Understanding Indolent B-cell Lymphomas

The most common MZL subtypes are:

Mucosa-associated lymphoid tissue (MALT) lymphoma or extranodal MZL is the most common form of MZL (61% of all MZL cases). This type of MZL affects tissues outside the lymph nodes (extranodal tissues) like the mucosa (inner lining) of some internal organs and body cavities. Listed below are the organs where MALT lymphomas are found:

Nodal MZL is a rare type of MZL (30% of all MZL cases) that occurs within the lymph nodes.

Splenic MZL is the rarest form of MZL (9% of all cases) and occurs most often in the spleen, blood, and bone marrow. It has been associated with hepatitis C virus (HCV) infection.

Lymphoplasmacytic cells can survive longer and multiply faster than normal B-cells (Figure 2). High numbers of these abnormal cells in the bone marrow can slow down its function and reduce the number of healthy blood cells and platelets. This can result in anemia (low levels of red blood cells), neutropenia (low levels of white blood cells called neutrophils), and thrombocytopenia (low levels of platelets). In some cases, the same abnormal cells can also be found in lymph nodes or the spleen, which might appear enlarged on a computed tomography (CT) scan (uses a computer linked to an X-ray machine to make pictures of areas inside the body).

Cutaneous B-cell Lymphoma (CBCL) CBCL is often indolent and rare, representing approximately 2% of the NHLs. CBCL starts in the Bcells of the skin and may appear on the skin as a rash, reddish bump, lump, or nodule, usually with a raised and smooth appearance.

Symptoms, Staging, and Diagnostic Procedure

MZL, WM and CBCL can present similar general symptoms. Symptoms depend on the tumor location (where the tumor is located in the body) and the extent (cancer stage and how far it has spread) of the disease.

Patients with WM have an increased level of a protein called immunoglobulin M (IgM) in their blood, which is produced by the abnormal lymphoplasmacytic cells. Very high levels of IgM can cause blood hyperviscosity (thickening of the blood). Thickened blood cannot flow easily through the body, which may lead to excess bleeding, vision or hearing problems, headache and/or lightheadedness. In some cases, the IgM in the blood can cause other issues, such as autoimmune hemolytic anemia (a condition where the body attacks and destroys its own red blood cells) or neuropathy (tingling, numbness or pain caused by damage to the nerves). However, some patients with hyperviscosity do not experience any symptoms.

CBCL can appear as a single lesion (area that looks abnormal or different from the surrounding skin) or multiple lesions in either one or several body regions (areas). Many skin conditions may look similar but are not CBCLs. The disease can relapse (return after treatment) or occur in new places on the skin, but it rarely spreads outside the skin. About 50% of patients with single lesions are cured after radiation therapy (uses high-energy radiation to kill cancer cells). However, patients with multiple lesions are more likely to continue to have new lesions appear. This fact does not affect prognosis (how well the patient will do), which remains very good.

When patients have stable disease (cancer is neither decreasing nor increasing in size or severity) or show no symptoms, doctors may decide to monitor the patient without treating the disease. This approach is called active surveillance, or watchful waiting. In this case, patients’ overall health and disease are monitored through regular check-up visits that may include laboratory (like a complete blood cell count) and imaging tests (such as CT scans). To know more about active surveillance, view the Active Surveillance fact sheet.

First Treatment after Diagnosis

Marginal Zone Lymphoma (MZL)

Treatment for MZL is started if the patient begins to develop lymphoma-related symptoms or there are signs that the disease is progressing (cancer is growing and/or spreading). Treatment selection for a patient with MZL depends on the MZL subtype, stage (the size of the cancer and whether it has spread), location, patient’s age and overall health, and signs or symptoms.

Gastric MALT Lymphomas

Since gastric MALT lymphoma is often the result of an infection with Helicobacter pylori, the initial treatment combines therapy with two antibiotics and one proton pump inhibitor (PPI, drugs that reduce the amount of acid in the stomach), typically given for two weeks. PPIs help to prevent or heal stomach ulcers (sores on the walls of the stomach). In about 80% of cases, MALT lymphomas go away after antibiotic and PPI treatment, although this may take several months. Most gastric MALT lymphomas are low-grade lesions that grow slowly and do not commonly spread to other places in the body. For patients who do not have an infection with Helicobacter pylori, radiation therapy is the standard of care approach.

Non-Gastric MALT Lymphomas

Non-gastric MALT lymphomas can appear throughout the body. Therefore, treatment is usually based on the exact location of the lymphoma and how far it has spread. For OAL, radiation therapy with or without antibiotic therapy is usually very effective, and patients may achieve durable remission (no signs or symptoms of disease for a long time). The antibiotic doxycycline has been shown to be effective in MALT that affects the area around the eye, especially in certain areas of the world where infection with Chlamydia psittaci is commonly associated with OAL. In localized cases, treatment usually includes radiation therapy, which is effective even at very low doses. In rare cases where radiation is not feasible, surgery can be used as an alternative. More advanced disease is usually treated with immunotherapy (drugs that use the body’s immune system to fight cancer) such as the monoclonal antibody (a protein made in the laboratory that binds to cancer cells and helps the immune system destroy them) rituximab (Rituxan), with or without chemotherapy.

