Let’s Talk About Primary CNS Lymphoma

Most primary brain tumors are formed from abnormal brain cells, but primary CNS lymphoma is different. Although it can appear as a brain mass on imaging, it’s a cancer of the body’s immune system that develops within the central nervous system. Because the cancer is a type of lymphoma, it requires a different treatment approach from other brain cancers.

What is Primary CNS Lymphoma (PCNSL)?

Primary CNS lymphoma is a rare and aggressive type of non-Hodgkin lymphoma (blood cancer) that forms tumors from abnormal white blood cells within the central nervous system. This can include the brain, spinal cord, cerebrospinal fluid, eyes, or the layers covering the brain and spinal cord (meninges). 

This type of lymphoma is different from secondary CNS lymphoma, which occurs when lymphoma has already developed elsewhere in the body and later spreads to the nervous system.

Key PCNSL Statistics & Risk Factors

• CNS lymphomas represent 1-6% of all non-Hodgkin lymphoma diagnoses, depending on the data source.
• According to CBTRUS, more than 1,700 Americans will be diagnosed with primary CNS lymphoma each year, accounting for 1.7% of all CNS tumors. 
• According to the National Cancer Institute (NCI), more than 95% of these tumors are made up of abnormal B cells (white blood cells that normally produce antibodies to fight infections).
• Because this type of tumor impacts the lymphatic system, individuals with weakened immune systems have a higher risk of developing primary CNS lymphoma. For example, individuals with HIV/AIDS or those who are on immunosuppressant drugs following an organ transplant have increased risk factors.

Let’s talk about what makes primary CNS lymphoma different from other brain tumors and about the experiences people living with this tumor type may face.

What are the Common Symptoms of Primary CNS Lymphoma?

The most common symptoms of primary CNS lymphoma are memory challenges, confusion, and difficulty walking or balancing. Unlike other brain tumors, headaches and seizures occur less frequently. 

“The majority of patients have symptoms related to tumors in the brain,” said Lakshmi Nayak, MD, Director of the Center for CNS Lymphoma at Dana-Farber Cancer Institute. “Memory loss and confusion are symptoms that are seen in about 50-60% of people. Difficulty with walking or gait imbalance can be seen in about 40% of people. Headaches are less common.”

Common primary CNS lymphoma symptoms include:

• Confusion
• Memory challenges
• Language disturbances
• Nausea and vomiting
• Personality changes
• Balance issues
• Headaches
• Vision changes (e.g., floaters)
• Seizures

“Seizures, which are more common in a lot of other brain tumors, such as gliomas or brain metastases, are less common in primary CNS lymphoma,” Dr. Nayak said. “We encounter seizures in 50-80% of people who present with brain metastases or gliomas. In primary CNS lymphoma, they occur in about 11-14% of people.”

The Annals of Lymphoma reports that 43% of patients experience neuropsychiatric or behavior changes. These can include depression, apathy, slowness of thought, impulsive behavior, or even hallucinations. Notably, personality changes are reported to impact 60% of the patients who experience these psychiatric symptoms. 

Because symptoms depend heavily on where the tumor is located in the central nervous system, they can vary widely from person to person:

• Ocular Lymphoma (Behind the Eye): Can cause vision loss, blurred vision, or the appearance of floaters
• Spinal Cord Tumors: May cause weakness or numbness in the arms or legs, back pain, or bladder issues

The Speed of Symptoms vs. Normal Aging

According to Dr. Nayak, the median age of diagnosis is 65 years. Because early symptoms often involve changes in memory or mobility, families frequently attribute them to normal aging or neurodegenerative disorders like Alzheimer’s. The difference with PCNSL is its relatively rapid progression.

“People who have memory or gait changes related to neurodegenerative disorders progress very slowly, over years,” Dr. Nayak said. “With PCNSL, these changes occur over days or weeks. When neurologic symptoms occur suddenly or worsen persistently over a few days, these are telltale signs that something else is going on.”

How is Primary CNS Lymphoma Diagnosed?

Primary CNS lymphoma is often first suspected based on MRI findings, but requires a surgical procedure called a stereotactic biopsy, which removes a small tissue sample for a pathologist to analyze and confirm the diagnosis. Because corticosteroids can temporarily shrink lymphoma cells, a biopsy should be performed before corticosteroids are administered to ensure an accurate diagnosis.

