Is Autologous Stem Cell Transplantation (ASCT) recommended as a first-line treatment for Central Nervous System (CNS) lymphoma?

Autologous Stem Cell Transplantation in First-Line Treatment of CNS Lymphoma

High-dose chemotherapy followed by autologous stem cell transplantation (HDC-ASCT) is strongly recommended as consolidation therapy in first-line treatment for fit patients with primary CNS lymphoma (PCNSL) who have responsive or stable disease after suitable induction chemotherapy. 1

Evidence-Based Recommendations for First-Line ASCT in PCNSL

Patient Selection Criteria

• Age and Fitness: Recommended for fit patients, typically younger than 70 years
• Disease Status: Patients must have responsive or stable disease after induction chemotherapy
• Evaluation: Fitness for ASCT should be dynamically assessed during treatment, as patients may gain or lose "ASCT fitness" during induction chemotherapy 1

Treatment Algorithm

1. Induction Phase:

   • High-dose methotrexate (HD-MTX) based chemotherapy at minimum dose of 3 g/m² delivered in a 3-hour infusion 1
   • Combinations with other agents that cross blood-brain barrier are recommended (e.g., MATRix, ReMBVP, rituximab-HD-MTX-carmustine-etoposide-prednisone) 1

2. Consolidation with ASCT:

   • Thiotepa-based conditioning regimens are strongly recommended 1
   • Common regimens include thiotepa-busulfan-cyclophosphamide or carmustine-thiotepa 2

Efficacy of ASCT as First-Line Consolidation

Recent high-quality evidence demonstrates superior outcomes with ASCT compared to whole-brain radiotherapy (WBRT):

• The randomized phase II PRECIS study showed 8-year event-free survival of 67% with ASCT versus 39% with WBRT (p=0.03) 3
• Significantly lower risk of relapse after ASCT (hazard ratio 0.13; p<0.001) 3
• Meta-analysis data shows 5-year overall survival of 70% and progression-free survival of 54% with ASCT as consolidation 2

Neurocognitive Outcomes

A critical advantage of ASCT over WBRT is preservation of cognitive function:

• Balance and neurocognition significantly deteriorated after WBRT compared to ASCT (52% vs 10% and 64% vs 13%, respectively; p<0.001) 3
• WBRT at doses of 36-40 Gy should be avoided or deferred in elderly patients due to high risk of disabling neurocognitive impairment 1

Alternative Consolidation Approaches

For patients who are not candidates for ASCT, alternative consolidation options include:

1. Whole-brain radiotherapy (WBRT):

   • Recommended at a dose of 36-40 Gy/20 fractions in young patients not suitable for ASCT 1
   • Should be avoided in elderly patients due to neurocognitive risks
   • Reduced-dose WBRT (23.4 Gy) is an option for patients with responsive disease

2. Non-myeloablative chemotherapy:

   • Options like rituximab-dexamethasone-etoposide-carboplatin (R-DeVIC) have been studied
   • However, randomized trials show inferior PFS compared to ASCT (51% vs 73% at 2 years) 1

Important Considerations and Caveats

• Treatment-related mortality: ASCT carries a risk of treatment-related mortality (approximately 5-8%) 3, 4
• Patient selection: Careful assessment of comorbidities and functional status is crucial
• Conditioning regimen: Carmustine-thiotepa conditioning appears to have the lowest transplant-related mortality 2
• Timing: ASCT should be performed after achieving maximum response to induction therapy
• Clinical trials: Enrollment in suitable prospective clinical trials should be offered to every patient with PCNSL when available 1

Special Populations

For patients with HIV-associated PCNSL who are on effective antiretroviral therapy with well-controlled HIV, the MATRix regimen followed by ASCT consolidation should be considered, similar to immunocompetent patients 1.

For elderly or unfit patients unsuitable for ASCT, alternative approaches such as reduced-dose WBRT, non-myeloablative chemotherapy, or watchful waiting (for those in complete remission) may be considered 1.