What is the next treatment for a 60‑year‑old woman with primary central nervous system lymphoma who has residual enhancing disease after induction with high‑dose methotrexate, temozolomide, and rituximab?

Management of Residual Disease After MTR Induction in Primary CNS Lymphoma

This 60-year-old woman with residual disease after methotrexate-temozolomide-rituximab (MTR) induction should proceed directly to consolidation therapy, with high-dose chemotherapy followed by autologous stem cell transplantation (HDC-ASCT) being the preferred option if she is fit, or reduced-dose whole-brain radiotherapy (WBRT) if transplant is not feasible.

Understanding the Clinical Context

The MTR regimen this patient received represents a less intensive induction approach compared to the gold-standard MATRix protocol (which includes high-dose cytarabine and thiotepa). 1 The presence of residual disease on MRI does not necessarily indicate treatment failure—it may represent partial response (PR) or stable disease (SD), both of which warrant proceeding to consolidation rather than salvage therapy. 1

Key Decision Point: Response Classification

• If the residual disease represents PR or SD (i.e., some tumor shrinkage or stability without progression), the patient should proceed to consolidation therapy as planned. 1
• If the residual disease represents progressive disease (PD), then salvage therapy would be indicated instead of consolidation. 1

Recommended Consolidation Strategy

First-Line Option: HDC-ASCT

For fit patients at age 60 with adequate performance status, HDC-ASCT with thiotepa-based conditioning is the preferred consolidation approach. 1

• Thiotepa-containing conditioning protocols have demonstrated superior efficacy compared to traditional BEAM regimens in PCNSL. 1
• The PRECIS trial showed 8-year overall survival of 69% after HDC-ASCT consolidation. 1
• This approach provides maximal blood-brain barrier-penetrating cytostatic therapy to overcome drug resistance. 1
• Eligibility must be assessed based on performance status, organ function, and comorbidities. 2

Second-Line Option: Reduced-Dose WBRT

If HDC-ASCT is not feasible due to inadequate stem cell harvest, patient refusal, or medical contraindications, reduced-dose WBRT (23-36 Gy) is the alternative consolidation strategy. 1

• The RTOG1114 trial demonstrated significant PFS improvement with reduced-dose WBRT consolidation, with median PFS not reached at 55 months versus 25 months for chemotherapy alone. 1
• For patients in complete or partial remission, doses of approximately 23 Gy can be considered to minimize neurocognitive toxicity. 2
• The PRECIS trial showed 8-year overall survival of 65% after WBRT consolidation, comparable to HDC-ASCT. 1
• Critical caveat: At age 60, this patient faces increased risk of delayed neurotoxicity from WBRT, particularly if combined with prior chemotherapy. 3, 2

Important Considerations About the MTR Regimen

The patient received MTR rather than the more intensive MATRix regimen, which may explain the residual disease:

• MTR lacks high-dose cytarabine, which has been shown to significantly improve complete remission rates when added to methotrexate-based therapy. 1, 2
• The MATRix regimen (methotrexate-cytarabine-rituximab-thiotepa) followed by consolidation achieves 7-year overall survival of 70%. 1
• MTR is considered an acceptable but less intensive induction option, particularly for patients who cannot tolerate more aggressive regimens. 1

Alternative Approach: Intensification Before Consolidation

If the residual disease is substantial and there is concern about proceeding directly to consolidation, consider adding high-dose cytarabine cycles before consolidation:

• The HOVON 105-ALLG NHL 24 trial used one course of high-dose cytarabine after initial induction before proceeding to consolidation. 1
• This approach could potentially convert a partial response to complete response before definitive consolidation. 1

What NOT to Do

• Do not treat this as relapsed/refractory disease unless there is clear progressive disease on imaging—residual disease after induction is expected and should proceed to consolidation. 1
• Do not use full-dose WBRT (>40 Gy) in this 60-year-old patient due to prohibitive neurocognitive toxicity risk. 2
• Do not delay consolidation once adequate response is achieved, as this increases relapse risk. 1
• Do not use single-agent temozolomide as salvage therapy if this represents true progressive disease—it has poor efficacy with objective response rates of only 14% and median overall survival of 4 months in relapsed PCNSL. 4

Clinical Algorithm

1. Obtain formal response assessment using International PCNSL Collaborative Group criteria with dedicated brain MRI. 3
2. If PR or SD: Proceed to consolidation therapy
   • Preferred: HDC-ASCT with thiotepa-based conditioning 1
   • Alternative: Reduced-dose WBRT (23-36 Gy) 1, 2
3. If PD: Consider salvage therapy with high-dose ifosfamide or high-dose cytarabine-based regimens, followed by HDC-ASCT or WBRT if response is achieved. 3
4. Consider adding 1-2 cycles of high-dose cytarabine before consolidation if residual disease burden is substantial and patient is fit enough to tolerate intensification. 1