Primary central nervous system (CNS) lymphoma is a rare type of non-Hodgkin lymphoma in which standards of care have not been well established. In light of recent insights into its pathophysiology and the emergence of novel approaches, The ASCO Post asked Tracy T. Batchelor, MD, a specialist in primary CNS lymphoma, to discuss this neurologic malignancy and his treatment recommendations. Dr. Batchelor is the Miriam Sydney Joseph Professor of Neurology at Harvard Medical School; Chair of the Department of Neurology at Brigham and Women’s Hospital; and Co-Director of the Neuro-Oncology Program at the Dana-Farber/Harvard Cancer Center in Boston.
How is primary CNS lymphoma usually detected by physicians?
Patients who are ultimately diagnosed with primary CNS lymphoma typically present with a brain mass that is discovered on magnetic resonance imaging (MRI) after they present with neurologic symptoms. Based on suspicion of primary CNS lymphoma in the MRI, a biopsy is typically performed, and the pathology report gives the definitive diagnosis.
Establishing the extent of disease is important for patient counseling, treatment decisions, and stratification for clinical trial enrollment.— Tracy T. Batchelor, MD
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The disease can affect the brain, spinal cord, eyes, and cerebrospinal fluid (CSF) without evidence of systemic, non-CNS involvement. Thus, it is important that evaluations include assessment of brain, CSF, eyes, and body. Primary CNS lymphoma typically relapses locally within the nervous system, although uncommon non-CNS relapses can also occur.
Staging and Prognosis
How is primary CNS lymphoma staged, and is the use of a prognostic scoring system important?
The International Primary CNS Lymphoma Collaborative Group (IPCG) recommends baseline evaluation to determine the extent of disease. This assessment is by contrast-enhanced MRI of the brain and spine (if spinal symptoms are present) and ophthalmologic and CSF analysis. The latter should be done only if a lumbar puncture can be safely performed, in light of the potential for increased intracranial pressure. Establishing the extent of disease is important for patient counseling, treatment decisions, and stratification for clinical trial enrollment.
Two scoring systems that are predictive of clinical outcomes are the International Extranodal Lymphoma Study Group score and the Memorial Sloan Kettering Cancer Center (MSK) score. Both systems perform well, but the MSK system is easier to use, as it is based solely on age and performance status.
Is there an optimal first-line treatment for primary CNS lymphoma, and what are your recommendations?
After the introduction of high-dose methotrexate years ago, the prognosis of primary CNS lymphoma improved. Why methotrexate? With methotrexate at high doses, we can achieve cytotoxic concentrations in the brain and CSF, which is not the case with some of the other drugs typically used in systemic lymphoma.
We treat these patients in two stages: induction, where we have multiple regimens, but all are built around methotrexate, and consolidation, where we have three main options with no one approach proven better than another. In our group, we’ve mainly emphasized chemotherapy alone for both induction and consolidation therapies. For induction, we tend to use methotrexate, temozolomide, and rituximab. This regimen is well tolerated, and the drugs we selected for it have shown prior activity as single agents. However, in light of recent data, the role of rituximab in primary CNS lymphoma is debatable.
For consolidation, we use a different chemotherapy regimen (high-dose chemotherapy) followed by autologous stem cell transplantation or an alternative, non-myeloablative chemotherapy approach. Given the risk of clinical neurotoxicity with whole-brain radiotherapy, especially in patients older than age 60, we have moved away from consolidative whole-brain radiotherapy. However, it remains an option for patients at relapse or for patients who are not good candidates for aggressive chemotherapy.
For patients who are eligible for stem cell transplantation, we usually advise this treatment. We don’t have conclusive evidence for transplantation vs whole-brain radiotherapy, but we do have readouts from randomized phase II clinical trials suggesting that transplantation is as effective as whole-brain radiotherapy and perhaps less neurotoxic.
Is maintenance therapy ever part of the treatment for primary CNS lymphoma?
We have generally moved away from the use of maintenance therapy for primary CNS lymphoma, in the era of more definitive and aggressive consolidation. One exception is the elderly patient who may not be a candidate for transplant or whole-brain radiotherapy (because of increased risks of neurotoxicity). Part of consolidation in this case may be some type of maintenance therapy, such as more methotrexate, or a different drug that is better tolerated in older patients, such as lenalidomide. Again, however, we have no randomized trial data to support this approach.
Are the approaches we’ve discussed curative?
Yes, our goal is curative when we approach most patients with primary CNS lymphoma. We can cure a percentage of them, the exception being some elderly patients, who we do not treat as aggressively as younger patients. Years ago, we published a study1 suggesting that with methotrexate-based monotherapy, about 25% of patients are likely cured. When we use something more aggressive for consolidation, such as transplantation, we may be curing more than 50%.
Relapse after 5 years is uncommon, and it is very rare after 10 years. However, we don’t have a “magic number” telling us when, or if, patients are “cured.”
Monitoring for Relapse
How do you monitor patients for relapse?
