Understanding Primary Central Nervous System Lymphoma

Primary central nervous system (CNS) lymphoma is an aggressive form of non-Hodgkin lymphoma (NHL) in which malignant (cancer) cells are found only in the CNS (the brain and spinal cord). Primary CNS lymphoma can start in the brain, spinal cord, meninges (sheets of tissue that protect the CNS) or the eye. When the lymphoma begins in other parts of the body and spreads to the CNS, it is referred to as secondary CNS lymphoma. In more than 95% of patients with primary CNS lymphoma, the cancer starts in white blood cells (cells that help the body fight infections and cancer) called B-cells.

The cause of primary CNS lymphoma is unknown but having a weakened immune system (for example, people with acquired immunodeficiency syndrome [AIDS] or patients who have undergone organ transplant) may increase the risk of developing the disease. Having one or more of these risk factors does not mean a person will develop primary CNS lymphoma. Most people diagnosed with primary CNS lymphoma have never been exposed to any clearly known risk factors.

Symptoms, Staging, and Diagnostic Procedure

Symptoms

The symptoms of CNS lymphoma depend on the part of the CNS that is affected. These can occur suddenly or develop over time, and may include:

Staging and Diagnostic Procedure

Early identification of symptoms and diagnosis of CNS lymphoma is important, followed by a quick start of treatment to reverse neurological deficits (problems in bodily functions due to damage in the brain, spinal cord or nerves) and improve outcomes (how well the patient will do). Upon diagnosis, tests are done to find out which parts of the CNS are involved as well as to determine if there is cancer elsewhere in the body. These can include:

Subtypes

Diffuse large B-cell lymphoma (DLBCL) accounts for up to 95% of the cases of primary CNS lymphoma in adults, and 49% to 70% of the cases in children and adolescents. The subtype of DLBCL may affect a patient’s prognosis (how well a patient will do with standard treatment [the proper treatment that is widely used by healthcare professionals and accepted by medical experts]) and treatment options. Most cases of DLBCL do not fall into a specific subtype and are referred to as DLBCL-not otherwise specified (NOS). The different types of DLBCL-NOS are named according to their cell of origin (the normal cell that originated the cancer) and include:

Germinal center B-cell-like (GCB)

The most common subtype in systemic DLBCL. Patients with the GCB subtype may have a better response to standard chemotherapy and, consequently, GCB is associated with better clinical outcomes.

Activated B-cell-like (ABC)

Less responsive to chemotherapy compared to GCB in patients with systemic DLBCL and associated with worse clinical outcomes in systemic DLBCL. This subtype is more common in patients with primary CNS lymphoma. How it impacts clinical outcomes vs. GCB primary CNS lymphoma is less clear.

Other less common subtypes of primary CNS lymphoma include follicular lymphoma, marginal zone lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia/ small lymphocytic lymphoma, Burkitt lymphoma, and peripheral T-cell lymphoma.

First Treatment after Diagnosis

Until the mid-1990s, radiation was the standard therapy for patients with CNS lymphoma. Now, chemoimmunotherapy which is a combination (two or more drugs given at the same time) of chemotherapy (drugs that stop the growth of or kill cancer cells) with immunotherapy (drugs that use the body’s immune system to fight cancer) is recommended for most patients as induction (initial) treatment. The most common combination regimen is high-dose methotrexate with the monoclonal antibody (a protein made in the laboratory that binds to cancer cells and helps the immune system destroy them) rituximab (Rituxan). Sometimes, this is given in combination with other chemotherapy agents such as cytarabine (Cytosar), thiotepa (Tepadina), or temozolomide (Temodar).

The initial treatment is often followed by other regimens or consolidation therapies (treatments given once the cancer has disappeared after initial treatment to kill any cancer cells that may be left in the body), to reduce the risk of relapse. These consolidation therapies include:

Consolidative chemotherapy with thiotepa based regimen (preferred in primary CNS lymphoma versus BEAM), carmustine (BiCNU), cytarabine (Cytosar), melphalan and etoposide (Etopophos, Toposar) (BEAM).

• Whole brain radiation therapy. This type of radiation therapy is rarely used because of permanent and progressive neurological complications (for example, loss of memory, problems with balance, or muscle coordination).

Relapsed and Refractory CNS Lymphoma

Some patients with CNS lymphoma respond to initial treatment and go into remission (disappearance of signs and symptoms of the disease). In other cases, the disease may relapse or become refractory (does not respond to treatment). For these patients, different therapies may result in improved treatment outcomes.

Many treatments (also referred to as investigational drugs) are currently being tested in clinical trials (a type of research study that tests how well new treatments work) in patients with primary CNS lymphoma. Results from these clinical trials may improve or change the current standard of care. The table below lists some of these investigational drugs that can be accessed through a clinical trial.

