What is the recommended approach for managing Central Nervous System (CNS) lymphoma?

Management of CNS Lymphoma

For newly diagnosed CNS lymphoma, initiate high-dose methotrexate (HD-MTX) at ≥3 g/m² as the cornerstone of therapy, with consolidation using autologous stem cell transplantation (ASCT) for eligible patients achieving complete response, as this approach offers the best curative potential with 2-year overall survival rates of 68%. 1

Initial Treatment Approach

Primary CNS Lymphoma (PCNSL) - Newly Diagnosed

Induction Chemotherapy:

• HD-MTX-containing regimens are mandatory as first-line therapy, administered at doses ≥3 g/m² to achieve cytotoxic concentrations in cerebrospinal fluid 1
• Combination regimens show superior outcomes: HD-MTX plus HD-cytarabine demonstrated failure-free survival benefit 1
• Alternative effective combinations include HD-MTX with rituximab, procarbazine, and vincristine (R-MPV), achieving 80-90% response rates 2
• HD-MTX with intravenous rituximab and oral temozolomide is a feasible immunochemotherapy option 1

Consolidation Strategy - The Critical Decision Point:

For patients achieving complete response after induction, ASCT is the preferred consolidation approach rather than whole-brain radiotherapy (WBRT) alone:

• ASCT with thiotepa/BCNU-based conditioning regimens achieves 63% complete response with 5-year overall survival of 68% 1
• Thiotepa and BCNU must be included in the conditioning regimen prior to ASCT 1
• German phase II data showed 50% complete response with 2-year overall survival of 68% post-transplantation using BCNU, thiotepa, and etoposide conditioning 1

Leptomeningeal Involvement

When leptomeningeal disease is documented:

• Add intrathecal (IT) liposomal cytarabine (LC) to HD-MTX regimens 1
• IT LC is superior to conventional cytarabine based on randomized trial data, providing sustained CSF concentrations for 14 days versus requiring 2-3 times weekly administration with conventional agents 1
• Dosing: IT LC 50 mg every other week for approximately 6 cycles 3
• Alternative: Triple IT therapy (MTX 15 mg, cytarabine 40 mg, hydrocortisone 20 mg) 1

Secondary CNS Lymphoma (SCNSL) - Synchronous Presentation

For patients presenting with both systemic DLBCL and CNS involvement:

• Combine R-CHOP for systemic disease with HD-MTX for CNS-targeted therapy 1
• Follow with etoposide and cytarabine consolidation in patients achieving systemic and CNS complete response 1
• For leptomeningeal cases: R-CHOP plus IT LC is an alternative approach 1

Special Populations

Elderly or Patients with Comorbidities

When HD-MTX is contraindicated due to age or comorbidities:

• IT liposomal cytarabine becomes the primary treatment recommendation 1
• This avoids systemic toxicity while maintaining CNS drug delivery 1

Patients Not Eligible for ASCT

For non-transplant candidates:

• Reduced-dose WBRT (23.4 Gy) as consolidation reduces neurotoxicity risk compared to standard doses 2
• High-dose cytarabine consolidation is an alternative, though associated with higher relapse risk 2
• Standard-dose WBRT carries unacceptable rates of delayed neurotoxicity, especially in older patients 1

Relapsed/Refractory Disease

CNS Relapse Management

ASCT represents the best currently available curative option for recurrent aggressive CNS lymphoma 1

Treatment algorithm based on MTX sensitivity:

MTX-Sensitive Relapse:

• Administer HD-MTX for maximum cytoreduction 1
• Follow with thiotepa or carmustine-based conditioning regimens and ASCT 1
• Better outcomes occur in patients achieving complete response before transplantation 1

MTX-Resistant or Early Relapse (<6 months post-consolidation):

• These patients are generally not candidates for high-dose rescue strategies 1
• Enroll in clinical trials or consider palliative treatment based on performance status 1
• Whole-brain radiotherapy may be considered for refractory cases 1

Adjuvant Radiotherapy Considerations

Limited role for radiotherapy in routine management:

• In SCNSL, radiotherapy may be considered for large masses or CSF flow blockade 1
• The true impact of WBRT combined with chemotherapy in PCNSL remains controversial 1
• Toxicity, particularly neurocognitive decline in older patients, limits routine use 1

Critical Pitfalls to Avoid

• Never delay systemic immunochemotherapy cycles when administering IV MTX prophylaxis - maintain treatment intensity 1
• Do not use standard-dose WBRT as routine consolidation in complete responders due to unacceptable neurotoxicity rates 1
• Ensure adequate MTX dosing (≥3 g/m²) - lower doses fail to achieve therapeutic CSF concentrations 1
• Consider renal function and performance status before each HD-MTX cycle to prevent toxicity 1

Emerging Therapies

Novel agents crossing the blood-brain barrier, including ibrutinib and lenalidomide, may further improve outcomes in future treatment paradigms 1