Low-dose lenalidomide for maintenance of remission in primary central nervous system lymphoma: A single-center experience. Free

Background: Curative therapy for primary central nervous system lymphoma (PCNSL) consists of methotrexate-based induction therapy followed by high-dose chemotherapy consolidation. There is no standard of care for patients unfit for dose-intensive consolidation, leaving these patients at high risk of relapse. Median progression-free survival (PFS) is as low as 7-12 months from the time of induction in newly diagnosed patients treated with methotrexate-based regimens without consolidation (Batchelor et al. J Clin Oncol 2003; Omuro et al. Lancet Haematol 2015). Patients with relapsed disease also have dismal outcomes. Lenalidomide is an immunomodulatory drug (IMiD) with single-agent activity in relapsed and refractory PCNSL. We have previously published our experience with 13 patients receiving low-dose lenalidomide for maintenance of remission in PCNSL (Vu et al. Br J Haematol 2019). Here, we report long-term follow up data from an expanded cohort.

Methods: We evaluated low-dose lenalidomide maintenance at a starting dose of 5 mg/day in two cohorts: (1) patients in complete remission after methotrexate-based induction and (2) patients in complete or partial remission after salvage therapy upon first relapse. Patients with PCNSL treated with methotrexate-based induction and subsequently treated with maintenance lenalidomide at a starting dose of 5 mg/day at UCSF between Jan 2011 – Jun 2025 were eligible for inclusion. Retrospective chart review was performed. Cox proportional hazards model was used for survival analysis.

Results: A total of 89 patients treated with lenalidomide maintenance were identified. We first evaluated outcomes for 39 patients who did not receive dose-intensive consolidation and were treated with lenalidomide maintenance following first-line methotrexate-based induction. 64% were ineligible for consolidation chemotherapy due to age (>74), 18% due to performance status/co-morbidities, and 18% declined consolidation. Median age at diagnosis was 76 (range: 57-86). 20 patients were male and 19 female. Median International Extranodal Lymphoma Study Group score at diagnosis was 3 (range: 1-4) and median Karnofsky Performance Status was 80 (range: 50-100). With median follow up of 73.9 months, median PFS was 38.5 months from the start of lenalidomide maintenance, and median overall survival (OS) was 64.5 months. 59% of these patients have not relapsed.

We next evaluated outcomes for 50 patients treated with lenalidomide maintenance after salvage therapy: methotrexate + rituximab (52%), focal XRT (20%), intraocular therapy (14%), dose-intensive etoposide + cytarabine (8%), ASCT (2%), and WBRT (2%). With median follow up of 91.4 months, median PFS was 13.4 months from the start of lenalidomide maintenance, and median OS was 43.9 months. 30% of these patients have not relapsed.

Low-dose lenalidomide was well tolerated, with adverse events consistent with the drug's known toxicity profile. Common toxicities included fatigue, rash, constipation, and mild myelosuppression. One patient experienced reversible bradykinesia and there was one pulmonary embolism. There were no episodes of febrile neutropenia. None of the patients treated with lenalidomide have yet developed a myeloid neoplasm.

Strikingly, among 42 patients drawn from both cohorts treated with lenalidomide maintenance who later relapsed, 60% achieved a complete response to the next line of therapy, 26% achieved a partial response, while 14% had refractory disease. 26 patients (62%) went on to receive subsequent IMiD maintenance therapy (27% lenalidomide at doses exceeding 5 mg/day, 73% pomalidomide); median PFS from IMiD re-initiation was 13.3 months.

Conclusions: Low-dose lenalidomide maintenance therapy after methotrexate-based induction therapy is an effective strategy for less fit PCNSL patients. Lenalidomide maintenance following salvage therapy likewise demonstrates impressive efficacy, with survival outcomes surpassing published historical values. Low-dose lenalidomide is well-tolerated in both of these settings, with low rates of discontinuation. Importantly, most patients progressing on lenalidomide maintenance achieve remission with salvage therapy and respond to further treatment with IMiDs. While our analysis has limitations including its small sample size and retrospective single-center design, the survival outcomes are encouraging and support further investigations of lenalidomide in PCNSL, including the ongoing Alliance A51901 trial.