Treating B-Cell Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma (NHL) is generally divided into 2 main types, based on whether it starts in B lymphocytes (B cells) or T lymphocytes (T cells).

There are many different types of B-cell lymphomas. Treatment usually depends both on the type of lymphoma and the stage (extent) of the disease, but many other factors can be important as well.

Diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) tends to grow quickly. Most often, the treatment is chemotherapy (chemo), usually with a regimen of 4 drugs known as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), plus the monoclonal antibody rituximab (Rituxan). This regimen, known as R-CHOP, is most often given in cycles 3 weeks apart. Because this regimen contains the drug doxorubicin, which can damage the heart, it may not be suitable for patients with heart problems, so other chemo regimens may be used instead.

Stage I and most stage II lymphomas

For DLBCL that is only in 1 or 2 lymph node groups on the same side of the diaphragm (the thin muscle that separates the chest from the abdomen), R-CHOP is often given for 3 to 6 cycles. This might be followed by radiation therapy to the affected lymph node areas, especially if the lymphoma is bulky.

Stages III, IV, and more advanced stage II lymphomas

First-line treatment options for these lymphomas include R-CHOP and Pola-R-CHP, which is a combination of the monoclonal antibodies polatuzumab vedotin and rituximab, and the chemo drugs cyclophosphamide, doxorubicin, and prednisone. Other regimens that include chemo and rituximab might be options as well.

After several cycles, doctors may get imaging tests such as a PET/CT scan to see how well treatment is working. People who have a higher risk of the lymphoma coming back later in the tissues around the brain and spinal cord may be treated with chemo injected into the spinal fluid (called intrathecal chemotherapy). Another option is to give high doses of methotrexate intravenously. (This drug can pass into the spinal fluid.)

For younger patients with a higher risk of the lymphoma coming back based on the International Prognostic Index (IPI) score, high-dose chemo followed by a stem cell transplant might be an option. But it’s not yet clear if transplants are better as the initial treatment. Most doctors feel that if a transplant is done as part of the first treatment, it should be done in a clinical trial.

If the lymphoma doesn’t go away completely with treatment or if it recurs (comes back) after treatment, doctors will usually suggest another chemo regimen. Several different regimens can be used, and they may or may not include rituximab. If the lymphoma shrinks with this treatment, it might be followed by a stem cell transplant if possible, as it offers the best chance of curing the lymphoma. Stem cell transplants are not effective unless the lymphoma responds to chemo. Unfortunately, not everyone is healthy enough for a stem cell transplant.

Other options for DLBCL that is no longer responding to chemo might include some type of immunotherapy (such as CAR T-cell therapy or a monoclonal antibody) or a targeted therapy drug such as selinexor (Xpovio).

DLBCL can be cured in about half of all patients, but the stage of the disease and the IPI score can have a large effect on this. Patients with lower stages have better survival rates, as do patients with lower IPI scores.

Primary mediastinal B-cell lymphoma

This lymphoma, which starts in the space between the lungs (the mediastinum), is treated like early stage diffuse large B-cell lymphoma. A common treatment is 6 courses of chemo with CHOP plus rituximab (R-CHOP). This may be followed by radiation to the mediastinum. Often a PET/CT scan is done after the chemo to see if there’s any lymphoma remaining in the chest. If no active lymphoma is seen on the PET/CT, the patient may be observed without further treatment. If the PET/CT scan is positive (shows possible active lymphoma), radiation may be needed. Sometimes, the doctor will order a biopsy of the chest tumor to confirm that lymphoma is still present before starting radiation.

Another treatment option is 6 cycles of chemo with dose-adjusted etoposide, doxorubicin and cyclophosphamide with vincristine, prednisone and rituximab (DA-EPOCH-R), which typically does not require any radiation.  

If the primary mediastinal B cell lymphoma comes back or does not respond to chemo, another chemo regimen (possibly with a stem cell transplant) or some type of immunotherapy such as CAR T-cell therapy or an immune checkpoint inhibitor may be an option.

