Primary CNS Lymphoma: Patient Guide

Primary central nervous system lymphoma is an aggressive lymphoma. It stays in the brain and its surroundings. There is no cancer elsewhere in the body.

The National Cancer Institute maps the territory exactly. It covers the cranial-spinal axis. That means the brain and the spinal cord. It also means the spinal fluid, in what is called the leptomeningeal space. And it means the vitreoretinal space inside the eye. Disease elsewhere in the body is absent by definition.

Almost all cases are diffuse large B-cell lymphoma. The subtype is activated B-cell, non-germinal center. More than 95% show a B-cell phenotype. The common driver changes hit B-cell receptor signaling. MYD88 and CD79B are the two named most often.

NCI notes it is seen more often in people with a weakened immune system. That includes people with HIV. In that setting it is almost always linked to Epstein-Barr virus.

That definition drives the workup. The lymphoma can sit in any of four compartments. Each one is checked separately.

• Brain and spinal cord tissue — by MRI.
• Cerebrospinal fluid — by lumbar puncture.
• The eye — by ophthalmoscopy and slit-lamp examination.
• Everywhere else, to rule it out — by PET-CT.

The eye exam is the one most often skipped. Ask for it by name.

The fluid check matters too. NCI cites a series of 282 patients. In that group, 17% had meningeal dissemination. That means lymphoma in the lining of the brain and spinal cord.

NCI's patient summary lists these signs and symptoms:

• Nausea and vomiting.
• Seizures.
• Headaches.
• Weakness in an arm or a leg.
• Confusion.
• Double vision and hearing loss.

These build over days to weeks, not months. That speed is part of why the diagnosis often happens in an emergency department.

NCI lists the tests used. A neurologic exam, then MRI with gadolinium contrast. A lumbar puncture and an eye examination. A stereotactic biopsy. Blood work covers a complete blood count, blood chemistry, and an HIV test.

Stereotactic biopsy means computer-guided sampling aimed at the lesion. It goes through a small opening in the skull. It is what confirms the diagnosis.

One imaging detail is worth knowing. On CT, NCI reports ring enhancement in 50% of patients with HIV. In patients without HIV, the enhancement is almost always even throughout. That is why HIV testing is part of the standard workup.

PET-CT is used to rule out hidden lymphoma elsewhere. NCI notes that a bone marrow biopsy may be skipped when the PET-CT is clear.

NCI states the standard here. High-dose methotrexate is the induction therapy used most often outside clinical trials. The amounts used in trials are far above the methotrexate doses given for other conditions, and the more intensive protocols repeat them every 2 weeks. They are given in hospital, with fluids and blood monitoring around them, and calculated by the team.

The limits are specific. NCI states the drug is too toxic below a creatinine clearance of 35 cc/min. It is also too toxic for most patients older than 75 years. Creatinine clearance is a measure of how well the kidneys filter.

So two questions belong in the first treatment talk. What is my creatinine clearance? How will kidney function be watched during each cycle?

Rituximab. This antibody targets CD20 on B cells. NCI cites a meta-analysis of adding it. Progression-free survival improved, with a hazard ratio of 0.65. The 95% confidence interval ran from 0.45 to 0.95. There was no difference in overall survival.

MATRix. This four-drug regimen combines methotrexate, high-dose cytarabine, rituximab, and thiotepa. In the randomized trial NCI cites, complete remission rates were 23% with the two-drug combination, 30% with three drugs, and 49% with MATRix. At a median follow-up of 88 months the overall survival rates were 21%, 37% and 56% in the same order. Adding rituximab and thiotepa improved complete response, progression-free survival and overall survival.

After induction, something is usually done to hold the response. The choice is radiation or transplant. That is where the sharpest data sit.

NCI reports a head-to-head comparison. It set whole-brain radiation at 40 Gy against autologous stem cell transplant. Gy stands for gray, the unit of radiation dose.

• Balance deteriorated in 52% after radiation, against 10% after transplant.
• Neurocognitive function worsened in 64% after radiation, against 13% after transplant.
• 8-year event-free survival was 39% with radiation, against 67% with transplant. Overall survival did not differ significantly between the two.

The authors drew a firm conclusion, as NCI reports it. Whole-brain radiation at 40 Gy should be avoided in first-line treatment. The reasons were nerve damage and weaker results.

A separate study enrolled 551 patients. It found no statistical difference in median overall survival. That was 32.4 months with whole-brain radiation at 45 Gy, against 37.1 months without it. Nerve-related side effects were clearly worse in the radiation arm.

Lower doses behave differently. NCI describes a trial of whole-brain radiation at 23.4 Gy. Two-year progression-free survival was 78% with it, against 54% without. Nerve-related toxicity, as rated by investigators, was under 15% in each arm.

So if radiation is proposed, ask for the dose in Gy. A dose of 23.4 and a dose of 40 are not the same conversation.

Autologous means your own stem cells are used. They are collected first, then returned after high-dose chemotherapy.

NCI reports the IELSG43 trial. It enrolled 346 patients aged 70 or younger, all with good performance status.

• 3-year overall survival was 86% with transplant, against 71% with chemotherapy alone, hazard ratio 0.47.
• 3-year progression-free survival was 79% against 53%.
• Neither arm showed a negative effect on thinking and memory in the absence of progression.

That last line is the one to hold onto when weighing transplant against radiation.

NCI states the range from published trials. Median overall survival generally runs from 2 to 5 years. One look-back series of 40 patients with low-grade disease did better. Median survival there was 7 years.

For disease that comes back, NCI gives a median survival of 6 to 12 months. That rises to 43 to 50 months when autologous stem cell transplant is used to consolidate.

NCI lists the factors linked to a worse outcome:

• Age over 60 years.
• HIV positivity.
• Raised serum lactate dehydrogenase.
• Raised protein in the cerebrospinal fluid.
• Involvement outside the brain hemispheres, such as periventricular, basal ganglia, brainstem, or cerebellum.
• Eye involvement together with brain involvement.

Call the treating team at once, or go to the emergency department, for:

• A seizure of any kind, or a first-ever seizure.
• New or worsening weakness in an arm, a leg, or the face.
• Sudden vision loss, new double vision, or a new floaters shower.
• Headache with vomiting, or a headache clearly worse than usual.
• New confusion, or difficulty speaking.
• A temperature of 100.4 °F (38 °C) or higher during chemotherapy, the threshold CDC gives.

Are you receiving high-dose methotrexate? Then report reduced urine output or new swelling at once. Clearing the drug depends on the kidneys.

• Was my cerebrospinal fluid examined, and was an eye exam done?
• What is my creatinine clearance, and does it permit high-dose methotrexate?
• Which induction regimen is planned, and is rituximab included?
• Is consolidation planned, and is it radiation or transplant?
• If radiation, what dose in Gy, and what is the expected effect on memory?
• Is a clinical trial open for me at this center or elsewhere?

Primary CNS Lymphoma: Diagnosis and Questions goes deeper on the workup. Primary CNS Lymphoma: Treatment Discussion covers the choice of regimen. Finding a Clinical Trial matters here.

• NCI PDQ — Primary CNS Lymphoma Treatment (Health Professional Version)
• NCI PDQ — Primary CNS Lymphoma Treatment (Patient Version)
• National Cancer Institute — Infection and Neutropenia during Cancer Treatment