Diffuse large B-cell lymphoma (DLBCL) is an aggressive, fast-growing type of non-Hodgkin lymphoma (NHL), and is the most common form of NHL worldwide. Every year, more than 25,000 new cases of DLBCL are diagnosed in the U.S. The condition accounts for around 31 percent of all NHL cases.

Diffuse large B-cell lymphoma can occur at any age, but most people with DLBCL are over 60 years old at the time of diagnosis.

To better understand diffuse large B-cell lymphoma, MyLymphomaTeam spoke with Dr. Timothy Fenske, a hematologist and medical oncologist who specializes in lymphoma. Dr. Fenske is a clinician and researcher at Froedtert Hospital in Milwaukee, Wisconsin. Innovative oncology treatments for aggressive NHLs, such as DLBCL, are among Dr. Fenske’s areas of expertise and he is involved in the design and execution of numerous clinical trials.

“For our most common type of lymphoma — diffuse large B-cell lymphoma — there have been several new drug approvals really just in the last year, and new cellular therapy options in the past few years,” he said. “It’s very exciting to have those options increasingly available to patients.”

Subtypes of Diffuse Large B-Cell Lymphoma

DLBCL is a blood cancer that affects B lymphocytes — or B cells — a type of white blood cell and part of the immune system. Healthy B cells produce antibodies that fight viruses and microbial pathogens, such as bacteria and fungi. B cells are produced in the bone marrow. They mature in the lymph nodes, where they are activated to fight infection, and then migrate throughout the lymphatic system.

DLBCL develops in lymph nodes, but approximately 40 percent of DLBCL cases are extranodal — outside of lymph nodes and the lymphatic system — and develop in the gastrointestinal system, testes, thyroid, skin, breast, bone, brain, or other soft tissues. DLBCL causes B cells to grow rapidly and uncontrollably into abnormally large tumorous cells that no longer function properly against infection. Because DLBCL is highly aggressive, it can be fatal if not treated.

There are two main subtypes of DLBCL, based on differences in lymphoma cells at the molecular level:

• Germinal center B cell (GCB) — Occurs in developing B cells
• Activated B cell (ABC) — Occurs in activated B cells, and does not respond well to standard therapies for DLBCL

Additional subtypes that have distinct features, and may be treated differently, include:

• Double-expressor DLBCL — Characterized by a co-expression of the MYC and BCL2 proteins in immunohistochemistry genetic lab tests
• Double-hit or triple-hit DLBCL — Characterized by various rearrangements of MYC and BCL2 genes in double-hit, and by MYC, BCL2, and BCL6 genes in triple-hit
• Primary extranodal DLBCL — Includes primary DLBCL of the central nervous system, originating outside the lymphatic system
• Primary mediastinal B-cell lymphoma — A rare type of DLBCL that typically affects adolescents and young adults and mainly affects the mediastinum (the space between the lungs)
• Epstein-Barr virus (EBV)-positive DLBCL of the elderly — Typically occurs in people over age 50
• DLBCL not otherwise specified (NOS) — Describes a large number of conditions not designated as a specific subtype and accounts for 25 percent to 30 percent of adult NHL cases in Western countries
• HIV-associated DLBCL — A type of DLBCL related to HIV
• Posttransplant DLBCL — Typically occurs following solid organ or bone marrow transplantation

Symptoms of Diffuse Large B-Cell Lymphoma

The most common symptom of DLBCL is painless swelling of lymph nodes in the armpits, neck, abdomen, or groin. DLBCL symptoms can appear quickly, and swollen lymph nodes can rapidly grow over the course of a few weeks. Approximately 1 in 3 people with DLBCL experience associated symptoms such as:

• Fever
• Night sweats
• Unexpected weight loss
• Fatigue
• Severe itching

The symptoms of DLBCL can mimic other diseases, particularly autoimmune conditions, Dr. Fenske said. “It can be challenging in some cases to get the diagnosis sorted out,” he said. “Sometimes it's a very winding road where they may have had very nonspecific symptoms such as rash, itching, fatigue, weakness, pain in various areas, or a whole constellation of different symptoms. This can lead to difficulty with getting the diagnosis pinned down.”

