<p>Although significant progress has been made in improving the treatment of primary central nervous system lymphoma (PCNSL), its management remains challenging given the limited number of personalized treatment options. Research presented at the recent <strong>67th American Society of Hematology (ASH) Annual Meeting and Exposition</strong> may help address this challenge.</p> <p><br></p> <p><em>Following these presentations, featured expert Christopher R. D’Angelo 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>

The 67th ASH Annual Meeting and Exposition included several important presentations on studies focusing on individualizing treatment for PCNSL. The first was the randomized phase 2 IELSG45 FIORELLA trial by Andrés José María Ferreri, MD, and colleagues (poster 1908). This trial assessed the impact of patient fitness on dropout rates in PCNSL studies. The authors noted a dropout rate of higher than 40% for early toxicities, despite people meeting initial eligibility criteria. This speaks to the challenge of patient frailty in PCNSL. Sometimes, frailty is not immediately observed or demonstrated in patients who walk into your clinic; it may not become apparent until extra stress is placed on them. And that stress could come from the disease alone or from therapies that are overwhelming them.

<br>

It is challenging to establish a single best identifier for frailty, but one test that I like in clinic is the Timed Up and Go (TUG) test. If someone can get out of a chair and walk approximately 10 feet in less than 10 to 12 seconds, to me, that is a sign of robustness. Incorporating tests such as this one has been studied in older adults with lymphoma and might help us personalize treatment and address the dropout rate.

<br>

Another key presentation from this year’s ASH meeting evaluated real-world treatment patterns and survival outcomes using data from the National Cancer Database (NCDB; poster 4494). Several signals from this analysis are important. Ayo Falade, MD, MBA, et al found that a relatively low number of patients received chemotherapy and an autologous stem cell transplant. This likely speaks to the older patient population we care for; many patients with PCNSL are not transplant eligible. However, if you have a borderline patient, it is still worth referring them for a transplant. Age alone is not necessarily a contraindication, and transplant is probably the most effective consolidation therapy we have.

<br>

In reality, our most intense therapies for PCNSL are only going to be useful in a minority of patients. Therefore, we need to make sure that future treatment options are effective, safe, and actually applicable to the patients we see in the clinic. These data sets could be very helpful with that in mind.

<br>

The data from the NCDB also showed that chemotherapy alone was used in approximately 82% of cases. Some patients receive chemoradiation as part of a consolidation approach, but the role of radiation in this space can be difficult. There is reluctance to use radiation—and rightfully so—but there are some emerging data showing that reduced doses of whole-brain radiation have less toxicity. When we speak to personalizing treatment, whole-brain radiation has demonstrated a consolidative effect in the right patients. If someone has already received a transplant and has relapsed, this could be something to consider.

<br>

There is also growing enthusiasm for targeted radiation, either stereotactic radiosurgery or focal therapy, directed toward some of the larger lesions. Focal radiation options are certainly going to be less neurotoxic in the long-term. One novel approach might involve starting with targeted radiation and following up with systemic therapy to treat the rest of the brain. It will be interesting to see this continue to evolve in larger retrospective data sets, and then, ideally, in prospective studies too.

<br>

We are also starting to consider how radiation can influence the tumor microenvironment. I think that we may be able to influence the microenvironment with radiation and focal radiation, allowing for a greater penetration of agents that are capable of altering the tumor microenvironment. I do not know that we have the pre and post samples from patients who underwent brain radiation therapy to prove this in PCNSL, but I do think that it shows how translational science can identify issues within the microenvironment.

<br>

Finally, a third key study by Lixia Sheng and colleagues presented at the 67th ASH Annual Meeting and Exposition investigated the use of cerebrospinal fluid (CSF)–derived circulating tumor DNA (ctDNA) to determine molecular response in patients with PCNSL (abstract 59). Interestingly, when the authors measured ctDNA in the CSF, they saw that it correlated well with the tumor mutation panel from the main biopsy. They observed this if patients cleared either their ctDNA biomarker or their MYD88 mutation. If these were undetectable in CSF by cycle 5, then these individuals did incredibly well. However, if these biomarkers were still detectable, the patients were at a much higher risk of relapse. In contrast, positron emission tomography/computed tomography response was not significantly associated with measures of survival (ie, progression-free or overall survival).

<br>

As we continue to move toward personalized approaches, I believe that this is where the future lies. This is among the better data sets highlighting just how impactful this biomarker can be. We will need approved options to test this, but this is something that our clinic is going to be very interested in.