What is the recommended initial treatment for primary central nervous system (CNS) lymphoma?

Primary CNS Lymphoma: Recommended Initial Treatment

The recommended initial treatment for primary CNS lymphoma is high-dose methotrexate (≥3 g/m²) combined with high-dose cytarabine (2 g/m² twice daily for 2 days) and rituximab, followed by consolidation therapy with either autologous stem cell transplantation or whole-brain radiotherapy depending on patient age and fitness. 1, 2

Induction Chemotherapy Regimen

Core Components

• High-dose methotrexate is mandatory at doses of at least 3 g/m² infused over 2-4 hours, with some experts recommending a 500 mg/m² bolus over 15 minutes preceding the main infusion 1, 2, 3
• High-dose cytarabine significantly improves outcomes and should be added at 2 g/m² every 12 hours for 2 days (4 total doses) 1, 3, 4
• The landmark IELSG20 trial demonstrated that HD-MTX plus HD-cytarabine achieved 69% overall response rate versus only 40% with HD-MTX alone, with 3-year PFS improving from 21% to 38% 4

Optimal Combination: MATRix Regimen

• The MATRix regimen (methotrexate, cytarabine, rituximab, thiotepa) has demonstrated the best long-term outcomes with 7-year overall survival of 56% 2
• This represents the current gold standard for fit patients aged <70 years 1, 2

Critical Treatment Principles

• Never use anthracycline-based regimens like R-CHOP as they have insufficient blood-brain barrier penetration and are ineffective 3
• Maintain dose intensity without reductions whenever possible, as this is critical for optimal outcomes 3
• Administer G-CSF support (filgrastim 5 µg/kg/day or pegfilgrastim 6 mg) starting 24-72 hours after chemotherapy to maintain dose intensity 3

Consolidation Therapy Strategy

For Fit Patients Aged <70 Years

Two equally effective consolidation options exist after achieving complete response: 1, 2

1. High-dose chemotherapy with autologous stem cell transplantation (HDC-ASCT)

   • Preferred option to minimize neurotoxicity risk 1, 5
   • Conditioning regimens should include thiotepa and BCNU 1
   • Achieves 7-year overall survival of 70% after MATRix induction 2
   • Long-term follow-up shows stable neurologic function and no disease recurrence beyond 2 years post-ASCT 6

2. Reduced-dose whole-brain radiotherapy (WBRT)

   • 23.4 Gy is the preferred reduced dose for patients with complete response 5
   • Standard consolidation dose is 36-40 Gy in 20-22 fractions 5
   • Also achieves 7-year overall survival of 70% after MATRix induction 2

For Elderly Patients (≥60-70 Years)

• Avoid or defer WBRT due to unacceptable risk of disabling neurocognitive impairment 1, 5
• Consider watchful waiting or maintenance therapy instead 5
• If WBRT is necessary, use reduced doses (23.4 Gy) 5

For Unfit Patients

• Palliative WBRT at 30-36 Gy in 10-15 fractions is appropriate for those unable to tolerate HD-MTX-based chemotherapy 5

Essential Supportive Care Measures

Tumor Lysis Syndrome Prophylaxis

• Mandatory given the high tumor burden in CNS lymphoma 3
• Monitor potassium, phosphate, calcium, uric acid, and LDH daily for first 3-5 days 3

Hepatitis B Screening and Monitoring

• Screen for hepatitis B surface antigen and core antibody before rituximab 3
• Monitor HBV DNA every 1-3 months during and for 6-12 months after rituximab 3

Neurologic Monitoring

• Perform neurological examination before each cytarabine dose, focusing on cerebellar function, as cerebellar toxicity is a significant risk 3

Response Assessment Protocol

• Perform gadolinium-enhanced brain MRI every two courses during induction chemotherapy 1, 2
• Repeat MRI 2 months after consolidation therapy 1, 2
• Compare all imaging with baseline MRI using International PCNSL Collaborative Group criteria 1
• Include ocular and CSF exams if involved at baseline 1

Critical Pitfalls to Avoid

• Do not omit high-dose cytarabine from the regimen, as it significantly improves complete remission rates from 18% to 46% 4
• Never administer G-CSF during concurrent chest radiotherapy due to increased mortality risk 3
• Avoid growth factors immediately before or simultaneously with chemotherapy due to severe thrombocytopenia risk 3
• Do not use standard-dose WBRT (45 Gy) in elderly patients due to neurocognitive toxicity 5
• Ensure creatinine clearance >50 ml/min, left ventricular ejection fraction >45%, and adequate hepatic function before initiating HD-MTX 1

Multidisciplinary Management

All patients should be managed at specialized centers by an experienced multidisciplinary team including neurosurgeons, neuroradiologists, haematopathologists, haematologists, oncologists, radiation oncologists, and ophthalmologists with PCNSL expertise 1, 2