Table 1. Treatments Under Investigation for Primary CNS Lymphoma Under Phase 2 or 3 Clinical Trials.

Agent (Drug)	Class (Type of treatment)	Condition
Abemaciclib (Verzenio)	Targeted therapy; CDK inhibitor	R/R PCNSL
Acalabrutinib (Calquence)	Targeted therapy; BTK inhibitor	R/R PCNSL
Anbalcabtagene autoleucel	Autologous CAR T-cell; anti-CD19	R/R PCNSL
Emavusertib (CA4948)	Targeted therapy; IRAK4 inhibitor	R/R PCNSL
Epcoritamab	Immunotherapy; Bispecific antibody anti-CD3 and anti-CD20	R/R PCNSL
Glofitamab	Immunotherapy; Bispecific antibody anti-CD3 and anti-CD20	R/R PCNSL
Lisocabtagene maraleucel (Breyanzi)	CAR T-cell therapy; anti-CD19	Untreated PCNSL
Nivolumab (Opdivo)	Immunotherapy; immune checkpoint inhibitor, antiPD1	Untreated PCNSL and R/R PCNSL
Obinutuzumab (Gazyva)	Immunotherapy; monoclonal antibody, antiCD20	R/R PCNSLPCNSL
Orelabrutinib (ICP022)	Targeted therapy; BTK inhibitor	Untreated PCNSL and R/R PCNSL
Paxalisib (GDC-0084)	Targeted therapy; PI3K/mTOR inhibitor	R/R PCNSL
Pembrolizumab (Keytruda)	Immunotherapy; immune checkpoint inhibitor, antiPD1	R/R PCNSL
Sintilimab (Tyvyt)	Immunotherapy; immune checkpoint inhibitor, antiPD-1	R/R PCNSL
Tafasitamab (Monjuvi)	Immunotherapy; monoclonal antibody, anti CD19	Untreated PCNSL and R/R PCNSL
Tirabrutinib (ONO4059)	Targeted therapy; BTK inhibitor	Untreated PCNSL and R/R PCNSL
Varlilumab (CDX-1127)	Immunotherapy; monoclonal antibody, anti-CD27	R/R PCNSL
Zamtocabtagene autoleucel (MB-CART2019.1)	CAR T-cell therapy; anti-CD19 and anti-CD20	R/R PCNSL

Treatment options may change as new treatments are discovered, and current treatments are improved. Because today’s scientific research is continuously evolving, it is important that patients check with their physician or with the Foundation for any treatment updates that may have recently appeared. It is also very important that patients consult with a specialist to clear up any questions.

Clinical Trials

Clinical trials are crucial in identifying effective drugs and optimal treatment doses for patients with lymphoma. They are not a “last resort” for patients. Every drug available today had to be tested in clinical trials before it was approved for general use, and all new and emerging treatments. There are four main types or phases of clinical trials. The phase is based on the study’s objective and the number of participants.

Patients interested in participating in a clinical trial should view the Understanding Clinical Trials fact sheet, talk to their physician, or contact the Foundation’s Lymphoma Resource Center for an individualized clinical trial search by calling (800) 500-9976 or emailing [email protected].

How to Be a Self-Advocate

Being a self-advocate and an active participant in healthcare decisions can be a positive experience. It may help patients regain a sense of control that they may have lost following the lymphoma diagnosis by making sure patients receive the best care. Patients and care partners should remember they are partners in their treatment plan.

• Do not be afraid to ask your doctors or nurses questions about your care. An educated patient asking questions is not ‘being a challenge to your physician’ (or ‘being a difficult patient’).
• Learn more about lymphoma by asking your doctor for information and visiting reliable websites, such as the Foundation’s at www.lymphoma.org.
• Take advantage of counseling, support groups, nutritional counseling, fitness classes, expressive arts, and other services offered at your doctor’s office, cancer center, or hospital.
• Consider joining the Foundation’s Lymphoma Support Network, a nationwide peer support program that matches patients and caregivers with people who have had similar experiences. For information about the program, call (800) 500-9976 or email [email protected].
• Finally, it is important that patients not be afraid to talk with the healthcare team about nonmedical issues such as transportation, finances, insurance, working through treatment or taking time off, and childcare. There are nurses, social workers, physician’s assistants that are be able to provide the support and resources to help.

Survivorship

As a cancer survivor, it is important that you practice self-care regularly to reset your physical and emotional well-being. Adopting routines of self-care will help you recharge your batteries and stay healthy. Talk with your healthcare team about developing a wellness plan to help you stay physically and emotionally healthy and improve your mood. Consider the following suggestions:

• Watch your health. Stay up-to-date with your own medical appointments and take any medications as prescribed.
• Exercise. Stay active with short periods of daily exercise (30 minutes of power walking, jogging or biking). If not possible, take the stairs instead of the elevator or park farther away than usual.
• Eat well. Include fruits and vegetables in your meals and maintain a balanced diet.
• Cut down on risk factors. Quit smoking and reduce alcohol intake.
• Sleep. Try to get 7 hours of sleep per night, or take naps when needed.
• Rest. Meditation, deep breathing and stretching can help you relax and reduce stress.
• Write it down. Keeping a journal with thoughts and feelings may help to let go of worries and fears.

