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Despite recent therapeutic progress and improved survival for many patients with primary central nervous system lymphoma (PCNSL), up to 50% of patients will experience refractory or relapsed disease following first-line treatment with high dose methotrexate (HD-MTX) based regimens. The majority of such events occur within 2 years of diagnosis although, unlike their systemic counterpart, the risk of PCNSL relapse remains, even for patients in radiologic complete response at 10 years following diagnosis. Currently, there are no approved therapies, and no widely accepted 'standard-of-care' approaches for the treatment of refractory or recurrent primary central nervous system lymphoma (rrPCNSL). Re-treatment with HD-MTX based regimens, use of non-cross resistant chemotherapy regimens, high-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT), and brain irradiation all remain important therapeutic approaches for rrPCNSL. However, the survival outcomes for patients with rrPCNSL remain extremely poor and the vast majority of patients will die of their disease. Increasingly, novel treatment approaches are being investigated in early phase clinical studies. Importantly, such therapies need to be evaluated in the context of both refractory and relapsed disease; in older patients and those with co-morbid conditions; and those with neurocognitive dysfunction. A deeper understanding of the molecular genetic mechanisms underpinning rrPCNSL and its unique tumor microenvironment is urgently needed to inform biologically rational and effective therapies. rrPCNSL remains a clear unmet clinical need and a high priority area for clinical research that will require national and international collaborative studies with embedded translational science in order to improve outcomes for patients.

Primary central nervous system lymphoma (PCNSL) is a rare disease of the brain, spine, cerebrospinal fluid (CSF) and/or vitreoretinal space. PCNSL is chemo and radiosensitive but relapse is common even years after initial treatment. Outside of consensus regarding the use of high-dose methotrexate (HD-MTX) for first line treatment, there is little uniformity in the management of newly diagnosed or relapsed PCNSL. The lack of consensus is driven by a paucity of randomized trials in this disease. Prospective studies are troubled by low enrollment, the lack of a standard induction regimen, and a varied approach to consolidation strategies. Moreover, the PCNSL patient population is heterogeneous and includes a high proportion of elderly or frail patients and consists of patients manifesting disease in varied compartments of the central nervous system (CNS). As a result, current treatment strategies vary widely and are often dictated by physician and institutional preference or regional practice. This review provides an overview of recently completed and ongoing therapeutic studies for patients with newly diagnosed and recurrent or refractory PCNSL. It discusses the existing evidence behind common approaches to induction and consolidation or maintenance regimens as well as the recent data regarding management of recurrent disease. Finally, it highlights the complexity of trial design in this disease and provides a framework for the design of future studies, which are needed to identify patient populations likely to benefit from specific induction, consolidation, or maintenance therapies.