• Diffuse large B-cell lymphoma (DLBCL) is staged based on which lymph nodes and organs are involved. If the disease has spread, it’s considered more advanced.
• Advanced DLBCL is usually treated with a combination of chemotherapy and immunotherapy drugs.
• Radiation therapy and other drug options may be recommended in specific cases of advanced DLBCL.

As with many cancers, diagnosing diffuse large B-cell lymphoma involves staging to help determine its extent or spread. DLBCL is a fast-growing blood cancer and the most common subtype of non-Hodgkin lymphoma. DLBCL is staged based on where the cancer is found in the body. Knowing the stage helps doctors recommend the most effective treatment options. Although DLBCL grows quickly, it can respond well to treatment, especially when it’s targeted to the correct stage.

Staging DLBCL

DLBCL affects your lymphatic system — the group of organs that help your immune system fight infections and support healthy fluid levels in your body. DLBCL staging is based on where cancer cells are found in the lymphatic system. The cells may show up in the lymph nodes (small, infection-fighting structures located throughout the body). Lymphoma can also occur in lymphoid organs such as the thymus, spleen, and tonsils.​

DLBCL is divided into four stages, sometimes written with Roman numerals (e.g., stage I, stage IV):

• Stage 1 — Lymphoma is in one area of lymph nodes or one lymphoid organ. One node region refers to a node or a group of nodes next to each other.
• Stage 1E — Lymphoma starts in one organ outside the lymphatic system and is only in that extranodal (outside the lymph nodes) site. This is known as extranodal lymphoma. The organs in which DLBCL commonly starts outside the lymphatic system are the bones or bone marrow, brain or spinal cord, and gastrointestinal tract.
• Stage 2 — Lymphoma is in two or more lymph node regions in only the upper half (above the diaphragm) or lower half (below the diaphragm) of the body.
• Stage 2E — Lymphoma affects one organ outside the lymphatic system and is also in at least one group of lymph nodes in only the upper or lower half of the body.
• Stage 3 — Lymphoma is in lymph nodes in both the upper and lower halves of the body or only above the diaphragm but involves the spleen.
• Stage 4 — Lymphoma starts in a group of lymph nodes and has spread to additional extranodal sites.

Although some aspects of treatment are similar in DLBCL regardless of stage, the use of certain drugs or radiation varies by stage and prognosis (outlook). Doctors use a tool called the International Prognostic Index (IPI) to better understand the outlook for DLBCL.

The IPI helps determine how serious diffuse large B-cell lymphoma (DLBCL) is. It considers factors like your age, the stage of your lymphoma, whether organs outside the lymphatic system are involved, your performance status (how well you can do daily activities), and the level of lactate dehydrogenase (LDH) in your body. LDH is a protein in your blood that can increase as lymphoma progresses.

A higher IPI score means that the disease has a worse outlook. Factors that make DLBCL higher risk include age above 60 years, stage 3 or 4 disease, lymphoma in more than one organ outside the lymph nodes, low performance status, and a high LDH level.

Read more about prognosis and survival rates with DLBCL.

Treating Early-Stage DLBCL

DLBCL is considered early when it’s either stage 1 or 2. For the past 20 years, first-line (used as the first option) treatment of DLBCL has been a combination of drugs called R-CHOP. The R-CHOP regimen consists of:

• Rituximab (Rituxan)
• Cyclophosphamide (Cytoxan)
• Doxorubicin (Adriamycin)
• Vincristine (vincristine sulfate, formerly sold as Oncovin)
• Prednisone

Three to six cycles of R-CHOP treatment alone are generally considered an acceptable treatment for early-stage DLBCL. Each 21-day R-CHOP cycle includes five days of chemotherapy followed by a rest period. Per a 2021 study in the American Journal of Hematology, R-CHOP has the potential to cure disease in 60 percent of people with acquired DLBCL — cancer that doesn’t run in families.

Rituximab is a monoclonal antibody, a type of immunotherapy that has a specific treatment target and less toxicity (fewer side effects). Monoclonal antibodies act like the body’s naturally occurring antibodies — proteins in the immune system that mark other proteins for destruction by immune cells.

Cyclophosphamide, vincristine, and doxorubicin are standard chemotherapy drugs, which kill fast-growing cells. Although the main target is cancer cells, fast-growing healthy cells are also affected (healthy blood cells, hair, nails, mucous membranes). Death of healthy cells results in the side effects seen with standard chemotherapy.

Prednisone is a steroid, a type of drug that reduces inflammation — and therefore some of the side effects — by suppressing the immune system.

