No Benefit of Rituximab in Primary Central Nervous System Lymphoma Patients: Results of the Randomised Phase III HOVON 105 / ALLG NHL 24 Intergroup Study

Background: Efficacy of rituximab in Primary Central Nervous System Lymphoma (PCNSL) is unknown: low penetration of the large rituximab molecule through the blood brain barrier may limit its effect. We aimed to establish the value of rituximab in PCNSL. Methods: This international, multicentre, open-label, randomised phase III study was performed at 24 sites in The Netherlands, Australia and New Zealand. Non-immunocompromised patients aged 18-70 years with newly-diagnosed PCNSL were randomly assigned to 2 cycles of Methotrexate-BCNU-teniposide-prednisone (MBVP) chemotherapy with or without rituximab using an online randomisation tool employing minimisation by centre, age (60 vs 61 years) and PS group (0-1 vs. 2-3). Patients subsequently received high dose cytarabine and, in those ≤60 years, low-dose whole brain radiotherapy (WBRT). Primary endpoint was 1-year event free survival (EFS1y) adjusted for age and PS on analysis by intention to treat. Secondary endpoints were response rates, progression-free and overall survival. The trial was registered in The Netherlands National Trial Register, NTR 2427, and the Australian New Zealand Clinical Trials Registry, ACTRN12610000908033. It was closed on May 27, 2016, after achieving complete accrual; follow-up is on-going. Findings: between August 2010 and June 2016, 200 patients were enrolled; 55% were men; median age was 61 years (range 26-70). EFS1y was 49% without and 52% with rituximab; HR 1.00, 95% CI 0.70-1.43, p=0.99. CR/CRu rate was 66% for MBVP and 68% for R-MBVP. Overall response rate was 87% in both arms. An unplanned subgroup analysis suggested a potential benefit for rituximab in patients <60 years (interaction HR 0.39, 95% CI 0.19-0.83, p = 0.015). After a median follow-up of 33 months, 79 patients had died; treatment related mortality was 7% after MBVP and 3% after R-MBVP. Grade 3 or 4 adverse events, of which infections were the most frequent, occurred in 59% of patients after MBVP, in 63% after R-MBVP. Interpretation: Rituximab, added to MBVP chemotherapy, does not improve outcome in PCNSL. Further study is needed to investigate effect in younger patients. Trial Registration Number: The trial was registered in The Netherlands National Trial Register, NTR 2427, and the Australian New Zealand Clinical Trials Registry, ACTRN12610000908033. Funding: Roche provided financial support of the study and provided rituximab free of charge. Additionally, the Dutch Cancer Society and the "Stichting Stophersentumoren" provided support for data- and trial management. Declaration of Interest: JEB, SI, KB, TS, MD, GC, HCS, WBS, JMZ, JWB, MN, KDM, AB, MB, and MG, have declared no conflicts of interest. MCM reported receiving consultancy fees from Amgen, Takeda, Celgene, Jansen Cilag, Servier and research funding from Celgene; MJB reported receiving consultancy fees from Roche; DdJ received consultancy fees from BMS, Takeda, Roche and Celgene, research funding from Celgene and Genmab and honoraria from Takeda and BMS; JD reported receiving honoraria from Roche. Ethical Approval: The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice, and approved by the Institutional Review Boards of the Erasmus MC University Medical Center, Rotterdam, The Netherlands and the respective ethics committes of both New Zealand and Australia.