Nodal MZL

Because nodal MZL is most often a slow-growing disease, physicians may recommend an active surveillance or watchful waiting approach until symptoms appear. When treatment is necessary, options include radiation therapy, chemotherapy, targeted therapy and/or immunotherapy, and other treatments commonly used in other types of slow growing lymphomas, such as follicular lymphoma.

Splenic MZL

Treatment is not always immediately necessary for splenic MZL, but when a treatment is needed, several options exist. In rare cases, patients may receive a surgery called splenectomy (removal of the spleen) while other patients may be given rituximab (Rituxan) with or without chemotherapy. When the splenic MZL is associated with hepatitis C virus (HCV) infection, treatment of the infection might cure the lymphoma.

The most common types of treatment for MZL include:

• Antibiotics (drugs that fight bacterial infections).
• Radiation therapy.
• Immunotherapy.
  • Monoclonal antibodies (proteins made in the laboratory that bind to cancer cells and help the immune system destroy them) such as rituximab (Rituxan).
  • Immunomodulatory drugs (drugs that work on the immune system directly by activating or slowing down the activity of specific proteins).
• Chemoimmunotherapy is a combination of chemotherapy (drugs that stop the growth of or kill cancer cells) with immunotherapy.
  • Bendamustine (Treanda) plus rituximab (BR).
  • R -CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisone)
  • R -CVP (rituximab [Rituxan], cyclophosphamide, vincristine, and prednisone).
• Targeted therapies (drugs that target molecules that cancer cells use to grow and spread) such as Bruton’s tyrosine kinase (BTK) inhibitors.
• Surgery.

Patients seeking information about immunotherapy should view the Immunotherapy and Other Targeted Therapies fact sheet on the Foundation’s website (lymphoma.org/publications).

For all subtypes of MZL, biosimilar therapies (drugs that are similar to an existing biological therapy [reference drug] but may cost less than the reference drug) may be an option for patients who are taking rituximab. These include rituximab-abbs and rituximab-pvvr. For more information, patients should view the Biosimilars fact sheet on the Foundation’s website at lymphoma.org/publications and talk to their physician.

Waldenström Macroglobulinemia (WM)

Treatment for WM is indicated (recommended) for patients with symptoms, evidence of decreased bone marrow function (low levels of blood cells and platelets, caused by the presence of lymphoplasmacytic, or lymphoma cells), and symptoms related with the excess of IgM protein, such as hyperviscosity syndrome, or autoimmune complications (when the body’s immune system attacks its own healthy cells), such as autoimmune hemolytic anemia. Although WM is an incurable disease, it is treatable, and many patients have a durable remission to treatment. For patients who require treatment, many factors help determine the best type of treatment, such as:

Treatment choice is based on an individual patient’s needs, as well as considerations for short-term (caused by treatment and usually goes away after treatment ends) and long-term (occurs during treatment and continue for months or years) side effects.

Patients with very high IgM and symptoms related to hyperviscosity undergo a procedure called plasmapheresis to temporarily reverse or prevent the symptoms associated with the excess of IgM protein. This procedure involves passing the patient’s blood through a machine that separates the plasma (the liquid part of the blood that contains the IgM protein) from the blood cells. The thickened plasma is replaced with a fluid containing albumin (a natural component of plasma) before returning the blood to the patient, now thinner and clearer of IgM protein. Physicians often follow plasmapheresis with other treatments, such as immunotherapy or chemotherapy.

Treatment options for patients with WM include:

• Targeted therapy with BTK inhibitors like ibrutinib (Imbruvica) and zanubrutinib (Brukinsa).
• Immunotherapy with the monoclonal antibody rituximab (Rituxan). Rituximab binds to a protein called CD20 located at the surface of WM cells and can be used in combination with ibrutinib (Imbruvica).

There are also many other drugs that can be used to manage WM, alone and/or in various combinations such as chemoimmunotherapy, including the following:

• Bendamustine (Treanda)
• Cyclophosphamide (Cytoxan)
• Bortezomib (Velcade)
• Carfilzomib (Kyprolis)
• Ixazomib (Ninlaro)
• Corticosteroids

The standard (proper treatment that is widely used by healthcare professionals and accepted by medical experts) immunotherapy or chemoimmunotherapy combinations are used for a set period of time. Once the desired number of cycles (regular treatment schedule that consists of treatment periods followed by a rest period) are administered, patients will stop treatment and be monitored over time for disease progression (when cancer continues to grow or spread).

Cutaneous B-cell Lymphoma (CBCL)

For indolent lymphomas with solitary/regional lesions, the most common treatment is local radiation therapy. Surgical treatment can be an option, but may result in wide, unnecessary scars.

Common treatments for CBCL include:

• Intralesional corticosteroids (applied directly into the lesion).
• Topical therapies (treatment applied to the skin), such as chemotherapy, bexarotene (Targretin), and imiquimod (Zyclara).
• Radiation therapy (applied directly to the lesions).