Follicular lymphoma

This type of lymphoma often grows slowly and responds well to treatment, but it is very hard to cure. It often comes back after treatment, although it can take many years to do so. It’s not always clear if the lymphoma needs to be treated right away, especially if the lymphoma isn’t causing problems other than mildly swollen lymph nodes. Some people may never need treatment at all. For those who do, sometimes it might be years before treatment is needed.

Stage I and early-stage II

If treatment is needed for follicular lymphoma that is only in 1 lymph node group or in 2 nearby groups that are both above or below the diaphragm (the thin muscle separating the chest from the abdomen), the preferred treatment is radiation therapy to the lymph node areas affected by lymphoma (called involved site radiation). Other choices include treatment with chemo plus a monoclonal antibody (rituximab [Rituxan] or obinutuzumab [Gazyva]), or rituximab alone, which might be followed by radiation therapy.

Stages III, IV, and most stage II bulky lymphomas

If treatment is needed, the most common option is a monoclonal antibody (rituximab or obinutuzumab) combined with chemo. The chemo can be a single drug (such as bendamustine) or a combination of drugs, such as the CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CVP (cyclophosphamide, vincristine, prednisone) regimens.

If some lymph nodes are very large from the lymphoma, radiation may be used to reduce symptoms. This is most often used for patients who are too sick to be treated with chemo.

The radioactive monoclonal antibody ibritumomab (Zevalin) is also an option for initial treatment, although this is more often used as a second-line treatment.

For patients who may not be able to tolerate more intensive chemo regimens, rituximab alone, rituximab with milder chemo drugs (such as chlorambucil or cyclophosphamide), or rituximab with lenalidomide may be good options.

If the lymphoma shrinks or goes away with the initial treatment, doctors may advise either close follow-up or further treatment. This might include continuing the monoclonal antibody (rituximab or obinutuzumab) for up to 2 years, or treatment with ibritumomab. Further treatment may lower the chance that the lymphoma will come back later and may help some patients live longer, but it can also have side effects.

If follicular lymphoma doesn’t respond to the initial treatment or if it comes back later, it may be treated with different chemo drugs, targeted drugs, immunotherapy (such as CAR T-cell therapy or a monoclonal antibody), or some combination of these. If the lymphoma responds to this treatment, a stem cell transplant may be an option.

A small portion of follicular lymphomas, known as grade 3B lymphomas, tend to grow quickly, more like diffuse large B-cell lymphoma (DLBCL). Some follicular lymphomas can also change (transform) into or return as DLBCL. For these lymphomas, your doctor will review which treatments you may have already had to decide which is the next best treatment option.

Small lymphocytic lymphoma (and chronic lymphocytic leukemia)

Small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL) are considered different versions of the same disease. The main difference is where the cancer cells are (the blood and bone marrow for CLL, and the lymph nodes and spleen for SLL). CLL and SLL tend to grow slowly, but they are very hard to cure.

Treatment for SLL is similar to that of CLL, which is described in detail in Treating Chronic Lymphocytic Leukemia.

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

When the lymphoma is only in one lymph node or lymph node area (stage I), it may be treated with radiation therapy alone.

For more advanced disease, the treatment is often the same as what is used for CLL. (See Treating Chronic Lymphocytic Leukemia.) Chemo, with or without rituximab or obinutuzumab (Gazyva) is one option for first-line treatment. Chlorambucil, fludarabine, or bendamustine are some of the chemo drugs that are used. A targeted drug such as ibrutinib (Imbruvica) or acalabrutinib (Calquence) is another option, as is rituximab alone (without chemo). Which treatment is used depends on a person’s age and health, as well as on whether the cancer cells have certain chromosome changes.

If the lymphoma doesn’t respond or comes back after initial treatment, different chemo drugs, targeted drugs, and/or other monoclonal antibodies may be used as second-line treatment.

