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Diffuse Large B-Cell Lymphoma (DLBCL)

Diffuse large B-cell lymphoma (DLBCL) is derived from white blood cells that grow in an uncontrolled, rapid manner and therefore require treatment. It is the most common form of lymphoma, comprising more than 25 percent of all lymphomas reported in the US (more than 25,000 cases of DLBCL diagnosed per year). While much progress has been made in treating the disease, many, but not all patients benefit from these treatment options and more work remains to be done. LLS has been at the forefront of advancing most of the therapies approved to treat DLBCL, and continues to support research to pursue new approaches to treatment, including immunotherapies and molecularly targeted therapies.

These cancerous white blood cells enlarge the lymph nodes and frequently migrate to the spleen, liver, bone marrow or other organs. In addition, patients with DLBCL often experience so-called “B-symptoms”, characterized by fever, night sweats, fatigue, and weight loss. For many patients, DLBCL may be the initial diagnosis. For other patients, an indolent lymphoma, such as follicular lymphoma, chronic lymphocytic leukemia, or extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) transforms and becomes DLBCL. DLBCL is the most common non-Hodgkin's lymphoma.

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Therapies for Newly-Diagnosed Patients

Fortunately, effective therapies are available for many, but not all, DLBCL patients. Typically, patients are treated initially with a standard therapy known as R-CHOP, which stands for  the antibody rituximab, or other similar antibodies that bind to the protein called CD20, plus cytotoxic chemotherapy. This regimen is highly effective in about 60 percent of patients and can eradicate the disease.

Such patients may be considered cured, although they still require vigilant follow up to monitor if the disease returns many years later or if they experience secondary effects of the therapy. Therapy with R-CHOP was developed more than two decades ago and remains the mainstay for most DLBCL patients.

The remaining 40% of patients treated with R-CHOP or similar therapy will experience either will fail to respond or transiently respond followed by a relapse. Relapsed/refractory DLBCL (R/R DLBCL) is more difficult to treat, but therapeutic alternatives have been approved by the FDA or are in late-stage clinical trials. LLS maintains an up-to-date list of trials and outcomes of the most promising therapies for patients with R/R DLBCL and can be provided by contacting LLS.


Therapies for patient with Relapsed / Refractory DLBCL

There are three FDA-approved therapies to treat R/R DLBCL.

The first two are called chimeric antigen receptor (CAR) T-cell therapy. CAR-T was developed with the over 20 years of support (greater than $50 M) for research and development by LLS, and further improvements continue to be developed with the support from LLS. In this therapy, the patient’s own normal (non-cancerous) immune cells, called T-lymphocytes, are purified from the blood. The T cells are then genetically engineered in the laboratory over a 14-20 day period to produce a protein that can detect a cell surface makers on the lymphoma cell surface called CD19. When these engineered cells are injected back into the patient they will home in and bind to the tumor cell. Once the binding occurs, the T cells will dramatically and rapidly multiply and kill the tumor cell.

Two products, known as axicabtagene ciloleucel (Yescarta ®) and tisagenlecleucel (Kymriah ®), are FDA-approved CD19 CAR T-cell therapies. These products produce a response in 70-80 percent of R/R DLBCL patients. In the case of Yescarta, the remissions can be sustained in approximately 50% of the patients for more than three years and possibly longer. It is still too early to know how long these remissions will last. This cellular therapy is not devoid of toxicity. It typically causes an immune activation known as “cytokine release syndrome” (CRS) that manifests as multiple symptoms including fever, fatigue, cardiac dysfunction that, in some serious cases, requires medical intervention. Neurotoxicity, manifesting as confusion, delirium, seizures or other symptoms, can also occur. Both CRS and neurotoxicity typically occur days after administration of T cells and reduce in intensity within weeks after administration of cells.

A second FDA-approved therapy for R/R DLBCL is the use of an antibody, which binds to the surface of DLBCL cells, and is attached to a cellular toxin.  This antibody-drug conjugate (ADC) therapy was initially developed for the treatment of leukemias more than 20 years ago and supported by LLS. The new ADC, known as polatuzumab vedotin, is designed to be used with bendamustine, another cellular toxin given intravenously. Approximately 50% of R/R DLBCL patients will experience significant tumor shrinkage that promotes survival in 50% of patients for 20 months.

Experimental Therapies for R/R DLBCL

Numerous experimental therapies are in clinical development for the treatment of R/R DLBCL. Beyond this, exploration of newly-approved therapies as first-line therapy are under way  because they may achieve a high response rates that have reduced toxicity compared to R-CHOP.

