What is the recommended maintenance therapy for a patient with primary central nervous system (CNS) lymphoma who has completed initial treatment?

Maintenance Therapy for Primary CNS Lymphoma

Maintenance therapy with oral alkylating agents (such as procarbazine) or immunomodulators (such as lenalidomide) can be considered on an individual basis for elderly patients in complete remission after induction chemotherapy, though this remains investigational with no established standard of care. 1

Current Evidence and Recommendations

For Fit Patients Undergoing Consolidation

• High-dose chemotherapy with autologous stem cell transplantation (HDCeASCT) is the recommended consolidation strategy for fit patients under age 65-70 years with responsive or stable disease after induction, eliminating the need for maintenance therapy in this population 1

• Thiotepa-based ASCT conditioning regimens should be used, with doses adjusted based on patient fitness and comorbidities 1

For Elderly or Unfit Patients

Watchful waiting is the preferred approach for elderly patients in complete remission after well-established induction immunochemotherapy (such as MATRix or similar HD-MTX-based combinations), rather than routine maintenance therapy 1

However, maintenance therapy may be considered in select cases:

• Oral alkylating agents (procarbazine, temozolomide, carmustine) can be considered as maintenance 1

• Lenalidomide (not EMA or FDA approved for this indication) has shown promising results as single-agent maintenance in small cohorts of elderly patients, with evidence suggesting it can prolong response duration after salvage therapy 1, 2

• Lenalidomide demonstrated good efficacy when used as maintenance and combined with BTK inhibitors in the relapsed/refractory setting 1

Ongoing Clinical Trials

The evidence base for maintenance therapy remains limited, with two key trials addressing this question:

• The BLOCAGE trial (NCT02313389) is evaluating maintenance immunochemotherapy (ReMT regimen) versus observation in patients achieving complete remission after HD-MTX-based induction 1

• The FIORELLA trial (NCT03495960) is randomizing patients between procarbazine versus lenalidomide as maintenance treatment after ReMP induction 1

Evidence Quality and Limitations

The recommendation for maintenance therapy carries a Level IV, Grade C evidence rating, reflecting the lack of randomized controlled trials and reliance on small single-arm studies 1. This is in stark contrast to the Level I, Grade A evidence supporting HDCeASCT consolidation in fit patients 1.

Key Clinical Considerations

• Maintenance therapy is feasible and associated with encouraging results in elderly patients based on phase II data 1

• In one small study, lenalidomide maintenance after salvage therapy in relapsed PCNSL showed significantly longer response durations compared to standard therapy alone, with 6 patients maintaining response ≥9 months and 4 maintaining response ≥18 months 2

• The CSF penetration of lenalidomide is adequate at 15-20 mg dose levels, with CSF/plasma partition coefficient ≥20% 2

Critical Pitfalls to Avoid

• Do not use maintenance therapy as a substitute for appropriate consolidation (HDCeASCT or reduced-dose WBRT) in fit patients who are suitable candidates 1

• Avoid conventional-dose whole-brain radiotherapy (36-40 Gy) in elderly patients due to high risk of disabling neurocognitive impairment; if maintenance is not used, watchful waiting or reduced-dose WBRT (23.4 Gy) are preferred alternatives 1

• Lenalidomide and other immunomodulators are not approved by regulatory agencies for PCNSL and represent off-label use 1

• Enrollment in prospective clinical trials should be prioritized over empiric maintenance therapy given the limited evidence base 1

Practical Algorithm

For patients completing first-line induction therapy:

1. Age <65-70 years + fit for transplant → HDCeASCT consolidation (no maintenance needed) 1

2. Age >65-70 years in complete remission → Watchful waiting preferred 1

3. Age >65-70 years with partial response or high-risk features → Consider maintenance with:

   • Procarbazine (dose per established protocols) 1
   • Lenalidomide 10-20 mg daily (off-label) 1, 2
   • Clinical trial enrollment (strongly preferred) 1

4. Unfit for any intensive therapy → Best supportive care or palliative options 1