Time is of the essence when confirming a diagnosis. Dr. Nayak advises against delaying a brain biopsy by opting instead for lumbar puncture to test cerebrospinal fluid (CSF) or vitrectomy if a biopsy is feasible.

“Not because we won’t find an answer that way, but there’s a 50% chance that we won’t find an answer by analyzing CSF, which will lead to a delay in the diagnosis,” Dr. Nayak said. “The sooner we know the diagnosis and start treatment, the more likely that patients will have a complete neurologic recovery.”

The Extent of Disease Evaluation

Once a biopsy confirms CNSL, patients undergo a thorough evaluation to see exactly which parts of the nervous system are involved and also to confirm there is no evidence of lymphoma in the body (systemic lymphoma). This comprehensive workup typically includes:

• A lumbar puncture for spinal fluid analysis
• A detailed, specialized eye exam
• An MRI of the spine (if spinal symptoms are present)
• CT/PET scan of the body (to rule out systemic lymphoma)

Lived Experiences: Real Stories from the PCNSL Community

Brain tumor community members generously shared the signs and symptoms they or their loved ones experienced before they were diagnosed with a primary CNS lymphoma.

Treatment for Newly Diagnosed PCNSL

Unlike most other primary brain tumors, surgery is not used to treat primary CNS lymphoma. Because these tumors respond remarkably well to systemic medicines and are often located deep within critical areas of the brain, surgery is limited to an initial diagnostic biopsy. 

“These tumors are often located deep in the brain and sometimes in eloquent locations,” Dr. Nayak said. “Removing the tumor from those areas could cause permanent neurologic deficits. This disease actually responds to standard of care chemotherapy treatment in about 80% of patients. Sometimes people come in a critical condition — sometimes completely out of it or comatose. Once we start the treatment and it takes effect, they can wake up. It’s really miraculous to see.”

First-Line Chemotherapy: High-Dose Methotrexate

Rather than oral chemotherapy pills taken at home, newly diagnosed PCNSL requires aggressive, intravenous (IV) chemotherapy administered in a hospital setting.

“High-dose methotrexate forms the backbone of treatment,” Dr. Nayak said. “Most institutions utilize a few other chemotherapy and immunotherapy agents in combination with high-dose methotrexate to quickly shrink the tumor and reverse neurologic symptoms. It’s a traditional chemotherapy that needs to be given in the hospital because it can cause damage to the kidneys due to the high doses that are recommended.”

The Hospital Clearance Process

The goal of high-dose methotrexate is to administer it at such high doses that it can cross the blood-brain barrier to kill tumor cells. To prevent organ damage, the care team must prepare the patient’s body to receive the drug and then flush it out. Twenty-four hours after the methotrexate is given, teams give protective medications while waiting for the patient’s kidneys to clear the chemotherapy completely. This hospital stay typically lasts three to four days per cycle.

“I learned right away to drink gallons of water to flush it all out the next three days after chemo because I wanted to go home,” Neil said. 

Common Combination Regimens in the U.S.

• The MTR Combination: methotrexate, temozolomide (oral chemotherapy pill), and rituximab (an IV medication)
• R-MPV Regimen: rituximab, methotrexate, procarbazine, and vincristine

Stem Cell Rescue

According to the NCCN standard of care guidelines, after completing high-dose methotrexate chemotherapy, high-dose chemotherapy and autologous stem cell rescue is often the next step.

An autologous stem cell transplant uses one’s own healthy stem cells to help the patient’s bone marrow recover and produce more healthy blood cells. However, because this procedure is quite intensive, it isn’t an option for every patient.

“If a patient is young and fit, physically well, and has good bodily functions of all organs, then they are considered for thiotepa-based autologous stem cell transplant (ASCT),” Dr. Nayak said.

Three Key Steps of a Stem Cell Rescue

1. Stem Cell Removal: Healthy blood stem cells are collected from the patient’s body and frozen.
2. High-dose Chemotherapy: The patient receives chemotherapy to wipe out any remaining lymphoma cells.
3. Stem Cell Replacement: The frozen stem cells are thawed and returned to the patient’s body.

Patient Perspectives on the Rescue Experience

While the clinical steps sound straightforward, the process can be taxing.

“I didn’t want to do a stem cell transplant, but two of the top neuro-oncology doctors agreed that it was the best chance of long-term survival,” Neil said. “Right before my eighth treatment, we heard I was classified as ‘no evidence of disease’ (NED). I felt miserable during chemo, and my doctors convinced me by saying, ‘Do you want to come back here and do this all again?’”

