Treating B-Cell Non-Hodgkin Lymphoma

Diffuse large B-cell lymphoma (DLBCL)

DLBCL tends to grow quickly, but it can often be cured with treatment. It can be cured in more than half of all patients. However, the stage of the disease and the International Prognostic Index (IPI) score can have a large effect on this.

People with lower-stage DLBCL and with lower IPI scores tend to have better survival rates.

Initial treatment

Most often, the initial treatment for DLBCL includes multiple chemotherapy drugs along with the monoclonal antibody rituximab (Rituxan).

Four chemo drugs are usually used. These are known as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). Along with rituximab, this regimen is known as R-CHOP. It is most often given in cycles 3 weeks apart.

Other chemo regimens may be used instead for people with heart problems or other serious health issues.

Checking if treatment is working

Your cancer care team may get imaging tests, such as a PET/CT scan, to see how well treatment is working. This is usually done after several treatment cycles. The results can help guide how much more treatment is needed. 

Preventing spread to the brain and spinal cord

A small number of people with DLBCL have a higher risk of the lymphoma coming back in the brain or spinal cord. This risk depends on the location of the lymphoma and other risk factors, not just the stage.

For some people with this risk, doctors might suggest one of the following treatments:

• Chemo given into the spinal fluid (intrathecal chemotherapy)
• High doses of the chemo drug methotrexate given into a vein

But recent studies suggest these treatments may not lower the risk much, and they can cause side effects. Not all doctors recommend them. Talk with your cancer care team about your risk and whether this treatment makes sense for you.

If DLBCL doesn’t go away or comes back

The next treatment often depends on how soon the lymphoma comes back.

If the lymphoma doesn’t go away with initial treatment or comes back within about a year, it is less likely to respond to more chemo. CAR T-cell therapy is often the preferred next treatment. Studies have shown it helps people in this situation live longer than chemo followed by a stem cell transplant.

If the lymphoma comes back later, it is more likely to respond to chemo. Doctors will usually suggest another chemo regimen. If the lymphoma shrinks with this treatment, it might be followed by a stem cell transplant, if possible.

Stem cell transplants aren’t likely to be effective unless the lymphoma responds to chemo.

Unfortunately, not everyone is healthy enough for a stem cell transplant. CAR T-cell therapy may also be an option for some people, such as those who can’t have a transplant or whose lymphoma doesn’t respond to chemo.

Other options for DLBCL that keeps coming back or stops responding to treatment include bispecific antibodies (such as epcoritamab or glofitamab), other monoclonal antibodies or antibody-drug conjugates, and targeted drugs. These treatments are sometimes used together.

Clinical trials of new treatments may be another good option for some people.

Primary mediastinal B-cell lymphoma

This lymphoma starts in the mediastinum, the area in the middle of the chest behind the breastbone. It is most common in younger adults. 

Initial treatment

Treatment usually starts with chemo plus rituximab. 

• One treatment option is usually 6 courses of the CHOP chemo regimen plus rituximab (R-CHOP).
• Another option is 6 cycles of chemo with dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R).

Checking to see if radiation is needed

After chemo, a PET/CT scan is usually done to see if any active lymphoma remains in the chest. The results help decide whether you need radiation therapy to the chest.

• If the PET/CT shows no active lymphoma: You can usually be watched closely without more treatment, no matter which chemo regimen you had. Studies have found that skipping radiation in this situation doesn’t affect survival. It also avoids the long-term risks of chest radiation, such as heart problems and other cancers later in life.
• If the PET/CT still shows possible active lymphoma: You may need radiation. Before starting radiation, the doctor might order a biopsy of the chest tumor first, to confirm lymphoma is still there.

If lymphoma comes back or doesn’t respond to chemo

If the lymphoma comes back or does not respond to chemo, treatment options might include:

• Another chemo regimen, possibly with a stem cell transplant
• Some type of immunotherapy, such as CAR T-cell therapy
• An immune checkpoint inhibitor, such as pembrolizumab

Follicular lymphoma

Follicular lymphoma usually grows slowly and responds well to treatment, but it is very hard to cure. It often comes back after treatment, although this can take many years. 

Initial treatment or watchful waiting

Not everyone needs treatment right away.

If the lymphoma isn’t causing problems other than mildly swollen lymph nodes, doctors often recommend watching it closely instead. This is called watchful waiting or active surveillance. It might be years before treatment is needed, and some people never need it at all. 

After initial treatment

If the lymphoma shrinks or goes away with the initial treatment, doctors may recommend either close follow-up or maintenance therapy.

Maintenance therapy means continuing the monoclonal antibody (rituximab or obinutuzumab) every few months for up to 2 years. It can keep the lymphoma from coming back for longer, but studies have not shown that it helps people live longer. It can also cause side effects.

Talk with your cancer care team about whether this is right for you.

