<p>Although the prognosis of primary central nervous system lymphoma (PCNSL) remains poor, the continuing elucidation of its pathogenesis and oncogenic pathways has led to the development of novel therapeutics. Presentations at the <strong>67th American Society of Hematology (ASH) Annual Meeting and Exposition</strong> addressed studies of emerging therapies and drugs in development for PCNSL.</p> <p><br></p> <p><em>Following these presentations, featured expert Christopher R. D’Angelo, MD, was interviewed by </em>Conference Reporter<em> Medical Director Lauren Weinand, MD. Clinical perspectives from Dr D’Angelo on these findings are presented here.</em></p>

Challenges exist in the development of novel therapies for PCNSL. We are currently trying to understand the molecular pathways that are involved in PCNSL to help design and introduce novel therapies that are capable of overcoming the blood-brain barrier and are focused on the pathways that are disrupted in PCNSL. Of equal importance is the frailty that comes along with this disease. PCNSL commonly presents in older adults, who inherently carry more frailty and comorbidities than younger patients. This needs to be considered when personalizing treatment approaches and designing novel therapies.

<br>

Lastly, we must acknowledge that PCNSL is a rare disease. It can be difficult to discern which new therapies can move the field forward. This is a call to collaborate—that is, to ensure that academic and community oncologists are working together, discussing patient cases, identifying clinical trials, and ultimately trying to move forward as we figure out the best way to care for these patients with PCNSL.

<br>

At the recent 67th ASH Annual Meeting and Exposition, we saw data presented on how we can target molecular pathways more rationally in both frontline and relapsed/refractory PCNSL. One of the most important abstracts—if not the most important abstract, in my opinion—was the work by Carole Soussain, MD, PhD, and colleagues on the phase 2 multicenter LOC-R01 study (abstract 58). This study compared lenalidomide plus rituximab, methotrexate, procarbazine, and vincristine (R-MPV) with the BTK inhibitor ibrutinib plus R-MPV in newly diagnosed patients with PCNSL aged 18 to 65 years.

<br>

In LOC-R01, immunocompetent patients were randomized to lenalidomide plus R-MPV or ibrutinib plus R-MPV. The primary end point was evaluated in 89 patients, so there were 44 patients in the lenalidomide arm and 45 in the ibrutinib arm. This was a decently sized study for newly diagnosed PCNSL. It is important to recognize that these were younger adults (ie, ≤65 years). Studies outside of PCNSL have demonstrated that adding extra agents can sometimes prove too toxic in older patients, which speaks to the frailty of these individuals. I think that the investigators were being thoughtful by making sure that the treatments were going to be safe.

<br>

Importantly, one early signal from the LOC-R01 study was that more patients in the BTK inhibitor–based group proceeded to transplant, with an approximately 10% difference between the lenalidomide arm and the ibrutinib arm. I think that this is important because, if patients are transplant eligible, we want to make sure that they can get there. That is one of the most critical missions of an induction regimen.

<br>

The complete response rates that came from this study are potentially practice changing. The investigators reported complete response rates of 86% and 82% for lenalidomide and ibrutinib, respectively, which we have not seen before in newly diagnosed PCNSL. The safety of these regimens also looks pretty good; however, we need to be mindful about bleeding if we are going to use a BTK inhibitor.

<br>

During this presentation, the following question came up: If you were going to pick the “winner,” which regimen would you use? I do not know whether LOC-R01 can answer that right now. I think that both regimens are valid options, but I was particularly impressed with the fact that more patients treated with ibrutinib than with lenalidomide proceeded to transplant (87% vs 75%, respectively). There was also a slightly greater progression-free survival in the ibrutinib arm than in the lenalidomide arm (82% vs 72%, respectively).

<br>

This study suggests how the addition of more targeted drugs can impact PCNSL. And, while both lenalidomide and ibrutinib downregulate NF-κB, they do so through different mechanisms. This is a good example of how 2 different targeted approaches can result in similar responses. Overall, I think that it is important to continue studying both treatment options. It is exciting to see how we can use a BTK inhibitor or an immunomodulatory drug up front in combination and do that safely.

<br>

A notable trial in progress presented at this year’s ASH meeting was by Christian Grommes, MD, et al (poster 3703). This phase 3 study evaluated the clinical benefit of tirabrutinib monotherapy vs rituximab and temozolomide in patients with relapsed/refractory PCNSL. Importantly, it really speaks to the interest that multiple stakeholders have in treating this rare disease. If this trial is completed, I suspect that tirabrutinib will outperform rituximab and temozolomide.

<br>

In fact, at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, we saw data from the phase 2 PROSPECT study showing favorable responses for tirabrutinib in the relapsed/refractory setting. The overall response rate was nearly 67%, and the median progression-free survival was 6 months. At face value, this might not sound great, but when managing relapsed/refractory disease, patients do not often respond to any treatment. It also highlights the lack of clear drug approvals from the US Food and Drug Administration (FDA) for PCNSL in the relapsed/refractory setting.