More Research Needed for Relapsed Primary CNS Lymphoma Patients

Tracy Batchelor, MD, MPH

The 2016 American Society of Clinical Oncology (ASCO) Annual Meeting is taking place June 3–7 in Chicago. As part of this year’s coverage, today we are speaking with Tracy Batchelor, MD, MPH, director of the division of neuro-oncology at Massachusetts General Hospital. At this year’s meeting, Dr. Batchelor will be speaking about primary central nervous system lymphoma during an Education Session.

 -Interviewed by Leah Lawrence 

Cancer Network: Dr. Batchelor, thank you for speaking with us today.

Dr. Batchelor: It’s my pleasure

Cancer Network: As background, tell us a little bit about primary central nervous system (CNS) lymphoma. How does it differ from other lymphomas and how many people does it affect?

Dr. Batchelor: Primary CNS lymphoma is a form of extranodal non-Hodgkin lymphoma. It is confined to the central nervous system and that could be either the brain, the leptomeninges, or the eye. We also consider vitreoretinal lymphoma a part of primary CNS lymphoma.

More than 90% of these cases are diffuse large B-cell lymphomas and more than 90% of diffuse large B-cell lymphomas are of the ABC subtype. It has similarities to other types of extranodal lymphomas but it also has some important differences. The prognosis, for one, of primary CNS lymphoma is inferior to that of other extranodal forms of non-Hodgkin lymphoma. Also, the age distribution is a bit different in that primary CNS lymphoma tends to be a disease of older individuals with a median age at diagnosis of about 65. It affects about approximately 1,500 individuals each year in the United States. In other words, there are approximately 1,500 new cases of primary CNS lymphoma diagnosed in the United States each year. It is certainly a rare tumor.

Cancer Network: What is considered the current standard of care for patients newly diagnosed with disease?

Dr. Batchelor: The standard of care would be chemotherapy. We of course use a chemotherapy regimen for induction of remission for these patients. The chemotherapy is built around a foundation of methotrexate. Typically, the dose of methotrexate that we use in this disease is 3.5 g/m² or higher. There are a number of different induction regimens that include methotrexate. One of them is a regimen that includes methotrexate, temozolomide, and rituximab, the so-called MTR induction regimen. Another commonly used regimen is methotrexate, procarbazine, vincristine, and rituximab-the RMPV induction regimen-and there are other variants, but those are the two most commonly used induction regimens.

Consolidation for this disease remains a matter of study. Historically, whole-brain radiation therapy has been considered an important component of consolidation. There are also chemotherapy regimens used to consolidate patients. One of the challenges of whole-brain radiation in this disease is that it is associated with neurotoxicity, especially in patients over the age of 60. There have been some investigators that advocate using chemotherapy induction and chemotherapy consolidation. Some of the types of chemotherapy consolidation include regimens such as etoposide and ara-c. This was studied in a multicenter trial conducted by the Alliance Cooperative Group.

Other approaches include high-dose chemotherapy and autologous stem cell transplantation. This is an area of active study as well. Obviously, the particular type of induction regimen and the particular type of consolidation regimen really will depend on the patient. For example, elderly patients typically would not be candidates for high-dose therapy and autologous stem cell transplant, and they might be at higher risk using whole-brain radiation. Really, the approach is tailored to the specific type of patient in terms of choosing the optimal treatment for induction and for consolidation.

Cancer Network: Because CNS lymphoma is relatively rare, clinical trials must be difficult. What are some of the current treatment approaches being researched? Do any of them seem to hold more promise than others?

Dr. Batchelor: Some of them I have eluded to already. High-dose chemotherapy and autologous stem cell transplant is an area of active investigation. There are a number of randomized clinical trials that are addressing high-dose chemotherapy and transplant. One of them is a trial that is ongoing in the Alliance Cooperative Group. This trial uses a standard induction regimen with methotrexate and patients are randomized to receive either etoposide and ara-c as a consolidation or high-dose treatment and a transplant. There are also some trials in Europe that are asking the same question regarding the role of high-dose therapy and transplant as consolidation for primary CNS lymphoma.

Another approach has been to look at potentially different forms of radiation. One approach is to use whole-brain radiation therapy but to use it at a lower dose. There are some trials looking at this. The idea here is that the dose would be sufficient to treat the lymphoma, but low enough so that it doesn’t cause the neurotoxicity that is seen with whole-brain radiation. These are a couple areas of active investigation. There are also some trials that are looking at new agents. These are typically done in the setting of relapsed or refractory disease.

Cancer Network: How often will patients relapse? What is your approach to treatment of patients with relapsed disease?

Dr. Batchelor: The majority of patients will ultimately relapse with primary CNS lymphoma. The options that are available have not been standardized for relapsed patients with this disease. Some of the approaches include, obviously, enrollment on clinical trials of potentially new agents. An agent that is being assessed is ibrutinib. Nivolumab is of interest in the relapsed/refractory setting as an experimental approach. Outside of a clinical trial there have been advocates of re-induction with methotrexate. This would typically be for patients who had a complete response with methotrexate at the time of initial diagnosis but have relapsed 6 months or a year or more after their initial treatment. So, re-induction with methotrexate alone or methotrexate in combination with some other drugs can sometimes be effective there.

In patients who have not previously received whole-brain radiation, it can be employed at the time of relapse. There are a couple of phase II studies that show that it retains activity even in the relapsed-disease setting. There are other chemotherapy approaches that have been used, but these are, again, largely based on small studies or anecdotal experience. We really need more trials in the relapsed setting to define a standard of care for these patients.

Cancer Network: All of cancer research has been entering into an age of targeted therapy. Have any treatable targets been identified in patients with CNS lymphoma?

Dr. Batchelor: There has been interest in a number of novel targets in primary CNS lymphoma. Our field, however, lags behind that of the study of targeted agents and novel approaches in systemic non-Hodgkin lymphoma. I think this is largely due to two factors. One is that this tumor, as I alluded to earlier, is rare. Also, the mode of diagnosis for this tumor is with a needle biopsy, so there is not really a sufficient amount of tumor tissue available many times to study the biology of CNS lymphoma.

Nevertheless, there have been some studies of targeted agents. Ibrutinib is one agent that has been studied as part of a multi-agent regimen at the National Cancer Institute. Ibrutinib appears to get into the cerebrospinal fluid (CSF) and appears to have some activity based on that study, but again, this is very early days.

Another agent that has been studied is temsirolimus, which is an mTOR inhibitor. This was studied in a phase II trial in Europe and it did show some level of activity, although, I think it was a relatively low level of activity in this first study. Other novel agents that have been examined include pemetrexed, which is a drug that has limited CSF penetration but does have some activity in primary CNS lymphoma at the time of relapse. Also, there are a number of PI3K inhibitors that are just entering clinical trials for primary CNS lymphoma. Immunotherapy is also an area of emerging interest for this tumor. There is a trial launching of the checkpoint inhibitor nivolumab for relapsed primary CNS lymphoma, and there has also been interest, potentially, in CAR T-cell therapy for primary CNS lymphomas.

Cancer Network: Thank you so much for giving us this overview and update on CNS lymphoma and some of its treatments.

Dr. Batchelor: My pleasure.