for definitive diagnosis 5

Treatment Algorithm for CNS Lymphoma

1. Parenchymal Brain or Spinal Cord Involvement

• First-line treatment:

  • HD-MTX (≥3 g/m²) is the cornerstone of therapy 1, 2
  • For patients with good performance status, the MATRix regimen (HD-MTX, high-dose cytarabine, thiotepa, and rituximab) has shown the best outcomes 2
  • In patients not suitable for HD-MTX due to age or comorbidities, intrathecal liposomal cytarabine (IT LC) is recommended 1

• Consolidation therapy:

  • For responding patients, consolidation with high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is recommended 1, 2
  • Thiotepa and BCNU should be included in the conditioning regimen prior to ASCT 1
  • Whole-brain radiotherapy is an alternative consolidation option, particularly for patients who cannot undergo ASCT 2

2. Leptomeningeal Involvement

• Treatment approach:
  • HD-MTX-containing regimens with associated intrathecal therapy 1
  • For patients with systemic DLBCL and leptomeningeal disease, R-CHOP plus intrathecal liposomal cytarabine is a possible approach 1
  • For occult leptomeningeal disease (negative conventional cytology but positive flow cytometry), HD-MTX and/or intrathecal chemotherapy should be considered 1

3. Combined Systemic and CNS Lymphoma

• Treatment approach:
  • Patients with synchronous systemic DLBCL and CNS involvement should receive immunochemotherapy for systemic disease and CNS-targeted therapy for CNS disease 1
  • R-CHOP plus HD-MTX followed by etoposide and cytarabine consolidation is recommended 1

Treatment for Relapsed/Refractory Disease

• For MTX-sensitive relapse:

  • HD-MTX to achieve maximum cytoreduction followed by thiotepa or carmustine-based conditioning regimens and ASCT 1

• For MTX-resistant relapse or early relapse:

  • Clinical trial enrollment when possible 2
  • Whole-brain radiotherapy as an alternative option 1
  • Palliative treatment for patients with poor performance status 1

Special Considerations

HIV-Associated CNS Lymphoma

• Rituximab plus HD-MTX (3 g/m²) combined with fully active antiretroviral therapy is recommended 6
• This regimen has demonstrated good outcomes with a median overall survival of 5.7 years 6

Primary Testicular Lymphoma with CNS Involvement

• Higher risk of CNS involvement (>15%) 1
• Treatment with R-CHOP plus intrathecal MTX and contralateral testis irradiation has shown reduced CNS relapse rates 1

Potential Complications and Monitoring

• Monitor for progressive multifocal leukoencephalopathy (PML) in patients receiving rituximab 7
• Screen for hepatitis B virus before initiating rituximab therapy to prevent reactivation 7
• Evaluate for tumor lysis syndrome, especially in patients with high tumor burden 7
• Neurotoxicity risk increases with combined chemoradiotherapy, particularly in patients >60 years 2

Clinical Pitfalls

• Lymphoma can mimic various neurological disorders, leading to diagnostic delays of months 5
• Red flags suggesting lymphoma include subacute but progressive symptoms, painful neurological deficits, and transient steroid responsiveness 5
• Negative CSF cytology does not exclude CNS lymphoma; flow cytometry has higher sensitivity 1
• Avoid routine testing for lymphoma in patients with typical amyotrophic lateral sclerosis, relapsing-remitting multiple sclerosis, Parkinson's disease, dementia, or new-onset seizures 1