If follicular lymphoma doesn’t respond or comes back

There are many treatment options if follicular lymphoma doesn’t respond to first treatment or comes back later. The choice depends on what treatments you’ve already had, how long the lymphoma stayed away, and your overall health.

Options might include:

• Different chemo drugs combined with a monoclonal antibody
• Lenalidomide plus rituximab, sometimes combined with another antibody such as epcoritamab or tafasitamab
• Bispecific antibodies, such as epcoritamab or mosunetuzumab, given alone
• CAR T-cell therapy
• Targeted drugs, such as tazemetostat or zanubrutinib

If the lymphoma responds well to treatment, a stem cell transplant may be an option for some people. Clinical trials of newer treatments may also be a good option.

Follicular lymphoma that grows faster or changes

A small portion of follicular lymphomas grow quickly, more like DLBCL.  These used to be called grade 3B lymphomas. They are now often called follicular large B-cell lymphoma.

Follicular lymphoma can also change (transform) into DLBCL over time or come back as DLBCL.

These lymphomas are usually treated like DLBCL. To determine your best treatment options, your cancer care team will review any treatments you’ve already had.

Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are considered different versions of the same disease. The main difference is where the cancer cells are found. In CLL, most of the cancer cells are in the blood and bone marrow. In SLL, they are mainly in the lymph nodes and spleen.

CLL and SLL tend to grow slowly, but they are very hard to cure.

Treatment is similar for both SLL and CLL. This is described in more detail in Treating Chronic Lymphocytic Leukemia.

Initial treatment

If the lymphoma isn’t growing quickly or causing any problems, it can often be watched closely without treatment for a time. If treatment is needed, it depends on the stage.

If the lymphoma doesn’t respond or comes back

If the lymphoma doesn’t respond or comes back after initial treatment, options might include:

• A different targeted drug, such as switching from a BTK inhibitor to venetoclax, or the reverse
• Pirtobrutinib
• CAR T-cell therapy
• Less often, chemo or other drugs 

Mantle cell lymphoma (MCL)

Mantle cell lymphoma (MCL) has often spread widely by the time it’s found.

Initial treatment

In the past, MCL was harder to treat than some other lymphomas. But newer treatments have helped people live longer in recent years, especially treatment with targeted drugs called BTK inhibitors.

Some people have a slow-growing form of MCL. If it isn’t causing problems, doctors might recommend waiting on treatment. They might suggest watching the lymphoma closely at first and starting treatment only if it grows or begins to cause symptoms.

If MCL doesn’t respond or comes back

The next treatment often depends on whether you’ve already had a BTK inhibitor. Options might include:

• A BTK inhibitor such as acalabrutinib (Calquence) or zanubrutinib (Brukinsa), if you haven’t had one before
• Pirtobrutinib (Jaypirca), a different type of BTK inhibitor that may still work after other BTK inhibitors have stopped working
• CAR T-cell therapy with brexu-cel (Tecartus) or liso-cel (Breyanzi)
• Other drugs, such as venetoclax (Venclexta), bortezomib (Velcade), or lenalidomide (Revlimid), often combined with rituximab or with each other
• Chemotherapy with drugs other than those used initially, often along with rituximab
• Stem cell transplant might also be an option in some situations.

Later lines of treatment are not always helpful for MCL. Because of this, it might also be worth considering entering a clinical trial.

MALT lymphoma

You might also hear this type of lymphoma called extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (EMZL or MALT lymphoma).

MALT lymphomas start in tissues outside the lymph nodes. They usually grow slowly. Treatment depends largely on where the lymphoma starts. MALT lymphomas in the stomach (gastric) are often treated differently from MALT lymphomas in other parts of the body.

Gastric MALT lymphoma

Gastric (stomach) MALT lymphoma is often caused by long-term infection with H. pylori bacteria. The lymphoma often goes away when the infection is treated.  

Non-gastric MALT lymphoma

Non-gastric MALT lymphomas start in parts of the body other than the stomach. Common places include the salivary glands, lungs, skin, thyroid, breast, and the tissues around the eye. Treatment depends on where the lymphoma is and how much it has spread.

If the lymphoma isn’t growing or causing symptoms, it may be watched closely without treatment at first, as long as it isn’t likely to affect how an organ works.

If treatment is needed, options for early-stage lymphomas include:

• Radiation therapy to the area containing the lymphoma. For lymphomas in the tissues around the eye, a very low dose of radiation is often enough. This helps limit side effects.
• Surgery for lymphomas in certain places, such as the lungs, breast, thyroid, or intestines
• Rituximab alone if radiation isn’t a good choice

More advanced disease (stage IV) is generally treated the same as advanced-stage gastric MALT lymphoma and follicular lymphoma (see above). 