Despite the hardships of the treatment, the potential long-term payoff can be worth it. 

“The stem cell rescue was critical,” Elke said. “He did well for five years after that.”

Keeping a mindset focused on the temporary nature of the hardships can help.

“I want patients going through the stem cell transplant process to know that as bad as it gets, it’s going to get better,” Neil said. “You don’t feel great now, but you’re in the right place, doing the right thing, and you will feel good again. It’s momentary.”

Radiation Therapy

If a patient is physically unable to tolerate intensive chemotherapy, NCCN guidelines state that radiation therapy can be utilized as a first-line treatment. More commonly, radiation is used after initial chemotherapy to eliminate any lingering cancer cells.

Because PCNSL can develop in multiple areas throughout the central nervous system, whole-brain radiation therapy (WBRT) is the standard approach. However, because WBRT carries a well-documented risk of long-term cognitive deficits, clinicians carefully weigh its risks and benefits.

“We always say, ‘We don’t want to go to radiation because we worry that radiation can have damaging effects in the long term on patients, but it doesn’t mean that we can’t use it, or we don’t have to use it,” Dr. Nayak said. “If people are declining very quickly, that needs to be considered. There are many factors I would use to make a decision: the rate of the tumor growth, the rate of the neurologic deterioration, how much time they have, and how much time it is going to take for what you’re thinking of using [for treatment].”

Managing Relapsed or Refractory PCNSL

While most patients experience remission after their initial treatment, the Annals of Lymphoma reports that up to 50% of patients will experience refractory or relapsed disease after first-line chemotherapy.

Most relapses occur within two years of diagnosis, though the risk of recurrence persists even a decade later. 

Refractory Primary CNS Lymphoma

Refractory primary CNS lymphoma is when the cancer does not respond to initial treatment, never achieves complete remission, or progresses during treatment. An article in Annals of Lymphoma reports that an estimated “10-15% of newly diagnosed PCNSL are refractory to high-dose methotrexate therapies and inherently have more aggressive disease.”

Relapsed Primary CNS Lymphoma

Relapsed primary CNS lymphoma occurs when the cancer initially responds to the initial treatment, but then the disease returns later. 

Treatment Options for Refractory or Relapsed PCNSL

Unlike treatment for newly diagnosed patients, there is currently no standard of care for refractory or relapsed primary CNS lymphoma (R/R PCNSL). 

When the disease resists the initial treatment or returns after a period of remission, a patient’s care team will evaluate options based on prior therapies and overall health. 

Traditional approaches to managing R/R PCNSL may include:

• High-dose methotrexate rechallenge (undergoing this chemotherapy regimen again, especially if the patient responded well the first time and relapse occurs after several years of being in remission)
• Whole-brain radiation therapy or focal radiation therapy
• High-dose chemotherapy followed by autologous stem cell transplant (if not previously given)

Clinical trial options are also important to consider for patients with R/R PCNSL. In fact, NCCN guidelines recommend “that everyone with primary CNS lymphoma consider joining a clinical trial for treatment.”

Patients, caregivers, and loved ones can look for clinical trial options through NBTS’s Clinical Trial Finder and discuss their options with their care team.

Clinical Trials and Targeted Therapies for PCNSL

Developing well-tolerated, innovative treatments is critical because a large percentage of the patient population cannot physically endure these intensive therapies.

“​​About 50-60% of people don’t actually qualify for some of these aggressive chemotherapy-based therapies or autologous stem cell transplant,” Dr. Nayak said. “That’s part of the reason understanding how BTK inhibitors or CAR-T cell therapies work in this space and how well they are tolerated by older people is important to the field.”

BTK Inhibitors

Primary CNS lymphoma is heavily driven by a chemical pathway called the B-cell receptor signaling pathway. This discovery has opened the door to targeted therapies, notably Bruton tyrosine kinase (BTK) inhibitors.

Inside cancerous B cells, a specific protein called BTK stays permanently switched on, sending continuous chemical signals that order the cell to grow rapidly and survive. BTK inhibitors work by entering the lymphoma cell and attaching directly to this protein. By blocking its activity, the drug shuts off the faulty growth signals, causing the cancer cells to stop dividing and die.

The phase II PROSPECT trial evaluated a once-daily oral pill called tirabrutinib in patients with relapsed/refractory PCNSL, as well as a combination treatment with high-dose methotrexate in newly diagnosed patients. 