Diagnosis of Diffuse Large B-Cell Lymphoma

When DLBCL is suspected, a CT scan is conducted to determine the site, or sites, of the disease. A biopsy is needed to confirm the diagnosis. Excisional biopsy is considered the most reliable form of diagnosis, and involves cutting out an entire lymph node for a laboratory analysis known as immunophenotyping, which determines the B-cell type.

“One of the first priorities for someone who's newly diagnosed with DLBCL is to make sure that the diagnosis is right,” said Dr. Fenske. “Being able to say ‘Yes, in fact this is lymphoma and this is the exact type.’ In some cases, this can be difficult and may even require more than one biopsy. It is always a good idea to obtain a second opinion on the pathology reading, especially if there is any uncertainty about the diagnosis.”

Staging of the Disease

Diagnosis of DLBCL is typically categorized according to the Ann Arbor Staging System, which designates the progression of the disease, along with symptoms and extranodal sites affected.

• Stage 1 — A single lymph node region is affected, and/or a single extralymphatic organ or site is affected
• Stage 2 — Two or more lymph node regions on same side of the diaphragm are affected, and/or a nearby extralymphatic organ or site on the same side of the diaphragm is affected
• Stage 3 — Lymph node regions on both sides of the diaphragm are affected, and/or the lymphoma is in the spleen
• Stage 4 — The lymphoma has spread to at least one organ beyond the lymphatic system

Treatment Options

Many people are anxious about starting treatment, Dr. Fenske said. “Their fear of the unknown really drives anxiety,” he explained. However, that usually subsides after treatment begins. “Then it's just a matter of defining a specific treatment plan and sticking to it,” he added.

Anxiety may creep up again after treatment is completed, Dr. Fenske noted. “Maybe they're still dealing with some leftover side effects,” he said. “Maybe getting back into the swing of things at work, or with the family, has been a lot harder than they expected. Sometimes people need to see a counselor, or maybe medication can help some people get through, or meditation. There are lots of different strategies people use to adjust to what often feels like a ‘new normal.’”

R-CHOP Chemotherapy

Approximately 60 percent of DLBCL cases are now cured due to treatments that include monoclonal antibodies, bioengineered versions of antibodies made by the immune system that target cancer cells. Chemotherapy regimens, combined with immunotherapy drugs, have become the standard treatment for DLBCL, according to Dr. Fenske. “There are a lot of exceptions to that, but that's the typical course.”

Most people with DLBCL will get a five-drug chemoimmunotherapy regimen, known as R-CHOP. This regimen combines an immunotherapy drug with three standard chemotherapy drugs and a corticosteroid, typically:

• Rituxan (Rituximab)
• Cytoxan (Cyclophosphamide)
• Adriamycin (Doxorubicin)
• Oncovin (Vincristine)
• Prednisone, a corticosteroid

A course of R-CHOP is typically administered slowly via IV for five days, over six cycles, said Dr. Fenske. “Most patients will get that regimen on an outpatient basis every three weeks,” he noted. “It takes most of the day to infuse these drugs.”

Potential side effects of R-CHOP chemotherapy may include:

• Fever
• Chills
• Itching
• Lightheadedness
• Fatigue
• Hair loss
• Poor appetite
• Nausea or vomiting
• Diarrhea
• Infertility

It’s important to talk to your doctor about side effects. Fatigue in particular is a gnawing problem for many people with DLBCL.

“Fatigue can be a challenge,” said Dr. Fenske. “It can be a symptom of lymphoma. It can be a side effect of treatment. It can also be a sign of other problems that may be related or unrelated, if someone's depressed. We spend a fair amount of time talking about that. In most cases, it’s better to address these concerns head on, rather than to suffer in silence or just hope it will magically get better,” he said.