Treating Advanced Stage DLBCL

DLBCL is considered advanced when it’s either stage 3 or 4. Because DLBCL grows so fast, 60 percent to 70 percent of people have advanced DLBCL by the time they’re diagnosed. Treatment options include chemotherapy combined with immunotherapy (drugs that use the immune system to treat disease) and radiation therapy. Six rounds of R-CHOP are considered the first-line treatment for advanced DLBCL. This means it’s the first treatment option doctors recommend for this stage.

If your DLBCL doesn’t have a complete response (go away completely) after first-line chemotherapy, your oncologist will try other chemotherapy drug combinations, sometimes including rituximab.

Pola-R-CHP

The U.S. Food and Drug Administration (FDA) has approved Pola-R-CHP as another first-line treatment option for previously untreated advanced DLBCL. This drug combination consists of polatuzumab vedotin-piiq (Polivy) plus rituximab, cyclophosphamide, doxorubicin, and prednisone. Like rituximab, polatuzumab vedotin-piiq is a monoclonal antibody. The FDA based its approval on a 2022 clinical trial in which 879 people were treated with either Pola-R-CHP or R-CHOP.

In the study, the risks of death, relapse (return of a disease after initial improvement with treatment), and worsening of disease were lower in people receiving Pola-R-CHP. As with R-CHOP, six cycles of Pola-R-CHP are given to treat advanced DLBCL.

Read more about the risk of relapse in DLBCL.

Radiation Therapy

Although radiation therapy is commonly part of early-stage DLBCL treatment, it’s generally used only in specific cases of advanced disease. Based on available clinical trials, radiation therapy is recommended for people with DLBCL who have bulky disease.

Bulky disease refers to lymphoma in which the largest tumor is more than 10 centimeters wide. In DLBCL, radiation is sometimes used even when the largest tumor is more than 7.5 centimeters wide. If you have advanced DLBCL without bulky disease, you may be offered radiation if a small amount of disease has spread to your bones.

Chemotherapy To Prevent Central Nervous System Relapse

If you’re at increased risk of a DLBCL relapse, that may guide your doctor’s recommendations for treatment options. A higher IPI score means a higher risk of relapse.

Some people with DLBCL are more likely to have their disease relapse in the central nervous system (CNS), which consists of the brain and spinal cord. They may be offered a chemotherapy injection directly into the fluid around the spinal cord. To prevent CNS relapse, methotrexate, a chemotherapy drug that stops cancer cells from producing faulty DNA, is sometimes given in addition to chemotherapy.

Bone Marrow Transplant

For people who are younger and have high-risk DLBCL based on IPI score, a bone marrow transplant is a second-line treatment option. That said, bone marrow transplants are not known to work unless DLBCL improves with chemotherapy.

CAR T-Cell Therapy

If DLBCL relapses after first-line therapy or if the patient is not a good candidate for transplant, chimeric antigen receptor (CAR) T-cell therapy may be an option. CAR T-cell therapy trains the T cells in your immune system to recognize and destroy cancer cells. In CAR T-cell therapy, immune cells called T cells are collected from your blood, genetically engineered to recognize lymphoma cells, and returned to your body to fight cancer.

If you relapsed within one year of receiving R-CHOP therapy or have refractory disease, your oncologist may suggest CAR T-cell therapy. Some examples of CAR T-cell therapy include:

• Tisagenlecleucel (Kymriah)
• Axicabtagene ciloleucel (Yescarta)
• Lisocabtagene maraleucel (Breyanzi)

Bispecific Antibodies

In 2023, two bispecific antibodies were approved to treat relapsed/refractory DLBCL that hasn’t responded to other treatments. Bispecific antibodies are a new type of drug with two parts. One part of the drug recognizes and binds to cancer cells, while the other part attacks and kills the cancer cells.

Bispecific antibodies approved to treat relapsed or refractory DLBCL include:

• Epcoritamab-bysp (Epkinly)
• Glofitamab-gxbm (Columvi)

Other new drugs approved for DLBCL include loncastuximab tesirine-lpylm (Zylonta).

Clinical Trials

If you or someone you love has been diagnosed with advanced DLBCL, it may be worthwhile to get involved in a clinical trial. This is especially true if the cancer hasn’t responded to first-line or second-line treatment.

Based on discoveries about genetic changes in DLBCL, researchers are looking at new targeted therapies (treatments aimed directly at cancer cells) and immunotherapies (treatments that boost the body’s immune system). Doctors are also researching new ways to combine chemotherapy drugs for the best survival results. If you’re interested in learning more about clinical studies in which you may be eligible to participate, ask your oncologist for more information.

Talk With Others Who Understand

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