If lesions are very widespread and symptomatic, systemic therapies (treatment with drugs that travel through the bloodstream and reach all parts of the body) may be appropriate. This includes monoclonal antibodies like rituximab (Rituxan), with or without chemotherapy. Regular skin examinations are very important, especially for indolent CBCLs, as the skin is the most common site of new lesions. General laboratory tests may also be done, but imaging is not needed unless there is a concern of systemic (widespread) disease.

Relapsed and Refractory Indolent B-cell Lymphomas

Some patients with indolent B-cell lymphomas respond to initial treatment and go into remission. 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.

Marginal Zone Lymphoma (MZL)

New treatments for all MZL subtypes have been recently approved for relapsed disease. Lenalidomide (Revlimid), is an immunomodulatory oral (taken by mouth such as pills) medication that has been approved by the FDA for the treatment of patients with MZL who have received at least one prior therapy, and it is used in combination with rituximab (Rituxan), often referred to as R2 (R-squared). Recently, another BTK inhibitor called zanubrutinib (Brukinsa) was approval for use in adult patients with relapsed or refractory (does not respond to treatment) MZL after at least one prior anti-CD20-based regimen.

Although most gastric MALT lymphomas are indolent, if the lymphoma relapses or becomes refractory after antibiotic therapy, there are many additional treatment options available. This includes another round of antibiotic treatment, radiation, and immunotherapy with monoclonal antibodies targeting CD20 such as rituximab (Rituxan), alone or in combination with chemotherapy (chemoimmunotherapy).

Waldenström Macroglobulinemia (WM)

For more information on stem cell transplantation, view the Understanding Cellular Therapy guide.

Cutaneous B-cell Lymphoma (CBCL)

Treatment for relapse of indolent CBCL can include observation, surgery, topical treatments, injected steroids, or radiation (low-dose). Indolent CBCLs usually remain indolent and relapse in the skin. Very rarely, indolent CBCLs relapse as systemic disease, most commonly in regional lymph nodes. In extremely rare cases, indolent CBCLs can transform into more aggressive types of lymphoma. Relapsed aggressive CBCLs may be treated with chemotherapy (with or without rituximab), targeted therapies such as ibrutinib (Imbruvica), lenalidomide (Revlimid), radiation therapy, and/or radioimmunotherapy.

Table 1. Investigational Drugs for Marginal Zone Lymphoma, Waldenstrom’s Macroglobulinemia and Cutaneous B-cell Lymphoma

Agent (Drug)	Class (Type of treatment)	Type of Lymphoma
Loncastuximab Tesirine (Zynlonta)	Immunotherapy antibody-drug conjugate; anti-CD19	R/R MZL and R/R WM
Maplirpacept(TTI-622)	Immunotherapy; fusion protein	R/R CBCL
Mosunetuzumab (Lunsumio)	Immunotherapy; bispecific antibody	Untreated MZL and R/R MZL
Nemtabrutinib (MK-1026)	Targeted therapy; BTK inhibitor	R/R MZL and R/R WM
Nivolumab (Opdivo)	Immune checkpoint inhibitor; anti-PD-1 receptor	R/R MZL, R/R WM and R/R CBCL
Obinutuzumab (Gazyva)	Immunotherapy; monoclonal antibody, anti-CD20	Untreated MZL, R/R MZL and untreated WM
Ontorpacept (TTI-621)	Immunotherapy; fusion protein	R/R CBCL
Pirtobrutinib (Loxo-305)	Targeted therapy; BTK inhibitor	Untreated MZL, R/R MZL and R/R WM
Pembrolizumab (Keytruda)	Immune checkpoint inhibitor; anti-PD-1 receptor	Untreated MZL, R/R MZL, untreated WM and R/R CBCL
Polatuzumab vedotin (Polivy)	Immunotherapy; antibody-drug conjugate	Untreated MZL and R/R MZL
Tafasitamab (Monjuvi)	Immunotherapy; monoclonal antibody, anti-CD19	R/R MZL and R/R CBCL
Varlilumab (CDX-1127)	Immunotherapy; monoclonal antibody, anti-CD27	R/R CBCL
Venetoclax (Venclexta)	Targeted therapy; BCL2 inhibitor	Untreated MZL, R/R MZL and untreated WM
Selinexor (Xpovio)	Targeted therapy; XPO1 inhibitor	R/R MZL and R/R WM
Sonrotoclax (BGB-11417)	Targeted therapy; BCL2 inhibitor	Untreated WM and R/R WM
Zanubrutinib (Brukinsa)	Targeted therapy, BTK inhibitor	Untreated MZL and R/R CBCL

It is critical to remember that today’s scientific research is always evolving. Treatment options may change as new treatments are discovered, and current treatments are improved. Therefore, 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 all patients consult with a specialist to clear up any questions.

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.

 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 , and the Clinical Trials Search Request Form, 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].

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.

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 clinical trials available that are 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?