We monitor patients with regular MRI scans for the first 5 years post-therapy. If the patient had prior eye involvement (which up to 20% of patients with primary CNS lymphomas do), he or she should also have ocular follow-up. In years 6 to 10, as long as they are stable, patients can be seen annually with an MRI scan. After year 10, ongoing imaging is not advised.
Options at Relapse
Is there a standardized approach for relapsed disease?
We have even less information from clinical trials to guide us in the relapsed setting, and there is no definitive recommendation. The choice of salvage therapy is dependent on the first-line regimen used, performance status, organ function, and duration of prior response.
We have generally moved away from the use of maintenance therapy for primary CNS lymphoma, in the era of more definitive and aggressive consolidation.— Tracy T. Batchelor, MD
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The first option is clinical trial enrollment, which we like to offer patients at relapse. The second option is more chemotherapy, generally if it’s been several years since the primary diagnosis. You might go back to methotrexate-based chemotherapy or choose a different regimen, such as cytarabine and/or etoposide, ICE (ifosfamide, carboplatin, etoposide) and R-ICE (ICE plus rituximab). We simply don’t have data showing one regimen is better than another, but I would recommend cytarabine and etoposide for patients who have not been treated with these drugs previously.
For patients who have had no prior radiotherapy, whole-brain radiotherapy is an option. Studies suggest it is as effective when used in the relapsed setting as it is at the time of initial diagnosis. Finally, another option is high-dose chemotherapy and stem cell transplantation, if the patient has not had one.
On the Horizon
What are the newer developments in primary CNS lymphoma, and which agents look most promising?
We have had a recent surge of novel insights based on genomic investigations of archival tissue from patients with primary CNS lymphoma. These studies have identified novel drivers of primary CNS lymphoma, and these alterations are now being targeted with small molecules and immune checkpoint inhibitors, mostly in clinical trials.
We’ve learned that aberrant activation of the BCR signaling axis is a significant driver of primary CNS lymphoma pathophysiology and can potentially be targeted at different signaling nodes. Using agents currently in clinical trials we can target, among other things, phosphoinositide 3 kinase and Bruton’s tyrosine kinase (BTK).
We currently have agents that can do these things. The BTK inhibitor ibrutinib, in fact, has already been included in the National Comprehensive Cancer Network® Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for relapsed or refractory primary CNS lymphoma, based on a number of small, nonrandomized studies showing objective activity. For instance, in a study from the National Cancer Institute, 83% of relapsed patients had a radiographic response after 2 weeks of single-agent ibrutinib.2 Lenalidomide is also included in the NCCN Guidelines, based on a phase II study in which lenalidomide/rituximab led to a 63% radiographic response and a median progression-free survival of 8.1 months.3
What motivates us is to build upon what we have done thus far—curing more patients and at the same time preserving neurocognitive function and quality of life.— Tracy T. Batchelor, MD
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Even newer approaches undergoing study are immunotherapies, including programmed cell death protein 1 inhibitors and chimeric antigen receptor T-cell therapy. We have just case reports or case series of activity with these approaches, but they appear promising, based on early indicators.
I think the next step will be to incorporate these novel agents into methotrexate-based induction. In the longer term, there is the potential to replace the current inpatient, methotrexate-based, induction therapy with an equally effective, more patient-friendly regimen.
Any closing thoughts about the future of treatment for primary CNS lymphoma?
There has never been more interest in this rare type of lymphoma, and that’s a good thing for our field. The collaborative group IPCG has met at the American Society of Hematology Annual Meeting & Exposition for nearly 20 years, and from that, we have generated a lot of ideas, guidelines, and clinical trial concepts. What motivates us is to build upon what we have done thus far—curing more patients and at the same time preserving neurocognitive function and quality of life. We are trying to thread the needle here: finding optimal antilymphoma treatments that target the brain and are not so neurotoxic.
More of Dr. Batchelor’s insights and recommendations on primary CNS lymphoma can be found in a 2019 publication.4 ■
DISCLOSURE: Dr. Batchelor has received honoraria from Champions Biotechnology, GenomiCare, Imedex, Merck, NX Development Corp, and UpToDate; has served in a consulting or advisory role for Amgen, GenomiCare, Merck, N NX Development Corp XDC; and has been reimbursed for travel, accommodations, or other expenses by GenomiCare and Merck.
1. Zhu JJ, Gerstner ER, Engler DA, et al: High-dose methotrexate for elderly patients with primary CNS lymphoma. Neuro Oncol 11:211-215, 2009.
2. Lionakis MS, Dunleavy K, Roschewski M, et al: Inhibition of B cell receptor signaling by ibrutinib in primary CNS lymphoma. Cancer Cell 31:833-843, 2017.
3. Ghesquieres H, Houillier C, Chinot O, et al: Rituximab-lenalidomide in relapse or refractory primary central nervous system or vitreo retinal lymphoma: Results of a ‘proof of concept’ phase II study of the French LOC network. 2016 ASH Annual Meeting & Exposition. Abstract 785.
4. Batchelor TT: Primary central nervous system lymphoma: A curable disease. Hematol Oncol 37(suppl 1):15-18, 2019.