Primary diffuse large B-cell (DLBCL) lymphoma of the central nervous system (CNS) (PCNSL) is a new lymphoma entity, recognized by the 2017 WHO classification of hematopoietic and lymphoid tumors. Unlike systemic DLBCL, the use of anthracycline-based chemotherapy combinations is associated with disappointing outcomes, due to low CNS bioavailability of related drugs. Therefore, international researchers investigated alternative strategies, mostly including drugs able to cross the blood–brain-barrier at low or high doses, with a progressive improvement in survival. Some effective chemotherapy combinations of high-dose methotrexate (HD-MTX) with alkylating agents and rituximab with or without cytarabine have been tested in international randomized trials and represent the induction treatment in everyday practice, with some variations among different geographical areas. In patients aged 70 years or younger, MATRix (HD-MTX/cytarabine/thiotepa/rituximab) chemotherapy followed by consolidative high-dose chemotherapy plus autologous stem cell transplantation or whole-brain irradiation has been associated with a significant improvement in overall survival. Other treatment options, such as non-myeloablative high-dose chemotherapy, oral drug maintenance, and some targeted drugs like ibrutinib or lenalidomide, are being tested in high-level international trials. These steps toward further effective treatments are motivated by an incessant search for less neurotoxic options. Thanks to international cooperation, we can affirm that PCNSL is a potentially curable tumor, especially in young patients. However, several questions remain unanswered: the optimal treatment for elderly patients as well as the management of intraocular and meningeal disease require further scientific efforts. Beside treatments, advances on molecular and radiological diagnostic tools will increase our knowledge of this disease, allowing the possibility to anticipate diagnosis and to better categorize patients' responses. This article analyzes the available literature in this setting and provides evidence-based recommendations for the management of PCNSL patients.

How we treat primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is, mainly, a diffuse large B-cell lymphoma (DLBCL) with a non-germinal center B-cell (non-GCB) origin. It is associated with a poor prognosis and an unmet medical need. Immunotherapy has emerged as one of the most promising areas of research and is now part of the standard treatment for many solid and hematologic tumors. This new class of therapy generated great enthusiasm for the treatment of relapsed/refractory PCNSL. Here, we discuss the challenges of immunotherapy for PCNSL represented by the lymphoma cell itself and the specific immune brain microenvironment. We review the current clinical development from the anti-CD20 monoclonal antibody to CAR-T cells, as well as immune checkpoint inhibitors and targeted therapies with off-tumor effects on the brain microenvironment. Perspectives for improving the efficacy of immunotherapies and optimizing their therapeutic role in PCNSL are suggested.

Emerging Landscape of Immunotherapy for Primary Central Nervous System Lymphoma.

Abstract The backbone induction therapy for primary central nervous system lymphoma (PCNSL) is high dose methotrexate (HD-MTX) and rituximab, which can be combined with other chemotherapeutic agents. The optimal dose of HD-MTX remains unclear, as doses between 3 and 8 g/m2 have been shown to be effective. In this retrospective study, HD-MTX dosed at 3–5 g/m2 demonstrated an overall response of 81.8%, with 11 (50%) complete responses. The median overall survival was not met at 29 months and median progression free survival was 12.5 months. There were two discontinuations due to nephrotoxicity. The most common adverse event was hepatotoxicity (18.5%), with no treatment-related mortality events observed. Overall, HD-MTX dosed at 3–5 g/m2 demonstrated similar efficacy and lower toxicity compared to higher doses in PCNSL patients. Reducing the initial HD-MTX dose may help ensure tolerability and completion of induction therapy, especially in patients with co-morbidities or older age who have poorer outcomes.

High-dose methotrexate dosing strategy in primary central nervous system lymphoma

ABSTRACT Primary Central Nervous System Lymphoma (PCNSL) is a rare, aggressive extranodal non-Hodgkin lymphoma. It is critical to get a diagnosis and start therapy as soon as possible to improve clinical results. Despite a new medicinal strategy that has increased survivability, the survival rate is still quite low. This report presents a new case of PCNSL that appears in an immunocompetent patient with two different rare genetic rearrangements and a necrotic histological appearance.

https://academic.oup.com/omcr/article-pdf/2023/3/omad026/49630794/omad026.pdf

A necrotic primary central nervous system lymphoma in immunocompetent patient with MYC and BCL6 rearrangements (double-hit lymphoma): a case report

Time spent in healthcare among older patients with primary central nervous system lymphoma treated with high-dose methotrexate.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/hon.47_2879

Matrix induction followed by autologous stem cell transplant or whole-brain irradiation in primary cns lymphoma. 7-year results of the ielsg32 randomized trial

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Matrix induction followed by autologous stem cell transplant or whole-brain irradiation in primary cns lymphoma. 7-year results of the ielsg32 randomized trial