What is the current first-line treatment for primary Central Nervous System (CNS) lymphoma?

First-Line Treatment for Primary CNS Lymphoma

The MATRix regimen (high-dose methotrexate, high-dose cytarabine, rituximab, and thiotepa) followed by consolidation with either autologous stem cell transplantation or whole-brain radiotherapy is the current standard first-line treatment for primary CNS lymphoma in fit patients under 70 years of age. 1

Patient Stratification for Treatment Selection

Treatment selection for primary CNS lymphoma (PCNSL) should be based on:

1. Age: Under vs. over 70 years
2. Performance status: ECOG 0-3
3. Organ function: Especially renal function (creatinine clearance >50 ml/min)
4. Comorbidities and frailty

For Fit Patients (typically <70 years with good performance status)

Induction Phase

• MATRix regimen 1, 2:
  • High-dose methotrexate (HD-MTX): 3.5 g/m² on day 1
  • High-dose cytarabine (HD-AraC): 2 g/m² twice daily on days 2-3
  • Rituximab: 375 mg/m² on days -5 and 0
  • Thiotepa: 30 mg/m² on day 4
  • Administered every 3 weeks for 4 cycles

The MATRix regimen has demonstrated significantly improved outcomes compared to HD-MTX alone or HD-MTX plus cytarabine, with:

• 7-year progression-free survival: 52% (vs. 20% for HD-MTX/cytarabine)
• 7-year overall survival: 56% (vs. 26% for HD-MTX/cytarabine) 1

Consolidation Options

1. Autologous stem cell transplantation (ASCT) with thiotepa-based conditioning
2. Whole-brain radiotherapy (WBRT) at 36-40 Gy/20 fractions

Both consolidation approaches have shown similar efficacy, but ASCT is generally preferred in younger patients to avoid the long-term neurocognitive toxicity associated with WBRT 1, 3.

For Elderly or Unfit Patients (typically >70 years or with comorbidities)

• Modified regimens 1:

  • HD-MTX (3-3.5 g/m²) plus temozolomide
  • HD-MTX plus procarbazine and vincristine (MPV)
  • HD-MTX plus temozolomide and rituximab (MTeR)
  • Rituximab plus HD-MTX and procarbazine (ReMP)

• Consolidation options:

  • Reduced-dose WBRT
  • Non-myeloablative chemotherapy
  • Observation (for those in complete remission)

Treatment Response Assessment

Response assessment should follow International PCNSL Collaborative Group (IPCG) criteria:

• Gadolinium-enhanced MRI of the brain every two courses during induction
• Final assessment 2 months after consolidation
• Additional ocular and CSF exams if involved at baseline 1

Relapsed/Refractory Disease

For relapsed/refractory PCNSL, treatment options include:

1. Early relapse or refractory disease (fit patients):

   • High-dose ifosfamide or cytarabine-based combinations
   • Followed by ASCT or WBRT (depending on prior treatment)

2. Late relapse (>12 months):

   • Re-treatment with HD-MTX-based regimen
   • Consider different consolidation than used in first-line

3. Targeted therapies for patients unfit for intensive therapy:

   • BTK inhibitors (ibrutinib 560-840 mg/day)
   • Immunomodulators (lenalidomide, pomalidomide)
   • Temozolomide 1

Clinical Pearls and Pitfalls

• Critical pitfall: Delaying treatment can worsen outcomes. Rapid initiation of therapy is essential for recovery and prognosis 4.

• Important consideration: HD-MTX requires adequate renal function (creatinine clearance >50 ml/min), which must be assessed before treatment initiation 1.

• Monitoring: Watch for grade 3-4 hematological toxicity, which is more common with combination regimens. The MATRix regimen has higher rates of neutropenia, thrombocytopenia, and anemia, but infection rates are similar to less intensive regimens 2.

• Emerging therapies: CAR-T cell therapy targeting CD19 has shown promising early results in relapsed/refractory PCNSL, with 50% complete response rates in a phase I/II trial, though with expected cytokine release syndrome and neurotoxicity 1.

• Treatment in specialized centers: Given the rarity and complexity of PCNSL, treatment should be carried out in specialist centers by experienced multidisciplinary teams 1.

The evidence strongly supports that high-dose methotrexate-based combination chemotherapy, particularly the MATRix regimen when feasible, followed by appropriate consolidation therapy, offers the best chance for long-term survival and should be the standard approach for eligible patients with newly diagnosed PCNSL.