Mantle cell lymphoma

Mantle cell lymphoma (MCL) has often spread widely when it’s first found. Although it doesn’t usually grow as quickly as some other fast-growing lymphomas, it often doesn’t respond as well to treatment, either. However, some newer treatments have been shown to be helpful in recent years.

Initial treatment of MCL

If the lymphoma has only spread to 1 lymph node group or to 2 nearby groups on the same side of the diaphragm (stage I and some stage II), which is rare, it can sometimes be treated with radiation therapy. Another option is to treat with chemo plus rituximab.

MCL that has spread more widely when first diagnosed is usually treated with chemoimmunotherapy, which is a combination of chemo drugs plus an immunotherapy drug (most often rituximab).

When possible, the chemo treatment is intense, using regimens such as:

• Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin (Adriamycin), and dexamethasone, alternating with high-dose methotrexate plus cytarabine)
• “Dose-intensified” R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), alternating with rituximab and cytarabine
• RDHAP (rituximab, dexamethasone, cytarabine, and cisplatin)

If the lymphoma responds well to these initial treatments, a stem cell transplant may be a good option. This is often followed by rituximab for several years.

Less intense chemo regimens, such as bendamustine with rituximab, may be used for people who are older or who have other health issues.

Some targeted drugs, such as bortezomib (Velcade), have been shown to be active against MCL as well, so one of these drugs might be included in the initial treatment.

Later lines of treatment for MCL

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

• A targeted drug, such as acalabrutinib (Calquence), zanubrutinib (Brukinsa), pirtobrutinib (Jaypirca), bortezomib (Velcade), or venetoclax (Venclexta). Sometimes a combination of 2 targeted drugs might be used, or a targeted drug might be combined with rituximab.
• Chemotherapy (with different drugs than those used initially), often with rituximab
• Immunotherapy drugs such as lenalidomide (Revlimid) plus rituximab
• CAR T-cell therapy with brexu-cel (Tecartus), usually after other treatments have been tried

A stem cell transplant might also be an option in some situations.

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

Extranodal marginal zone B-cell lymphoma – mucosa-associated lymphoid tissue (MALT) lymphoma

Gastric (stomach) MALT lymphoma, the most common type, often occurs as a result of a chronic infection with the bacterium H. pylori, and it often responds to treatment of the infection. Because of this, gastric lymphomas are treated differently from other lymphomas in this group.

Stages I and II gastric lymphoma in people who test positive for H. pylori

Early-stage gastric MALT lymphomas are treated with antibiotics combined with drugs that block acid secretion by the stomach (called proton pump inhibitors). Usually the drugs are given for 10 to 14 days. This may be repeated after a couple of weeks. Examination of the stomach lining using upper endoscopy (where a flexible tube with a viewing lens is passed down the throat and into the stomach) is then repeated at certain intervals to see if the H. pylori is gone and if the lymphoma has shrunk.

About 2 out of 3 of these lymphomas go away completely with antibiotic treatment, but it can sometimes take several months to be effective. In cases where symptoms need to be relieved before the antibiotics take effect or where antibiotics don’t shrink the lymphoma, radiation therapy to the area is often the preferred treatment. The monoclonal antibody rituximab may be another option.

Stages I and II gastric lymphoma in people who test negative for H. pylori

For these early-stage gastric MALT lymphomas, treatment is usually either radiation therapy to the stomach or rituximab.

Stage III or IV gastric lymphoma

For more advanced gastric MALT lymphomas, which are rare, treatment is often similar to that for follicular lymphoma (see above). Lymphomas that are not growing quickly may be watched and not treated right away. If the lymphoma is large, is causing symptoms, or is growing, it can be treated with radiation therapy to the stomach, rituximab, chemo, chemo plus rituximab, or a targeted drug such as zanubrutinib (Brukinsa). The chemo drugs used are the same as those used for follicular lymphoma, and may include single agents such as chlorambucil or fludarabine or combinations such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CVP (cyclophosphamide, vincristine, prednisone).