The drug successfully shrank tumors and improved brain-related symptoms in roughly two-thirds of patients, keeping the disease under control for over nine months — an improvement over traditional treatments. The drug has since progressed to a phase III trial, which is currently enrolling patients.

Previously, the U.S. Food & Drug Administration (FDA) granted tirabrutinib orphan drug designation, a special status that provides financial incentives to companies developing treatments for rare diseases. In February 2026, the FDA accepted an application to consider the drug for accelerated approval for relapsed/refractory PCNSL, with a decision expected in December 2026. 

Because this treatment is a simple pill taken at home rather than a complex hospital infusion, it dramatically increases accessibility. As Dr. Nayak points out, “This is the kind of therapy that can be available and offered in smaller community oncology centers as well. Importantly, it works very quickly — an aspect that is important in rapidly progressive brain tumors”

CAR T-cell Therapy

CAR T-cell therapy is a highly advanced form of immunotherapy. It involves removing a patient’s own T cells (a type of immune cell), genetically reprogramming them in a laboratory with a special protein that acts as a radar to identify cancer, and infusing them back into the patient in large numbers to hunt down and destroy lymphoma cells.

Historically, patients with primary CNS lymphoma were excluded from CAR T-cell therapy clinical trials due to concerns over potential neurological side effects. However, recent clinical data from Dr. Nayak and her team at the Dana-Farber Cancer Institute helped demonstrate that CAR T-cell therapy could be used safely in some patients with PCNSL. These findings prompted the FDA to allow patients with PCNSL to receive a type of CAR T-cell therapy.

“The recommendation was to lift that exclusionary criteria,” Dr. Nayak said. “That’s still a huge win for our patients because this allows it to be accessible to those with relapsed/refractory primary CNS lymphoma now.”

Dr. Nayak considers many factors to determine whether a patient might be a fit for CAR T-cell therapy:

• What is the location of the tumor?
• What is the timing from when they received the last treatment?
• What is their physical condition?
• How is their body function otherwise, not just neurologically — what is their organ function like? How are their kidneys? How is their heart?
• Are they able to tolerate the treatment?

“CAR T-cells work really well based on our experience, but it takes about three months after initiation of treatment to achieve what we call best response,” Dr. Nayak said. “Because it’s a type of immunotherapy, we’re increasingly recognizing that in the beginning we might see some inflammation in the brain in a small number of patients.”

Lingering Side Effects

Treatments for primary CNS lymphoma can have lasting effects on the brain, including long-term cognitive changes such as challenges with memory, processing speed, and word-finding.

“I’m not as sharp as I was,” Neil said. “I developed code and software. There was one time when I picked up a piece of code and couldn’t understand what it was. I had written it before cancer. I also really struggle with word associations. After treatment, I had gaps in my memory and ability to put it together. My doctor told me, ‘You traded some of your mental acuity for longevity.’”

Adjusting to this new normal requires patience from both survivors and families. For survivors, it can be easy to focus on the cognitive abilities lost, while caregivers can see the bigger picture of recovery.

“From my perspective, he doesn’t see how far he’s come,” Dawn said. “We had an hour-long assessment done a year after treatment because he was so worried about his memory. They told him he had nothing to worry about after the assessment.”

Looking Ahead

Right now, researchers are actively looking for better ways to predict how a patient’s disease will behave. While biomarker testing is standard in many other cancers, including most brain tumors, to help predict prognosis or treatment response, that’s not yet the case for primary CNS lymphoma.

“Unfortunately, at this time, we don’t have any specific biomarkers [for PCNSL] that can predict response to treatment or overall survival,” Dr. Nayak said. “We conduct experimental biomarker tests in our group, in the context of clinical trials.”

Scientists are working to find more effective, targeted treatments, such as BTK inhibitors and CAR T-cell therapy, with the goal of achieving tumor remission, long-term disease control, and improvement in neurocognitive function after the first line of treatment.

“At the end of the day, the goal is that patients are cured upfront, and that we don’t have to find options for when it comes back,” Dr. Nayak said. “One hit to the brain is hard enough. Multiple hits to the brain, even with good treatments, are damaging to the brain and its recovery.

“These are very unique aspects of brain tumor patients to consider when we think of therapies. We want to drive the field forward and modify treatments to make them very robust from the beginning.”

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