Real-world survival, cognitive and health-related quality of life outcomes of methotrexate/ifosfamide plus whole brain radiotherapy for newly diagnosed primary central nervous system lymphoma

Abstract Background: Outcomes for primary central nervous system lymphoma (PCNSL) have been improved with high-dose methotrexate (HD-MTX)/Thiotepa-based chemotherapy followed by autologous stem cell transplantation. In limited-resource settings, HD-MTX/Ifosfamide plus whole-brain radiotherapy (WBRT) has become the local standard of care. Objectives: This study investigated the real-world effectiveness, neurocognitive functions, and health-related quality of life (HRQoL) of HD-MTX/Ifosfamide in newly diagnosed PCNSL patients. Design: A single center retrospective and prospective study. Methods: Newly diagnosed PCNSL patients treated with HD-MTX (± Ifosfamide) between 2011 and 2024 were analyzed for treatment effectiveness. For neurocognitive function and HRQoL assessments, the age- and education-matched PCNSL and non-CNS lymphoma patients in first remission were evaluated using standardized cognitive tests (Montreal Cognitive Assessment, digit span test, symbol search test and Wisconsin card sorting test-short form) and the European Organization for Research and Treatment of Cancer QLQ-C30/BN20 questionnaires. Results: Among 94 PCNSL patients enrolled in our study, 56 patients received HD-MTX/Ifosfamide (median age 56 years; 68% ECOG 0-1) and 38 patients received HD-MTX monotherapy (median age 66 years; 63% ECOG ≥2). HD-MTX/Ifosfamide demonstrated a significantly longer event-free survival (39 vs. 8 months, p=0.021) than HD-MTX monotherapy. Poor performance status (ECOG ≥2) was associated with inferior response (54.8% vs. 78.8%, p=0.013) and overall survival (Hazard ratio 2.4 [95% Confidence interval 1.57-4.56], p=0.007). Patients who received WBRT consolidation had a significantly superior 2-year progression-free survival (74.5% vs. 35.6%, p<0.001). Comparing neurocognitive tests in 20 PCNSL and 20 non-CNS lymphoma survivors in remission showed no significant difference in overall scores, but trends toward lower attention and executive function scores in the PCNSL group. Most (16/20) PCNSL survivors received WBRT. Compared to non-CNS lymphoma patients, PCNSL patients reported significantly lower HRQoL, particularly in physical functioning, which might be attributed to residual neurological deficits. Conclusion: This study supports HD-MTX/Ifosfamide as an effective, well-tolerated regimen for younger, fit PCNSL patients. WBRT remains a valuable consolidation therapy to prevent recurrence without a pronounced decline in cognitive function compared with other lymphoma survivors. However, PCNSL survivors may experience subtle declines in attention, executive function, and HRQoL.