If MALT lymphoma doesn't respond or comes back

If gastric or non-gastric MALT lymphoma comes back after treatment, options might include:

• Rituximab, either alone or combined with chemo or lenalidomide (Revlimid)
• A targeted drug called a BTK inhibitor, such as zanubrutinib (Brukinsa)
• CAR T-cell therapy with liso-cel (Breyanzi), usually after at least 2 other treatments
• Radiation therapy to areas of lymphoma

If MALT lymphoma changes

MALT lymphoma can change into a fast-growing diffuse large B-cell lymphoma (DLBCL), although this is rare. When it happens, it is treated like DLBCL.

Nodal marginal zone lymphoma

This rare type of lymphoma is usually indolent, meaning it grows slowly. It often doesn’t need to be treated right away.

Initial treatment or watchful waiting

• If the lymphoma is not causing problems, it can often be watched closely without treatment at first.
• If treatment is needed, it is similar to treatment for follicular lymphoma, which also tends to grow slowly.

If you have a long-term HCV infection: Some people with this type of lymphoma also have a long-term infection with the hepatitis C virus (HCV). Treating the infection with antiviral drugs can sometimes cause the lymphoma to shrink or go away. Doctors may try this first to see if the lymphoma can be watched without treating it right away.

After initial treatment

If the nodal marginal zone lymphoma shrinks or goes away with the initial treatment, doctors may recommend either close follow-up or maintenance therapy.

Maintenance therapy means continuing rituximab every few months for up to 2 years. This can keep the lymphoma from coming back for longer. However, studies have not shown that it helps people live longer. It can also cause side effects. Talk with your cancer care team about whether this is right for you.

If the lymphoma doesn't respond or comes back

If the nodal marginal zone lymphoma doesn’t respond to the initial treatment or comes back later, options may include:

• Rituximab alone, with chemo, or with lenalidomide (Revlimid)
• A targeted drug called a BTK inhibitor, such as zanubrutinib (Brukinsa)
• CAR T-cell therapy with liso-cel (Breyanzi), usually after at least 2 other treatments
• Radiation therapy to areas of lymphoma

If the lymphoma responds to this treatment, a stem cell transplant may be an option.

If the lymphoma changes

Nodal marginal zone lymphoma can change into a fast-growing diffuse large B-cell lymphoma (DLBCL), but this is rare. If it happens, it requires more aggressive chemotherapy. See Treating DLBCL, above.

Splenic marginal zone B-cell lymphoma

This is typically a slow-growing lymphoma. If it isn’t causing symptoms like low blood cell counts or an enlarged spleen that causes discomfort, it is often watched closely without treating it right away.

Initial treatment

Some people with this type of lymphoma also have a long-term infection with the hepatitis C virus (HCV). If you are diagnosed with this lymphoma, you will be tested for HCV. Treating the HCV infection with antiviral drugs can cause the lymphoma to shrink or go away about half the time.

If that doesn’t work, or if you are not infected with HCV, treatment with rituximab alone is usually the preferred option.

Surgery to remove your spleen might be another option. This can be very helpful in relieving symptoms if the spleen is enlarged.

If the disease is more advanced or progresses, it’s usually treated with rituximab plus chemo. This is similar to the treatment used for advanced-stage follicular lymphoma, described above.

If the lymphoma comes back after treatment

If the lymphoma comes back after treatment, options might include:

• Rituximab, alone or with chemo or with lenalidomide (Revlimid)
• A targeted drug called a BTK inhibitor, such as zanubrutinib (Brukinsa)
• CAR T-cell therapy with liso-cel (Breyanzi), usually after at least 2 other treatments

This lymphoma can change into a fast-growing diffuse large B-cell lymphoma (DLBCL), but this is rare. If it happens, it is treated like DLBCL.

Burkitt lymphoma

Burkitt lymphoma tends to grow very fast. It needs to be treated right away, but it can often be cured with treatment. Treatment depends to some extent on whether the lymphoma is considered low risk or high risk. It also depends to some extent on a person’s age.

Initial treatment

Chemotherapy (chemo) is the main treatment for Burkitt lymphoma. The chemo is intense, so it is often given in the hospital. The monoclonal antibody rituximab is often part of treatment as well.

Some examples of chemo regimens used for Burkitt lymphoma include:

• Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dexamethasone), alternating with methotrexate and cytarabine (ara-C), plus rituximab
• CODOX-M (cyclophosphamide, vincristine [Oncovin], doxorubicin, and high-dose methotrexate), sometimes alternating with IVAC (ifosfamide, etoposide [VP-16], and cytarabine [ara-C]), plus rituximab
• DA-EPOCH-R, a dose-adjusted version of EPOCH (etoposide, prednisone, vincristine [Oncovin], cyclophosphamide, and doxorubicin), plus rituximab. This is less intense than the other chemo regimens. It may be an option for people who are older or have other health problems.

