What is the recommended initial treatment approach for a patient with Non-Hodgkin's Lymphoma (NHL) and brain involvement?

Treatment of Non-Hodgkin's Lymphoma with Brain Involvement

Initial Treatment Approach

For NHL with brain involvement, initiate high-dose methotrexate (HD-MTX) at ≥3 g/m² as the cornerstone of therapy, combined with high-dose cytarabine and rituximab (MATRix regimen for eligible patients), followed by consolidation with autologous stem cell transplantation in responding patients under age 65-70 years. 1

Treatment Algorithm by Clinical Scenario

Primary CNS Lymphoma (Brain-Only Disease)

Induction Therapy:

• MATRix regimen (preferred for patients ≤65 years, ECOG PS 0-3): HD-MTX 3.5 g/m², high-dose cytarabine 2 g/m² every 12 hours for 2 days, rituximab 375 mg/m², and thiotepa, achieving 7-year OS of 70% when followed by consolidation 1
• HD-MTX must be dosed at minimum 3 g/m² with rapid 2-4 hour infusion (some experts recommend 500 mg/m² bolus over 15 minutes first) to achieve adequate CNS penetration 1
• Alternative for patients >65 years or unable to tolerate intensive therapy: HD-MTX + rituximab + temozolomide, showing pooled complete response rate of 60% 2

Consolidation Options (in order of efficacy):

• High-dose chemotherapy with ASCT (first choice): Achieves 2-year OS 80%, 2-year PFS 74%, 5-year OS 77%, 5-year PFS 63% 2
• Conditioning regimen must include thiotepa or BCNU for CNS penetration 1
• Whole-brain radiotherapy is not recommended as first-line consolidation due to severe delayed neurotoxicity (49% clinical neurotoxicity, 71% radiologic changes) without OS benefit (HR 1.06, p=0.71) 3

Secondary CNS Lymphoma (Systemic DLBCL + Brain Involvement)

Synchronous Parenchymal and/or Leptomeningeal Disease:

• Combine systemic immunochemotherapy (R-CHOP for systemic disease) with HD-MTX-containing regimens for CNS disease 1
• Add intrathecal liposomal cytarabine for leptomeningeal involvement 1
• Consolidate with etoposide and cytarabine in patients achieving complete response in both compartments 1

Leptomeningeal Disease Only:

• R-CHOP plus intrathecal liposomal cytarabine is feasible alternative 1
• Intrathecal methotrexate 12 mg achieves therapeutic CSF levels (>1 μmol/L) for 24-48 hours, requiring administration with each chemotherapy cycle for total 4-8 doses 1, 4
• Use preservative-free normal saline as diluent, perform isovolumetric administration (remove CSF volume equal to instilled volume) 4
• Administer oral leucovorin 10 mg twice daily starting on treatment day, continuing for 3 days to reduce systemic toxicity 4

CNS Relapse

MTX-Sensitive Disease (relapse >6 months after initial therapy):

• Re-administer HD-MTX to achieve maximum cytoreduction 1
• Consolidate with thiotepa or carmustine-based conditioning followed by ASCT 1
• ASCT is the best currently available curative option for recurrent aggressive CNS lymphoma 1

MTX-Resistant Disease (relapse <6 months or refractory):

• These patients are generally not candidates for high-dose rescue strategies 1
• Prioritize clinical trial enrollment or consider palliative treatment based on performance status 1

Critical Pre-Treatment Requirements

Mandatory Screening:

• Hepatitis B surface antigen (HBsAg) and Hepatitis B core antibody (HBcAb) testing before any anti-CD20 antibody therapy 1
• Prophylactic antiviral therapy (avoid lamivudine due to resistance) required for HBsAg-positive patients, maintained up to 12 months after treatment ends 1
• Assess renal function (creatinine clearance >50 ml/min), hepatic function, and cardiac function (LVEF >45%) as HD-MTX requires adequate organ function 1

Baseline Evaluation:

• Gadolinium-enhanced brain MRI (compare with baseline every 2 cycles during induction, 2 months after consolidation) 1
• CSF examination with cytology and flow cytometry to detect occult leptomeningeal disease 1
• Lumbar puncture mandatory for blastic variants or patients with CNS symptoms 1

Key Pitfalls to Avoid

• Do not use CHOP-like regimens alone for brain involvement—these agents have insufficient blood-brain barrier penetration 1
• Do not reduce HD-MTX dose below 3 g/m²—lower doses fail to achieve therapeutic CNS levels 1
• Do not use whole-brain radiotherapy as first-line consolidation in patients who can tolerate ASCT—the neurotoxicity risk outweighs any PFS benefit without OS improvement 3
• Do not administer intrathecal methotrexate in patients with renal insufficiency, large pleural effusions/ascites, or abnormal CSF flow 4
• Do not use intraventricular Ommaya reservoir for routine prophylaxis, but it is superior to lumbar puncture for treatment of established leptomeningeal disease (10-fold higher ventricular CSF exposure) 4

Age-Specific Modifications

Patients 65-75 years:

• Treatment stratification should be based on performance status, organ function, comorbidities, and frailty—not age alone 1
• MATRix regimen can be used in patients up to age 70 with ECOG PS ≤2 1

Patients >75 years or poor performance status:

• Consider HD-MTX + rituximab + temozolomide as less intensive alternative 2
• If HD-MTX contraindicated due to comorbidities, use intrathecal liposomal cytarabine 1