Efficacy of pemetrexed-based regimens in primary central nervous system lymphoma: A single-center experience.

e19078 Background: Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin’s lymphoma with limited treatment options and overall poor prognosis. Multiagent chemotherapy with high-dose methotrexate (HD-MTX) remains the cornerstone of treatment, but ~50% of patients have refractory disease or relapse after initial therapy. Pemetrexed (Pem), a multitargeted antifolate, has shown objective response rates (ORRs) of 55-65% in prior studies with a favorable toxicity profile and amenable to outpatient administration. Pem-based regimens are used at our center for patients with R/R PCNSL and for those not eligible to receive HD-MTX. This retrospective cohort analysis evaluates the clinical outcomes of Pem-based regimens. Methods: This retrospective analysis included 11 patients with PCNSL treated with Pem-based regimens as of January 1st, 2025. Treatment responses were assessed using IPCG criteria. Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Results: Most (9/11) patients had biopsies demonstrating large B-cell lymphoma. Median age was 74 years (range: 59-78), with 64% aged 70 years or older. Regimens included Pem in combination with rituximab (R) (n=4), R and temozolomide (n=3) or R and ibrutinib (n=2). Two patients were treated with Pem and zanubrutinib in the context of a clinical trial (NCT05681195). Six patients had disease refractory to HD-MTX (see Table 1), and 1 received Pem-based therapy as frontline treatment. The best ORR and CR/CRu were 90.9% and 54.6%; respectively. The median number of cycles to best response was 4 (range: 1-5) cycles. At a median follow-up of 18.0 months, the median DOR, PFS, and OS were not reached. Among transplant-eligible (ASCT) patients, 4/5 achieved a CR with Pem-based treatment, all responders underwent ASCT consolidation and remain in remission at a median follow-up of 37.0 months. Non-ASCT candidates (n=6) had a median PFS of 4.0 months (95% CI: 2.0-NR) and OS of 10.0 months (95% CI: 2.0-NR). Conclusions: The high response rates, along with outpatient administration and feasibility of combination with other PCNSL active agents, suggests that Pem-based regimens should be explored further in prospective studies. Additionally, Pem-based regimens can offer an effective bridge to ASCT, which is associated with prolonged survival, and should be also studied as a bridge to CAR T-cell therapy. Patient characteristics and outcomes in the HD-MTX refractory PCNSL cohort. Age/Sex ECOG Regimen Cycles Best Response Progression Post-Pem Tx Current Status 74 M 3 R-Pem + 30GyWBRT 8 CRu No None CRu 71 F 3 R-Pem-Tem 6 PR Yes R2I CRu 76 M 2 Pem-Zan 4 CRu No Ongoing CRu 78 M 1 R-Pem-Tem 6 PR No N/A Death due to cardiac event 76 M 3 R-Pem 1 SD Yes WBRT, gamma knife Death due to progression 60 M 2 Pem-Zan 5 CRu No ASCT CRu