What is the recommended treatment approach for high-risk central nervous system (CNS) diffuse large B-cell lymphoma?

From the Guidelines

The most effective treatment approach for high-risk central nervous system (CNS) diffuse large B-cell lymphoma (DLBCL) is a multimodal strategy that includes high-dose methotrexate-based chemotherapy regimens combined with rituximab, followed by consolidation therapy, despite recent evidence suggesting that high-dose methotrexate may not significantly reduce the risk of CNS relapse or confer a survival benefit 1.

Treatment Approach

The standard regimen includes:

• High-dose methotrexate (3-8 g/m² every 2-3 weeks) with rituximab (375 mg/m²)
• Combination with other agents such as cytarabine (2-3 g/m² twice daily for 2 days), thiotepa (30 mg/m²), or temozolomide (150-200 mg/m² for 5 days)
• Induction therapy usually consists of 4-6 cycles

Consolidation Therapy

• Whole-brain radiotherapy (WBRT) at doses of 23-45 Gy
• High-dose chemotherapy followed by autologous stem cell transplantation (ASCT)

Additional Considerations

• Intrathecal chemotherapy with methotrexate (12-15 mg), cytarabine (50 mg), or both may be added, especially for patients with leptomeningeal involvement
• Corticosteroids (dexamethasone 16-40 mg/day) are often included initially to reduce cerebral edema and provide rapid symptom relief This intensive approach is necessary because CNS lymphoma has historically poor outcomes due to the blood-brain barrier limiting drug penetration, with high-dose methotrexate being one of the few agents that effectively crosses this barrier at sufficient concentrations to treat the disease 1.

From the FDA Drug Label

The trial was planned to enroll 600 patients with 1:1 randomization. Demographic and disease characteristics of the randomized trial population are displayed in Table 13 Disease Type B-AL37%34% Burkitt or Burkitt-like NHL55%56% DLBCL8%8% Bone marrow involvement45%45% CNS involvement27%27% Efficacy was established based on event-free survival (EFS), where an event was defined as occurrence of progressive disease, relapse, second malignancy, death from any cause, or non-response as evidenced by detection of viable cells in residue after the second CYVE course, whichever occurs first.

The recommended treatment approach for high-risk central nervous system (CNS) diffuse large B-cell lymphoma is not explicitly stated in the provided drug label.

• High-risk CNS DLBCL treatment is not directly addressed.
• The label provides information on the efficacy of rituximab in combination with chemotherapy for DLBCL, but it does not specifically discuss high-risk CNS DLBCL.
• CNS involvement is mentioned as a disease characteristic, but the label does not provide guidance on treating high-risk CNS DLBCL. 2

From the Research

High-Risk CNS DLBCL Treatment Approach

The recommended treatment approach for high-risk central nervous system (CNS) diffuse large B-cell lymphoma (DLBCL) is a subject of ongoing research and debate.

• The use of intrathecal methotrexate (IT MTX) and high-dose methotrexate (HD MTX) therapy has been explored for CNS prophylaxis in patients with DLBCL 3, 4, 5.
• A study published in 2021 found that prophylaxis with IT MTX or HD MTX tended to delay CNS relapse rather than prevent it, with a similar CNS relapse risk in patients who received IT and HD MTX 3.
• Another study published in 2015 reported that high-dose methotrexate-based prophylaxis significantly reduced CNS failures in high-risk patients stratified by involvement of specific extranodal sites and International Prognostic Index 5.
• However, a more recent study published in 2023 found that HD MTX prophylaxis did not reduce CNS relapse risk in high-risk systemic DLBCL without leptomeningeal involvement by CSF analysis at diagnosis 6.
• The importance of baseline cerebrospinal fluid analysis to exclude asymptomatic leptomeningeal involvement has also been highlighted 6.
• Targeted therapy approaches, including biologically rational strategies, are being explored to improve the cure rate of CNS lymphomas, particularly in patients with relapsed or chemotherapy-refractory disease 7.

Key Considerations

• The CNS-International Prognostic Index has been identified as a predictive model for CNS relapse in patients with DLBCL 4.
• The use of rituximab treatment has significantly improved the outcomes of DLBCL, but CNS relapse remains a serious and fatal event for patients with DLBCL 4.
• Patients with synchronous leptomeningeal involvement are at increased risk of further CNS disease events and inferior survival compared to patients without CSF involvement 6.