The most promising experimental therapies include new antibodies, combination therapies with drugs approved for other blood cancers, as well as application of certain therapies to distinct segments of DLBCL patients based on the molecular subtypes. While the list of some 20 new therapies is too numerous to describe here, a few of the most promising therapies are worth mentioning.

Bispecific antibodies have the ability to bind to the tumor cell and the T cell at the same time. Hence, this product acts in a similar fashion to CAR-T cells, except no cellular manufacturing is needed. The product binds to the same surface marker as rituximab (CD20) and is attached to another antibody that binds T cells. High response rates have been achieved with CD20 bispecific antibodies, although it is still too early to know how long responses will be sustained.

Other antibody therapy with encouraging results include magrolimab and tafasitamab, which have been combined with rituximab and lenalidomide (used to treat myeloma), respectively, in R/R DLBCL patients.  LLS is supporting the development of magrolimab through our Therapy Acceleration Program. The use of a more potent form of the anti-CD20 rituximab antibody, known as obinutuzumab (which is approved to treat chronic lymphocytic leukemia and follicular lymphoma) is also being explored in R/R DLBCL patients, although there was no benefit when used as a replacement for rituximab in newly diagnosed DLBCL patients.

There are two major types of DLBCL known as germinal center B-cell and activated B-cell (ABC). The ABC type of DLBCL is associated with hyperactivation of Bruton’s tyrosine kinase (BTK). Since BTK inhibitors have already been approved to treat other blood cancers, most notably CLL, the use of ibrutinib, an oral medication, given either alone or in combination with other approved therapies is being explored. While the use of ibrutinib monotherapy has been disappointing, combination therapies with BTK inhibitors is encouraging. ABC-type DLBCL also have activation of the so-called PI3K delta enzyme.  PI3K delta inhibitors have already been approved for mantle cell lymphoma and are currently being explored in DLBCL when used in combination therapy.

The Future of DLBCL Therapy

To advance our agenda, LLS has more than 20 active grants and two venture philanthropy-funded biotechnology companies that have a major focus on DLBCL. This represents a $25 million commitment over the next three to five years. Our support ranges from basic research to clinical trials.  Beyond this, since a greater understanding of all blood cancers are likely to be relevant to DLBCL, LLS brings to forefront its entire ~200 active grant portfolio, which represents more than a $200 million commitment (over approximately three to five years) to blood cancer research. Further discussion of these programs can be provided upon request.

A molecular understanding of DLBCL will be critically important for the development new therapies. It will enable us to better predict who will do best on particular therapies and justify rational drug combinations for the right patients. The most substantial latest advances on the molecular basis of this disease include:

  1. Characterization of the mutations in more than 1,000 DLBCL patients as well as description of the immune environment of cells that surround the malignant cells. This research is expected to lead to new therapies and increase our understanding why therapies can fail.
  2. Further subdivision of DLBCL into five classes using sophisticated computational analysis of multiple molecular alterations in DLBCL. This will justify new therapeutic combinations.
  3. Detection of molecular alterations due to DLBCL within the blood of patients leading to early detection of disease relapse months before detection by radiological methods. The use of liquid-biopsy have the potential to transform treatment because they can be done repeatedly and often, thereby indicating if more treatment is needed or it should be withheld and therefore avoid further toxicity and impaired quality of life.
  4. Understanding the role of epigenetic alterations in DLBCL.  Based on emerging studies, there are numerous mutations in genes that influence the expression of a wide variety of other genes in DLBCL patients. One of these genes, EZH2, can alter the ability of DLBCL tumor cells to be detected by the patients’ immune system. As immune evasion plays a central role in cancer progression, new therapies to reactivate the immune system, such as EZH2 inhibitors, are being explored in DLBCL patients, especially when combined with novel therapies that require immune-mediated killing of DLBCL tumor cells.
  5. Quality of Life Assessment. Patients treated for lymphoma are at risk of secondary cancer, immune deficiencies and heart disease. These outcomes may be associated with malignancies, or other comorbidities, and is significantly higher than the general (age-adjusted) equivalent populations. As survival time are extended with new therapies (e.g. CAR-T), additional secondary complications need to be monitored and alternative therapies need to be developed to avoid these events. Beyond this, clinical studies will be needed to evaluate if targeted therapies can replace the use of cytotoxic agents.

Photograph by CoRus13, distributed under a CC BY-SA 4.0 license