View the Foundation’s Survivorship Series factsheet on the Foundation’s website at lymphoma.org/publication for more info.

Long Term Follow-Up Care Plan

All lymphoma survivors should have a long-term follow-up plan (also called a “survivorship care plan”) after treatment ends. This plan is arranged by your healthcare team and includes a summary of the treatments you received, recommendations for follow-up care based on your medical history, and schedules for medical exams to check if the lymphoma has come back (recurrence). This allows your healthcare team to monitor your overall health and look out for long-term effects or other problems that may occur at any point after treatment. Your doctor will let you know how often you need to return for checkup appointments and which physical exams and blood tests are necessary. These checkups usually include a review of your medical history, physical exam and bloodwork, as well as specific exams or screenings recommended by your doctor (see Health Screenings to Consider on next page).

A follow-up care plan may also provide information to help you meet any emotional, social, legal, and/or financial needs. Your health care team can help you decide which doctor to see for your follow-up care plan (the same doctor who treated your lymphoma, a health care provider specialized in caring or cancer survivors, or your primary care provider [PCP]). Some clinics specialized in follow-up cancer plans offer comprehensive support to cancer survivors (called “survivorship clinics”). You can visit oncolink.org/clinics/search to check for survivorship clinics in your area.

Health Screenings To Consider

As a survivor, there are specific health screenings and exams that you may do at an earlier age than the general population. These will be adapted to the type of lymphoma you had and the treatment you received. For instance, due to the increased risk of secondary breast cancer from radiation therapy, women who received radiation therapy to the chest area during childhood, adolescence, or young adulthood should have clinical breast examinations yearly until age 25, then every six months thereafter. In addition, these women should receive yearly mammograms and breast magnetic resonance imaging (MRI) beginning at age 25 or eight years after completion of the radiation therapy, whichever comes last.

Other health screenings the physician may suggest include:

• Bone density scans
• Cardiovascular monitoring
• Chest or whole body imaging
• Screening for other cancers (e.g. colorectal or skin)
• Dental screenings
• Eye exams
• Lipid blood tests
• Thyroid function tests

Because everyone is different, survivors should talk with their physicians about which screenings are most appropriate and when they should be started.

Care Partners

There are many ways you can help a loved one with lymphoma, as follows:

• Be present. The most important thing that a care partner can do is to “just show up.”
• Be prepared. Talk with the healthcare team so that you know what to expect throughout the treatment, how to manage symptoms and when to ask for help.
• Listen. Each person asks for help in different ways, verbally (through words) and nonverbally, and some may require more comfort while others are more action oriented.
• Avoid “cheerleading”. Do not disregard your love one’s negative feelings (sadness, anger or worry).
• Organize the help. A rush of sudden help upon diagnosis can make the situation harder to manage and create unproductive tension.
• Set up remote access with computer and/or phone access. This is helpful for regular communication with your loved one.
• Offer rides. This is important for people with decreased mobility or limited resources.
• Take notes. If you go into the appointments, write down notes with the doctor’s plan, medications, potential side effects and other relevant information.

Patients and their care partner are encouraged to keep copies of all medical records. This includes test results as well as information on the types, amounts, and duration of all treatments received. Medical records are important for keeping track of any side effects resulting from treatment or potential disease recurrences. The Foundation can help patients manage this documentation.

View the Care Partners factsheet on the Foundation’s website atl ymphoma.org/publication for more info.

• What is my exact diagnosis? What subtype of lymphoma do I have? May I have a copy of the report from the pathologist?
• What is the stage of my disease? In what area of the body is it specifically located?
• What are my treatment choices? Which do you recommend for me and why? Would choosing one treatment prevent me from getting a different kind of treatment later on? How are the different treatments administered?
• Do I need more than one type of treatment?
• What is the goal of treatment? What are the expected benefits of each type of treatment?
• How will we know if the treatment is working? What tests will I need to determine if treatment is working, and how often will I need to be tested?
• How long will the treatment last?
• What are the chances the treatment will be successful?
• What is a clinical trial? Are there clinical trials studying new treatments for my type of lymphoma? Would a clinical trial be appropriate for me? How would I benefit? Are there any drawbacks of participating in a clinical trial?
• Will I be able to work during treatment? Will I be able to drive or take public transportation during my treatment?
• Should I take care of other medical or dental issues before I start treatment?
• How much will the treatment cost? Will my insurance cover some or all of it? What will my out-of-pocket costs be?