Not everyone tolerates R-CHOP well, and other chemoimmunotherapy combinations may be used instead. For example, the chemotherapy drug Etopophos (Etoposide) may be used instead of Adriamycin.

Radiation Therapy

Radiation therapy may be used in combination with chemoimmunotherapy when tumors are localized in early stage DLBCL. Radiation is also sometimes used among the 30 percent to 40 percent of DLBCL cases that relapse following chemotherapy. During this treatment, a focused beam of radiation is aimed at the area affected from outside of the body. Side effects may include:

• Skin dryness, itching, blistering, or peeling
• Fatigue
• Late effects, such as the development of another cancer

Stem Cell Transplantation

Autologous stem cell transplants can be effective for some people with DLBCL. During this treatment, healthy stem cells are removed from the body of the person undergoing treatment. They are then reintroduced to replace the bone marrow that has been damaged by chemotherapies and radiation, and to help rebuild the immune system. Stem cell transplantation is sometimes referred to as bone marrow transplantation.

There are usually relatively few immediate side effects from autologous stem cell transplantation, but some people may experience one or more of the following:

• A funny taste in their mouths
• Hives
• Headache
• Coughing
• Chest tightness
• Weakness

CAR-T Cell Therapy

For people who do not fully respond to chemoimmunotherapy, or who relapse after a stem cell transplantation, chimeric antigen receptor (CAR)-T cell therapy is a new treatment that has shown very promising results in treating DLBCL.

“It's been a very exciting several years in the field of oncology in general, but specifically within lymphoma, there's been a lot of activity,” said Dr. Fenske. “In the last few years, we've really gotten a lot into this new, exciting immunotherapy called CAR-T cell therapy. In some cases, the results have been truly remarkable.”

CAR-T cell therapy harnesses T cells — a type of white blood cells — sourced from the person undergoing treatment. First, T cells are extracted from blood. The T cells are then genetically modified to add a custom-made receptor that will target cancer cells. The CAR-T cells are then infused back into the blood.

Side effects can be serious if too many CAR-T cells proliferate in the body. Excess CAR-T cells can result in an overproduction of cytokines, inflammatory proteins produced by the immune system. Excess cytokines can cause symptoms like high fever and low blood pressure. But doctors have learned to recognize this situation early and can treat it if it occurs.

Prognosis for DLBCL

Since 1993, the International Prognostic Index (IPI) has been used to assess how aggressive a case of DLBCL is likely to be and predict the prognosis. With the advancement of immunotherapy treatments, the index was first updated to the revised International Prognostic Index (R-IPI), and later to an enhanced IPI that draws on the National Comprehensive Cancer Network (NCCN) database.

The NCCN-IPI is now considered the most effective clinical tool for assessing the prognosis of people with DLBCL. Risk factors considered during assessment include age, stage of disease, the results of certain blood tests, and which locations in the body are affected by lymphoma. This prognostic factor helps doctors recommend the best course of treatment for each case of DLBCL.

Learning and Participating in Treatment Decisions

While the complexity of the condition can be daunting, Dr. Fenske encourages people with DLBCL to take time to understand it.

“It's important that the patient participate in the decision-making,” he said. “That's where things have moved with medicine in our country. It's good that we have a more collaborative approach now. Of course, as the treating physician, I will give the patient my recommendations. However, I do believe it is very important to factor in the patient’s goals for treatment, how willing they are to risk side effects, and their current living situation. For example, if the patient is 80 years old and lives three hours away from our facility, a treatment that requires weekly follow-up visits may not be a good fit.”

His other advice is for people with DLBCL to be open to taking part in clinical trials. “Every blockbuster drug that we have now was in trials at some point,” Dr. Fenske noted. “There were patients who really benefited from being on those trials, in addition to all the patients who came after them. Everyone benefits from the knowledge gained during trials.”

He also dispelled the idea that clinical trials should only be considered as a last resort. “For many patients, a clinical trial may actually be their best treatment option,” he said. “Clinical trials are not just for cases in which all other treatment options have been tried — this is a misconception that I find many patients have.”

Connect With Others Who Understand

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