Combination of Rituximab with Chemotherapy Improved Outcome of Newly Diagnosed Primary CNS Lymphoma: A Retrospective Study of 209 Unselected Patients Referred to a Single Institution
Authors: Ghesquieres Herve , Segura-Ferlay Celine , Fossard Gaelle , Ducray Francois , Safar Violaine , Rey Philippe , Nicolas-Virelizier Emmanuelle , Sebban Catherine , Belhabri Amine , Biron Pierre , Jouanneau Emmanuel , Meyronnet David , Chassagne-Clement Catherine , Honnorat Jerome , Blay Jean-Yves 
Published: October 2019

Abstract
Introduction: Treatment of first-line therapy of primary CNS lymphoma (PCNSL) is based on high-dose methotrexate and cytarabine combination chemotherapy. Consolidation radiotherapy is mainly withdrawal for patients older than 60 years old regarding the excessive rate of neurological toxicity. Rituximab improved outcome of systemic diffuse large B-cell lymphoma but no data from randomized phase III trial is available to prove such outcome improvement for PCNSL. We introduced in daily practice intravenous rituximab in combination with chemotherapy for B-cell PCNSL in first-line therapy in 2004. The goal of this study is to determine whether such therapeutic modification improves PCNSL patient's outcome.
Methods: Patients were from consecutive PCNSL cases (N=209) included in Leon Berard Cancer Centre registry (Lyon, France), from 1987 to 2011 (date of diagnosis). Median age of patients was 63 years (range, 26-87), 56% were male, 51% had a performance status (PS) >1, 63% had an involvement of deep structures of brain, 66% a high CSF protein level, 12% a meningeal involvement and 42% a high LDH level. Of the 171 available patients, 16% had 0-1, 60% had 2-3, and 24% had 4-5 adverse IELSG prognostic scores, respectively. Patients were all treated by chemotherapy, 92% and 63% of them by high-dose methotrexate and cytarabine containing chemotherapy, respectively followed by brain radiotherapy for 108 patients (58%). Intravenous rituximab was used in combination with chemotherapy in 61 patients (29%) between 2004 and 2011.
Results: No difference in term of clinical characteristics (median age, PS, tumor site, CSF protein level, meningeal involvement, LDH level) was observed between patients treated with or without rituximab in combination with chemotherapy. With the median of 86.3 months (18.2-259), the median progression free survival (PFS) and overall survival (OS) for whole series were 17.3 months (95%CI, 10.7-25.9) and 35.6 months (95%CI, 22.7-50.0), respectively. The 3-year PFS were 55.5% (95%CI, 43-67) and 31.1% (95%CI, 24-39) for patients treated or not with rituximab, respectively (P=0.001). The 3-year OS were 73.6% (95%CI, 61-83) and 39.9% (95%CI, 32-48) for patients treated or not with rituximab, respectively (P<0.0001). A multivariate analysis was performed to test the impact of the addition of rituximab over clinical prognostic factors (age, PS, tumor site, CSF protein level, meningeal involvement, LDH level, IELSG score). Age>60 years (HR=1.74; 95%CI, 1.22-2.46; P=0.002), meningeal involvement (HR=2.33; 95%CI 1.42-3.85; P=0.0009) and used of rituximab (HR=0.50; 95%CI, 0.32-0.78; P=0.002) were identified as independent predictors of PFS. OS was significantly influenced by age>60 years (HR=1.94; 95%CI, 1.36-2.77; P=0.0002), PS (HR=1.76; 95%CI, 1.26-2.46; P=0.001), meningeal involvement (HR=2.17; 95%CI, 1.30-3.61; P=0.003) and used of rituximab (HR=0.39; 95%CI, 0.24-0.62; P=0.0001) in multivariate analysis. In a prognostic model integrating the IELSG score (0-1 vs. 2-3 vs. 4-5) (P=0.0002 for PFS and P<0.0001 for OS), used of rituximab was independently associated with the improvement of PFS (HR=0.60; 95%CI, 0.39-0.91; P=0.02) and OS (HR=0.44; 95%CI, 0.26-0.72; P=0.001). Disease free survival including patients who reached a complete response at the end of the first-line treatment was also improved by the used of rituximab (not reached versus 3.2 years, P=0.04). We also observed in this daily practice study, a reduction of the used of radiotherapy as first-line consolidation treatment (69% vs. 34%, P<0.001) before (1987-2003) and after (2004-2011) rituximab period.
Conclusion: In this retrospective analysis, we showed that PCNSL patients treated with intravenous rituximab in combination with first-line chemotherapy had a better outcome. The frequency of consolidation radiotherapy was reduced for these patients treated at rituximab era. In multivariate analysis, CSF involvement was an independent adverse prognostic factor that inclines to improve meningeal explorations and propose new therapeutic options for CSF positive PCNSL patients.

Disclosures
No relevant conflicts of interest to declare.