Understanding Rare CNS Involvement in Large B-Cell Lymphoma: Largest Study Yet

Secondary central nervous system involvement (SCNSL) in large B-cell lymphoma is a rare but serious complication. Despite advancements in lymphoma treatments, SCNSL remains a significant unmet therapeutic need, with limited data available on prognostic factors, survival outcomes, and the effectiveness of various treatment strategies. 

To reduce the knowledge gap on this topic, we interviewed Dr.  Juan Alderuccio at the 2024 ASH Conference, the lead investigator of the analysis we’ll cover in this article. In this analysis, he and his colleagues conducted a multicenter international analysis to identify prognostic factors and outcomes in SCNSL at diagnosis or after frontline treatment.

What is Secondary CNS Involvement in Large B-cell Lymphoma?

SCNSL is a complication of the disease. It happens when large B-cell lymphoma spreads to the central nervous system (CNS), including the brain, spinal cord, or surrounding areas. This can happen at diagnosis (“de novo”) or after the first treatment. 

The symptoms may manifest in different ways depending on the affected area. They can be nonspecific and present as nausea and vomiting, weakness, hearing loss, difficulty swallowing, headaches, confusion, and, in some cases, vision problems (such as blurry vision, seeing double, floaters). 

How is SCNSL Diagnosed and Classified?

Diagnosis of SCNSL involves a combination of imaging techniques, such as MRI, cerebrospinal fluid analysis, and biopsy when necessary. In the analysis, Dr. Alderuccio and his team collected data from patients treated between 2001-2023 at 35 centers. This included a total of 1,173 patients with SCNSL. 

Of these patients: 

• 44.7% had involvement in the brain parenchyma (white matter)
• 40.4% had leptomeningeal involvement (brain protective layers) 
• Approximately 13.8% had transformed large B-cell lymphoma

The study also highlighted that SCNSL can present at the moment of diagnosis or after treatment of systemic large B-cell lymphoma.

What Treatment Options are Available for SCNSL?

Treatment strategies for SCNSL vary depending on its timing (at initial lymphoma diagnosis vs. after initial treatment) and the patient's overall health. Key findings from the study include:

Initial Treatments

• High-dose methotrexate-based regimens, such as R-CHOP, were frequently used.
• Over 50% of patients, received chemotherapy directly into the blood-brain barrier (usually by lumbar puncture, also known as intrathecal therapy).

Consolidation Strategies

• Thiotepa-based autologous stem cell transplantation significantly improved survival in both de novo and relapsed SCNSL.
• CAR-T cell therapy was an emerging option, though it showed higher relapse rates compared to thiotepa-based ASCT

Despite these interventions, relapse rates of 21.1% after thiotepa-ASCT and 55.8% after CAR-T cell therapy within the first year indicate the need for more therapeutic advancements to maintain longer remission times.

What Factors Influence Survival Outcomes?

Patients with de novo SCNSL had significantly better median progression-free survival (13.4 months) and overall survival (47.4 months) compared to those with SCNSL after initial treatment or multiple relapses. Some other factors that influence the outcomes are: 

• Age below 60 years
• Absence of genetic markers like MYC rearrangement or double-hit lymphoma
• Achieving complete or partial remission in both systemic and CNS after initial treatment.
• Use of high-dose methotrexate-based regimens and consolidation with thiotepa-based ASCT.

Looking Forward

This analysis is the largest international study on SCNSL. It highlights both challenges and progress. While SCNSL remains a difficult diagnosis, advancements in treatment strategies, (including thiotepa-based ASCT and tailored chemotherapy regimens) have improved outcomes for many patients.

Ongoing research into CAR-T cell therapies and new medications is crucial for achieving longer remissions and better quality of life in patients with CNS involvement. Collaborative efforts in clinical trials across countries can accelerate the advancements in effective strategies, paving the way for better prognosis and quality of life for patients.

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Source: 

• Prognostication and Treatment-Related Outcomes in Secondary Central Nervous System Involvement of Large B-Cell Lymphoma (SCNSL): Evidence from a Large International Cohort