Safety and efficacy of glofitamab in combination with lenalidomide in relapsed or refractory central nervous system lymphoma: Real-world data

Abstract Background: Central nervous system lymphoma (CNSL) is a rare and aggressive subtype of non-Hodgkin lymphoma, predominantly diffuse large B-cell lymphoma (DLBCL)， characterized by insidious onset, rapid progression, and high recurrence rate. Conventional therapies, including craniotomy, radiotherapy, intrathecal chemotherapy, and high-dose methotrexate achieve limited success, with a poor 3-year survival rate of approximately 30%. In recent years, the CD20×CD3 bispecific antibody (glofitamab) has improved outcomes in systemic relapsed/refractory (R/R) B-cell lymphomas (remission rates: 50%~80%). Emerging evidence indicates glofitamab can partially penetrate the blood-brain barrier and induce clinical remission in CNSL, but the concentration of glofitamab in cerebrospinal fluid (CSF) is only 0.1%~0.4% of that in peripheral blood, which limits its clinical efficacy. Lenalidomide, a CNS- penetrant immunomodulatory agent, has demonstrated synergistic anti-CNSL activity with favorable tolerability. So the study was aimed to evaluate the safety and preliminary efficacy of combination therapy with glofitamab and lenalidomide in patients with R/R CNSL. Methods: We conducted a retrospective analysis of four patients with R/R CNSL treated with glofitamab combined with lenalidomide at the First Affiliated Hospital of Chongqing Medical University between October 2024 and June 2025. Pretreatment with obinutuzumab (1000 mg) was administered intravenously 7 days before the first dose of glofitamab. Glofitamab was then administered intravenously by step-up dosing during cycle 1 (day 8: 2.5 mg; day 15: 10 mg), followed by fixed-dose glofitamab 30 mg on day 1 of cycles 2~12 To mitigate the risk of cytokine release syndrome (CRS), patients received premedication (dexamethasone 20mg intravenously, acetaminophen 1000mg orally, isopropanazine 25mg intramuscularly) 1 hour before glofitamab therapy. Lenalidomide was administered orally with dose of 15 mg/day on days 1 to 21 of each cycle. All patients had undergone prior craniotomy for brain tumors, and biopsy confirmed CD20 and CD79 positivity consistent with CNS DLBCL (three primary CNSL and one secondary CNSL). Two patients had relapsed twice and had received autologous stem cell transplantation (ASCT), while the other two were ineligible for ASCT due to poor performance status (Eastern Cooperative Oncology Group [ECOG] ≥ 3) or patient refusal, had relapsed once. Treatment response was assessed by brain magnetic resonance imaging (MRI) every two cycles and CSF cytology every cycle. Results: The cohort comprised one male and three females, with a mean age of 58 years (range: 51~69). Median time to relapse after last treatment was 5 months (range: 3~8). Relapse symptoms included neurological symptoms (such as headache, lethargy, limb weakness, gait disturbance, slurred speech, visual deficits, etc.) and systemic symptoms (such as nausea, anorexia, fatigue, etc.) After two cycles of treatment, all patients achieved rapid remission (two complete responses [CR], two partial responses [PR]), resulting in an objective response rate (ORR) of 100%. By cycle 4, three patients achieved CR and one maintained PR. No treatment-related CRS, immune effector cell-associated neurotoxicity syndrome (ICANS) or hematological toxicity of grade≥ 3 was observed. Treatment was well-tolerated with no discontinuations due to adverse events (AEs). Conclusions The glofitamab-lenalidomide combination demonstrates promising activity and excellent tolerability in patients with R/R CNSL, potentially addressing the critical need for effective salvage regimens. These findings warrant validation in prospective randomized clinical trials to establish optimal dosing and long-term outcomes.