Relapsed and refractory primary CNS lymphoma: treatment approaches in routine practice

Abstract

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.

Efficacy and Safety of BTKis in Central Nervous System Lymphoma: A Systematic Review and Meta-Analysis

“…BTKi combination therapy had a higher response rate and longer survival for CNSL patients compared to monotherapy [ 27 , 28 , 29 , 41 ]. High-dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT), ifosfamide-based immunochemotherapy, and folate antimetabolites are also effective treatment options for relapsed/refractory patients [ 7 , 44 ]. Among relapsed/refractory CNSL patients who received rituximab, high-dose cytarabine, and thiotepa followed by HDT-ASCT consolidation with carmustine/rituximab/thiotepa conditioning, 56% of them achieved CR [ 45 ].…”

Primary central nervous system lymphoma: a practical guide for neurologists

“…Relapsed and refractory disease treatment is very challenging, with repeat high-dose methotrexate considered in fitter patients if duration of remission was >2 years, or ifosfamide-based immunochemotherapy if not 30. Whole-brain radiotherapy may be used in selected, radiation-naïve patients, but is considered a palliative option 44. Current trials, including the phase 1 trial CAROUSEL (NCT04443829), are assessing the use of chimeric antigen receptor cell therapy in PCNSL 45.…”

Clonally unrelated primary large B‐cell lymphomas separated by over a decade involving the central nervous system and testicle: Possible predisposition to lymphomas of immune‐privileged sites?

“…eJHaem published by British Society for Haematology and John Wiley & Sons Ltd. however, it is assumed that IP-LBCLs arise due to decreased immune surveillance [3]. Although patients may present with localized disease, the overall prognosis remains poor, with high rates of relapse typically at the site of origin or within another immune-privileged site [1,2,[4][5][6].…”