Surgery: Surgery isn’t usually part of treatment for this Burkitt lymphoma. However, this type of lymphoma often starts in the abdomen (belly), where it can sometimes block the bowel, especially in children. You might need surgery to fix a blocked bowel or get a biopsy.

Preventing spread to the cerebrospinal fluid

Burkitt lymphoma tends to spread to the area around the brain and spinal cord. Most treatment plans include chemo to help prevent or treat this. This often includes one or both of the following:

• Chemo given directly into the spinal fluid (intrathecal therapy)
• High-dose methotrexate given into a vein, which can reach the spinal fluid

People whose lymphoma has already spread to the spinal fluid usually need more intensive treatment.

Preventing tumor lysis syndrome

Because Burkitt lymphoma grows so fast, chemo can kill a large number of lymphoma cells very quickly. When this happens, the dying cells release substances into your blood that can harm your kidneys and heart.

This is called tumor lysis syndrome. Preventing it is an important part of the first treatment. You’ll get plenty of fluids, along with drugs such as allopurinol or rasburicase. You’ll also have blood tests often during the first days of treatment, to check for problems.

If the lymphoma doesn’t go away or comes back

If the lymphoma doesn’t go away or if it comes back after treatment, another chemo regimen might be tried. If the lymphoma goes into remission, the doctor might suggest a stem cell transplant.

Burkitt lymphoma that comes back can be hard to treat, so a clinical trial of newer treatments may be a good option.

Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia)

This lymphoma usually grows slowly. If it isn’t causing symptoms, it’s often watched closely without treatment at first.

If treatment is needed, options might include:

• Chemo and/or the monoclonal antibody rituximab
• A targeted drug called a BTK inhibitor, such as zanubrutinib (Brukinsa) or ibrutinib (Imbruvica)

To learn more, see Treating Waldenstrom Macroglobulinemia.

Hairy cell leukemia (HCL)

HCL is a slow-growing lymphoma that is mostly found in the bone marrow, spleen, and blood. People without symptoms often don’t need to be treated right away. Treatment is usually started if low blood cell counts or an enlarged spleen cause problems.

When treatment is needed, most often the chemo drugs cladribine (2-CdA) or pentostatin are used. Rituximab is often added to cladribine.  

To learn more, see Treating Hairy Cell Leukemia.

Primary central nervous system (CNS) lymphoma

Primary CNS lymphoma begins in the brain or spinal cord or sometimes the eyes (see Lymphoma of the Eye, below). It is most common in older people or in people with immune system problems, such as those who’ve had an organ transplant or have AIDS.

Steroid medicines can quickly shrink this lymphoma, which can make it harder to diagnose. If possible, doctors try not to give steroids until after a biopsy is done.

Treatment usually includes 2 phases, known as induction and consolidation.

Induction

Most chemo drugs used for lymphoma don't reach the brain when they are put into a vein (IV). This can be a problem for using chemo to treat primary CNS lymphoma.

For people in reasonably good health:

• High IV doses of the drug methotrexate have been shown to be the most effective treatment. To help limit serious side effects, this is given along with IV fluids and the drug leucovorin.
• High-dose methotrexate is usually combined with rituximab and other chemo drugs. For example, the MATRix regimen combines high-dose methotrexate with cytarabine, thiotepa, and rituximab. Other combinations might include drugs such as temozolomide.

If you cannot tolerate high-dose methotrexate, doctors may try less intensive chemo regimens or radiation therapy alone.

Radiation therapy to the brain isn’t usually part of the initial treatment, because it can cause long-term problems with thinking and memory, especially in older people. When radiation is used, doctors may limit the dose to try to lessen this problem.

Consolidation

A second round of treatment is often given to try to get rid of any remaining lymphoma cells in the body. This round is known as consolidation.

• For people who are healthy enough and whose lymphoma responds to induction, high-dose chemo followed by a stem cell transplant is often the preferred option.
• This has been shown to help people live longer than other types of consolidation. Other options might include chemo, radiation, or some combination of these.

If the lymphoma doesn’t go away or comes back

If CNS lymphoma keeps growing or comes back after treatment, further options may include:

• More chemo, sometimes high-dose methotrexate again or different drugs
• Targeted therapy
• Radiation therapy
• Stem cell transplant if you are healthy enough

Newer treatments are being studied, such as CAR T-cell therapy. A clinical trial may be a good option.

Your options will depend on the treatment you had before and how well the lymphoma responded to that treatment.

Treating primary intraocular lymphoma (lymphoma of the eye)

Primary CNS lymphoma sometimes starts inside the eye, in the retina or in the gel that fills the eye (the vitreous). When this happens, you might hear it called primary intraocular lymphoma or primary vitreoretinal lymphoma.

This type of lymphoma can also involve both the brain and the eye. If it starts only in the eye, it often spreads to the brain later. Because of this, regular brain imaging is an important part of follow-up.