<p>Although the use of high-dose methotrexate–based therapies has improved the prognosis of newly diagnosed primary central nervous system lymphoma (PCNSL), clinical questions remain and innovative treatment options are still needed. Several novel approaches, including the role of BTK inhibitors in combination with high-dose methotrexate–based induction regimens, were recently discussed at the <strong>67th American Society of Hematology (ASH) Annual Meeting and Exposition</strong>.</p> <p><br></p> <p><em>Following these presentations, featured expert Matthias Holdhoff, MD, PhD, was interviewed by </em>Conference Reporter<em> Medical Director Lauren Weinand, MD. Clinical perspectives from Dr Holdhoff on these findings are presented here.</em></p>

We have experienced incremental growth in our treatment options for newly diagnosed PCNSL based on methotrexate-based backbone therapy. In terms of therapeutics, we know that BTK inhibitors have led to really significant response rates. But, unfortunately, we have seen that these responses are not long-lived in recurrent disease. Therefore, for a while, the question has been: Should we use BTK inhibitors up front in combination with high-dose methotrexate–based therapy, with the hope of getting more patients to achieve a complete response (CR) or an unconfirmed CR (CRu)?

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At the 67th ASH Annual Meeting and Exposition, one of the most prominently presented abstracts on this topic was from Carole Soussain, MD, PhD, et al on the LOC-R01 trial. It was a randomized phase 2 study of lenalidomide or ibrutinib combined with rituximab, methotrexate, procarbazine, and vincristine as a targeted induction treatment for patients with newly diagnosed PCNSL (abstract 58). This study looked at 2 very different drugs, but it demonstrated that both of them seemed to show improved response rates compared with what we see with previously published high-dose methotrexate–based therapies. At the end of the induction phase, 86% of patients in the lenalidomide arm were in CR or CRu, 4% achieved partial response (PR), and 4% had progressive disease. In the ibrutinib arm, 82% of patients were in CR or CRu, 11% had a PR, and 7% had progressive disease. Treatment was, overall, reasonably well tolerated.

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This was followed by a presentation of data looking at the efficacy and safety of zanubrutinib, rituximab, and high-dose methotrexate as first-line treatment in newly diagnosed PCNSL (abstract 60). This study showed quite impressive rates of antitumor responses; the objective response rate was 89.7%, the CR rate was 89.7%, and the treatment was well tolerated in this study.

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We do not have randomized prospective data on high-dose methotrexate–based induction therapy with or without a BTK inhibitor, but, based on the data presented at this year’s ASH meeting, these regimens seem to show acceptable tolerability. We can also see that there is likely an added benefit in terms of achieving CR or CRu when we add a BTK inhibitor to the treatment regimen for newly diagnosed patients.

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There are some limitations, of course. For example, the study by Dr Soussain did not include patients over the age of 65. In real-world practice, the highest incidence of PCNSL is in patients older than that.

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Clearly, there is interest in the role of first-line combinations that include a BTK inhibitor. I think that the question of whether to add a BTK inhibitor up front is incredibly important. If we could get even 10% or 20% more people into CR and to consolidation with high-dose chemotherapy and autologous stem cell transplant, we might give more patients a higher chance for long-term disease control and, potentially, a cure.

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When treating those with newly diagnosed PCNSL, we are trying to identify all patients who are suitable for aggressive high-dose methotrexate–based induction followed by consolidation with high-dose chemotherapy and stem cell transplant, a potentially curative paradigm. One of the big-picture questions that still remains is: If we have a patient in CR but they are not a candidate for high-dose chemotherapy and autologous transplant, what do we do then? What is the role of maintenance treatment or alternative strategies for consolidation?

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It is difficult to establish unifying guidelines for PCNSL because there are so many different treatment approaches. Virtually every center has its own preferred algorithm. Sometimes, even within a single center, different investigators can have different treatment approaches because we do not yet have sufficient information from large data sets or phase 3 studies.