Non-gastric MALT lymphoma

For MALT lymphomas that start in sites other than the stomach (non-gastric lymphomas), treatment depends on the location of the lymphoma and how much it has spread. Early-stage lymphomas can often be treated with radiation to the area containing the lymphoma. In certain sites (such as the lungs, breast, or thyroid), surgery may be an option. For more advanced disease (stage III or IV), treatment is generally the same as for stage III and IV gastric MALT lymphoma and follicular lymphoma (see above).

Nodal marginal zone B-cell lymphoma

This rare type of lymphoma is generally slow growing (indolent), and it often doesn’t need to be treated right away. If it does need treatment, it is usually treated the same way as follicular lymphoma (which also tends to grow slowly).

Stage I and early-stage II

If treatment is needed for lymphoma that is only in 1 lymph node group or in 2 nearby groups on the same side of the diaphragm (the thin muscle separating the chest from the abdomen), the preferred treatment is radiation therapy to the lymph node areas affected by lymphoma (called involved site radiation). Other choices include treatment with rituximab (Rituxan), chemo, or both, which might be followed by radiation therapy.

Stages III, IV, and most stage II bulky lymphomas

If treatment is needed, the most common option is rituximab combined with chemo. The chemo can be a single chemo drug (such as bendamustine or fludarabine) or a combination of drugs, such as the CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CVP (cyclophosphamide, vincristine, prednisone) regimens. If the lymphoma shrinks, a total of 6 cycles of chemo plus rituximab is usually given.

Other options for initial treatment include rituximab alone or chemo alone (either one or several drugs). If some lymph nodes are very large from the lymphoma, radiation may be used to reduce symptoms. This is most often used for patients who are too sick to be treated with chemo.

The radioactive monoclonal antibody ibritumomab tiuxetan (Zevalin) is also an option for initial treatment, although this is more often used as a second treatment.

For patients who may not be able to tolerate more intensive (stronger) chemo regimens, rituximab alone, milder chemo drugs (such as chlorambucil or cyclophosphamide), or both may be good options.

If the lymphoma shrinks or goes away with the initial treatment, doctors may advise either close follow-up or further treatment. This might include either rituximab for up to 2 years or treatment with ibritumomab tiuxetan. Further treatment may lower the chance that the lymphoma will come back later and may help some patients live longer, but it can also have side effects.

If the lymphoma doesn’t respond to the initial treatment or if it comes back later, it may be treated with different chemo drugs, immunotherapy, targeted drugs, or some combination of these. If the lymphoma responds to this treatment, a stem cell transplant may be an option.

Nodal marginal zone B-cell lymphoma can also change into a fast-growing diffuse large B-cell lymphoma (DLBCL), which would require more aggressive chemotherapy (see above).

Splenic marginal zone B-cell lymphoma

This is typically a slow-growing lymphoma. If it is not causing symptoms, it is often watched closely without treating it right away.

About 1 in 3 people with this type of lymphoma have chronic hepatitis C virus (HCV) infection. Treating the infection with anti-viral drugs can often cause these lymphomas to go into remission.

If that doesn’t work, or if a person isn’t infected with HCV, surgery to remove the spleen can sometimes lead to a long-term remission. This can be very helpful in relieving symptoms if the spleen is enlarged. Treatment with rituximab may be another option.

If the disease is more advanced or progresses, it’s usually treated with chemo with or without rituximab (similar to what is used for advanced stage follicular lymphoma, which is described above). Another option might be a targeted drug such as zanubrutinib (Brukinsa), or rituximab with lenalidomide.

Sometimes this lymphoma can transform into an aggressive large-cell lymphoma, which then requires more intensive chemo.

