Objective Real-life studies on patients with primary CNS lymphoma (PCNSL) are scarce. Our objective was to analyze, in a nationwide population-based study, the current medical practice in the management of PCNSL. Methods The French oculo-cerebral lymphoma network (LOC) database prospectively records all newly diagnosed PCNSL cases from 32 French centers. Data of patients diagnosed between 2011 and 2016 were retrospectively analyzed. Results We identified 1,002 immunocompetent patients (43% aged >70 years, median Karnofsky Performance Status [KPS] 60). First-line treatment was high-dose methotrexate-based chemotherapy in 92% of cases, with an increasing use of rituximab over time (66%). Patients 60 years of age, WBRT and HCT-ASCT consolidation were administered in only 9% and 2%, respectively. The complete response rate to initial chemotherapy was 50%. Median progression-free survival was 10.5 months. For relapse, second-line chemotherapy, HCT-ASCT, WBRT, and palliative care were offered to 55%, 17%, 10%, and 18% of patients, respectively. The median, 2-year, and 5-year overall survival was 25.3 months, 51%, and 38%, respectively (60 years: 15.4 months, 44%, and 28%). Age, KPS, sex, and response to induction CT were independent prognostic factors in multivariate analysis. Conclusions Our study confirms the increasing proportion of elderly within the PCNSL population and shows comparable outcome in this population-based study with those reported by clinical trials, reflecting a notable application of recent PCNSL advances in treatment.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We previously reported the results of a randomized phase II study in patients with newly diagnosed primary CNS lymphoma (age 18-60 years). Patients were treated with high-dose methotrexate-based induction chemotherapy followed by whole-brain radiotherapy (WBRT) or high-dose chemotherapy (thiotepa-busulfan-cyclophosphamide) with autologous stem-cell transplantation (ASCT). The median follow-up was 33 months. In this report, we provide long-term data (median follow-up, 8 years) regarding the outcomes and toxicities. Fifty-three and 44 patients received induction chemotherapy followed by WBRT or ASCT, respectively. Their 8-year event-free survival from random assignment was 67% and 39% in the ASCT and WBRT arms, respectively ( P = .03), with a significantly lower risk of relapse after ASCT (hazard ratio, 0.13; P < .001). One third of patients who relapsed after WBRT were alive after salvage treatment. Five and four patients died of ASCT and WBRT-related toxicities, respectively. The 8-year overall survival was 69% and 65% in the ASCT and WBRT arms, respectively (not significant). Balance (52% v 10%, P ≤ 0.001) and neurocognition (64% v 13%, P < .001) significantly deteriorated after WBRT compared with ASCT during the follow-up. This study shows that 40 Gy WBRT should be avoided in first-line treatment because of its neurotoxicity and suboptimal efficacy in reducing relapses while ASCT appears to be highly efficient in preventing relapses.

The prognosis of relapsed primary central nervous system lymphoma (PCNSL) remains dismal. CAR T‐cells are a major contributor to systemic lymphomas, but their use in PCNSL is limited. From the LOC network database, we retrospectively selected PCNSL who had leukapheresis for CAR‐T cells from the third line of treatment, and, as controls, PCNSL treated with any treatment, at least in the third line and considered not eligible for ASCT. Twenty‐seven patients (median age: 68, median of three previous lines, including ASCT in 14/27) had leukapheresis, of whom 25 received CAR T‐cells (tisa‐cel: N = 16, axi‐cel: N = 9) between 2020 and 2023. All but one received a bridging therapy. The median follow‐up after leukapheresis was 20.8 months. The best response after CAR‐T cells was complete response in 16 patients (64%). One‐year progression‐free survival from leukapheresis was 43% with a plateau afterward. One‐year relapse‐free survival was 79% for patients in complete or partial response at CAR T‐cell infusion. The median overall survival was 21.2 months. Twenty‐three patients experienced a cytokine release syndrome and 17/25 patients (68%) a neurotoxicity (five grade ≥3). The efficacy endpoints were significantly better in the CAR T‐cell group than in the control group (N = 247) (median PFS: 3 months; median OS: 4.7 months; p < 0.001). This series represents the largest cohort of PCNSL treated with CAR T‐cells reported worldwide. CAR T‐cells are effective in relapsed PCNSL, with a high rate of long‐term remission and a reassuring tolerance profile. The results seem clearly superior to those usually observed in this setting.

The treatment of primary vitreoretinal lymphoma (PVRL) remains controversial regarding the use of local, systemic, or combined treatments. The aim of this study was to analyze the efficacy and toxicity of intravenous high‐dose methotrexate (IV HD‐MTX) based systemic therapy in a uniformly treated population of PVRL patients. From a nationwide French database, we retrospectively selected 59 patients (median age: 70 years, median Karnofsky Performance Status: 90%) with isolated PVRL at diagnosis who received first‐line treatment with HD‐MTX between 2011 and 2018. 8/59 patients also received a local treatment. No deaths or premature discontinuations of MTX due to toxicity were reported. A complete response was obtained in 40/57 patients after chemotherapy. Before treatment, IL‐10 was elevated in the aqueous humor (AH) or in the vitreous in 89% of patients. After treatment, AH IL‐10 was undetectable in 87% of patients with a CR/uCR/PR and detectable in 92% of patients with PD/SD. After a median follow‐up of 61 months, 42/59 (71%) patients had relapsed, including 29 isolated ocular relapses as the first relapse and a total of 22 brain relapses. The median overall survival, progression‐free survival, ocular‐free survival and brain‐free survival were 75, 18, 29 and 73 months, respectively. IV HD‐MTX based systemic therapy as a first‐line treatment for isolated PVRL is feasible, with acceptable toxicity, even in an elderly population. This strategy seems efficient to prevent brain relapse with prolonged overall survival. However, the ocular relapse rate remains high. New approaches are needed to improve local control of this disease, and ocular assessment could be completed by monitoring AH IL‐10.

High-dose methotrexate (HDMTX) is used in the treatment of a range of adult and childhood cancers. Although HDMTX can provide effective anti-tumor activity with an acceptable safety profile for most patients, delayed methotrexate elimination (DME) develops in a minority of patients receiving HDMTX and may be accompanied by renal dysfunction and potentially life-threatening toxicity. A panel of European physicians with experience in the use of HDMTX as well as of glucarpidase convened to develop a series of consensus statements to provide practical guidance on the prevention and treatment of DME, including the use of glucarpidase. Robust implementation of supportive measures including hyperhydration and urine alkalinization emerged as critical in order to reduce the risk of DME with HDMTX treatment, with leucovorin rescue critical in reducing the risk of DME complications. Early recognition of DME is important to promptly implement appropriate treatment including, intensified hydration, high-dose leucovorin and, when appropriate, glucarpidase.