Role of CNS Prophylaxis in Aggressive B-Cell Lymphoma Treatment

In a debate at the 2023 Great Debates & Updates in Hematologic Malignancies conference in New York, Adam Olszewski, MD, Brown University, Providence, Rhode Island, discussed the role of central nervous system (CNS) prophylaxis in the treatment of aggressive B-cell lymphoma like diffuse large B-cell lymphoma (DLBCL).

The topic of debate was “CNS Prophylaxis in Aggressive Lymphoma, and Dr Olszewski argued on the side of CNS prophylaxis as having a valuable role. He discussed this topic with Elizabeth Brem, MD, MD, University of California, Irvine, California, who debated the opposite side. 

Transcript: 

Hello, my name is Adam Olszewski. I'm an Associate Professor of Medicine at Brown University and I'm a lymphoma clinician treating lymphoma patients at Rhode Island Hospital in Providence, Rhode Island. It was a great pleasure and challenge for me to participate in the Great Debates in Hematology, to discuss the role of central nervous system, or CNS, prophylaxis in aggressive B-cell lymphomas. 

This is a subject of great interest to many clinicians who treat aggressive B-cell lymphomas, partly because of how dramatic central nervous system recurrences are. They are associated with poor prognosis, a significant functional impairment to patients, and historically have been very difficult to treat.

At the same time, because the occurrence is rare, the event only affects between 3 and 5% of patients with aggressive B-cell lymphomas. It has received less attention in clinical trials, and the available evidence is based primarily [on] observational studies or subsets of other trials.

My job was to convince the audience, and I hope I was, to some extent, successful that CNS prophylactic treatment still has a role. This is under question. For many years, clinicians have been applying central nervous system prophylaxis using either intrathecal therapy, with methotrexate, with or without cytarabine, or using a systemic high dose methotrexate. A fairly cumbersome and potentially toxic treatment that was added on top of the regular, after an [rituximab, cyclophosphamide, doxorubicin, vincristine sulfate, and prednisone] (R-CHOP)-based chemotherapy to try to prevent central nervous system relapses or CNS relapses.

There are multiple observational studies in recent years, collectively including thousands of patients, that consistently suggest that neither of these strategies may be particularly efficacious. As my opponents eloquently discussed, some institutions and many clinicians have aborted this practice. The point that I wanted to make is that this problem is still fairly significant and real and is affecting patients on a daily basis. The inconsistency in data where some observational studies suggest the benefit and others don't, leaves clinicians and patients with a lot of anguish and difficulty making decisions.

The main point that we both agreed on is that the problem will require a solution using prospective randomized trials. There are always questions about retrospective studies and how patients were selected for treatment and what was their real risk.

There are a few additional points that I made. While I agree that both the role of intrathecal and systemic high-dose methotrexate is questionable, we have now learned a lot about CNS relapses. First of all, in the era of R-CHOP or R-CHOP-like therapy, most relapses–over 80%– involve brain parenchyma. These are no longer purely leptomeningeal relapses in the majority, and so interventions need to address that. It doesn't appear that intrathecal therapy will have a role moving forward, but high-dose methotrexate alone may not be sufficient treatment. 

There is a number of studies, most recently, a very large retrospective of studies from France and Germany that indicates that using intensified treatments that use CNS drugs like methotrexate, and adipocyte, is associated with a lower chance of parenchymal relapse in aggressive B-cell lymphomas. 

These regimens are not commonly used in the United States. Regimens like RABVCP are more commonly used in France, but it does appear that this may be a way moving forward for a very selective group of patients who have high-risk diseases. 

My second point was that our current selection criteria using the CNS [International Prognostic Index] (IPI), which essentially reflects the burden of lymphoma are insufficient. We have learned now from molecular studies that specific molecular subgroups of diffuse r B cell lymphoma, specifically the MCD subtype associated with mutations in MYD88 and CD79B have a significantly higher risk of CNS recurrence. We don't use this yet in treatment selection, but this is the next step moving forward.

Importantly, this is not the only group of patients who have CNS recurrences. The second group, which constitutes almost half of patients in clinical experience, are patients with high-grade B-cell lymphoma, which are of germinal center origin.

These are double-hit lymphomas, lymphomas with MYC rearrangements and P53 mutations, as well as other morphologically defined high-grade lymphomas, so-called NOS unspecified. The treatment for this group remains poorly defined, and they may not benefit from traditional treatments like high-dose methotrexate alone. My point was that we will need to study better selection criteria for this prophylaxis, and we have made some advances using both genomic analyses as well as potential study of cell-free DNA in the cerebral spinal fluid.

This is an experimental procedure, which is currently being studied as a potential way of selecting patients for CNS prophylaxis. I concluded that I still use CNS prophylaxis for selected patients at very high clinical risk for CNS prophylaxis. I don't use CNS IPI alone, but some additional criteria like having a high-grade lymphoma histology, as well as an extensive extra-nodal disease with involvement of testicle, so a testicular lymphoma, breast...These are all still groups that I consider offering CNS prophylaxis with a thorough discussion with the patients about the potential pros and cons and the potential uncertain benefits.

I admit that most patients decline this treatment at this point, and I simply did not represent to the patient that some treatment is absolutely necessary, but I think it is still an important part of our armamentarium, and it just needs to be refined. Refined in terms of the context of who needs this treatment and also refined in terms of what treatment is needed. Ultimately, we may need a cellular product like CAR T-cell therapy to address this issue. There are not many patients with CNS relapses who can be safely salvaged with CAR T-cell therapy. Because the data [is] sparse, I think this is still a major issue that will require further research.

I hope that we will not throw the baby with the bath water and completely forget about the issue of CNS relapse or stop worrying about this because I think this will remain an important part of clinical practice.

Source:

Olszewski, A. Debate - CNS prophylaxis in aggressive lymphoma - Aggressive. Presented at Great Debates & Updates in Hematologic Malignancies Conference; April 13-15, 2023; New York, NY.