Burkitt lymphoma

This is a very fast-growing lymphoma that is similar to a type of acute lymphocytic leukemia. It is usually treated in the hospital with intensive chemo, which usually includes at least 5 chemo drugs. Rituximab may also be added. Some examples of chemo regimens used for this lymphoma include:

• Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dexamethasone), alternating with methotrexate and cytarabine (ara-C)
• CODOX-M (cyclophosphamide, vincristine [Oncovin], doxorubicin, and high-dose methotrexate), alternating with IVAC (ifosfamide, etoposide [VP-16], and cytarabine [ara-C])
• EPOCH (etoposide, prednisone, vincristine [Oncovin], cyclophosphamide, and doxorubicin)

Because this lymphoma tends to invade the area around the brain and spinal cord, the chemo drug methotrexate is often given into the spinal fluid (called intrathecal therapy). This may not be needed if high-dose methotrexate is given as a part of the main chemotherapy regimen.

An important part of the initial treatment of this disease is making sure a person gets plenty of fluids, as well as drugs like allopurinol, to help prevent tumor lysis syndrome (described in Chemotherapy for Non-Hodgkin Lymphoma).

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.

Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia)

The main treatment for this lymphoma is usually chemo or rituximab. For more detailed information see Treating Waldenstrom Macroglobulinemia.

Hairy cell leukemia

This is a slow-growing lymphoma that tends to invade the spleen and lymph nodes as well as the blood. Patients without symptoms often don’t need to be treated right away. When treatment is needed, most often the chemo drugs cladribine (2-CdA) or pentostatin are used. For more detailed information, see Treating Chronic Lymphocytic Leukemia.

Primary central nervous system (CNS) lymphoma

This lymphoma begins in the brain or spinal cord. It often develops in older people or those with immune system problems caused by AIDS or drugs given to keep transplanted organs from being rejected.

Most patients are treated with chemo and/or radiation. One problem with treating this disease is that most chemo drugs commonly used to treat lymphoma don’t reach the brain when given intravenously (IV). For people in reasonably good health, high IV doses of the drug methotrexate have been shown to be the most effective treatment. This is given along with the drug leucovorin and IV fluids, which help limit serious side effects. Other chemo drugs, such as cytarabine, may be added. Rituximab may be added as well. For those who aren’t able to tolerate this treatment, other, less intensive chemo regimens or radiation therapy alone may be tried.

An issue with radiation therapy to the brain, especially in older patients, is that it can often cause mental changes. Doctors limit the dose of radiation to try to lessen this problem.

If CNS lymphoma keeps growing or comes back after treatment, further options may include chemo (using different drugs), radiation therapy, or a stem cell transplant if the person is healthy enough.

Primary intraocular lymphoma (lymphoma of the eye)

Most often doctors treat these cancers with radiation therapy, chemotherapy (chemo), or a combination of the two.

External beam radiation therapy is given if the cancer is limited to the eye. Radiation to both eyes may be recommended if lymphoma is found in both eyes. Because these lymphomas are commonly linked with lymphoma of the brain (CNS lymphoma), they have sometimes already spread outside the eye or to the brain when the cancer is first diagnosed. If this is the case, radiation therapy to the brain and spinal cord may be included because it can help prevent the lymphoma from spreading there or help destroy cancer cells that are there but haven’t been seen by imaging. Problems with thinking, concentration, and memory are possible side effects from radiation to the brain and spinal cord.

Depending on the type of lymphoma, chemo may be used alone or in combination with radiation therapy, especially if it has grown outside the eye or spread to other places in the body. Chemo can be given into a vein (systemic chemo), directly into the cerebrospinal fluid (intrathecal chemo), or directly into the eye (intraocular chemo). Intraocular chemo gets higher doses of the drug to the tumor without causing severe side effects in other parts of the body. Methotrexate is the most commonly used chemo drug, but others can be used as well. Monoclonal antibodies such as rituximab may also be given directly into the eye. The best combination and dosage of drugs is not yet known, and the choice may be influenced by the type of lymphoma. Sometimes systemic chemo may be given along with therapy given directly to the eye such as external radiation or intraocular chemo.

If the lymphoma does not respond to treatment or if it comes back (recurs), high-dose chemotherapy followed by a stem cell transplant may be an option for some people.