Diffuse Large B-Cell
DLBC is the most common of all the lymphomas, and by far the most common of the aggressive types of lymphoma. It comprises about 35% of all NHL cases in North America, and about 60% of all aggressive cases. The term diffuse refers to the fact that the cancer cells are spread around and not concentrated in one particular part of the node or in clusters within a part of the node. In other words the cancer cells don't clump together very well. This is the opposite behaviour of follicular lymphoma, which is an indolent variety.
This diffuse pattern of growth contributes to the aggressive behaviour of DLBC. These patients are more likely to experience "B" symptoms which includes fever, recurrent night sweats, fatigue or weight loss. However their aggressive natures is also what contributes to their high cure rate because chemotherapy is most effective at targeting rapidly dividing cells. The International Prognostic Index, is highly predictive of those who are at risk of early relapse.
Diagnosis and Prognosis
See our diagnosis page for more detailed information how how NHL is diagnosed. The prognosis for patients with DLBC varies widely according to the number of risk factors on the International Prognostic Index (IPI). With combination chemotherapy with or without radiation DLBC can be cured in about 50-80% of patients, and as high as 90% of patients with no risk factors can be cured. Most relapses if they occur, occur within the first two years. After two years a relapse is unlikely but doctors will generally not use the "cure" word until 5 years. See the section below on relapsed DLBC for more information.
A recent study looks at the dramatic improvement in survival since the introduction of Rituxan. R-CHOP is the new Gold Standard for treating DLBC.
In addition to the IPI current studies show that the absolute lymphocyte count at diagnosis is a strong predictor of outcome. A low absolute lymphocyte count predicts for worse outcomes. Below are two recent studies on this.
Here is another study that looks at which genetic features predict for outcome.
One variant of diffuse large B-cell lymphoma known as double hit lymphoma carries a less favourable prognosis. The type of lymphoma carries two genetic mutations, the MCY and BCL2 mutation. Click here for more information
Additional information about what genetic features may affect the prognosis are found at the bottom of this page in the Other information section. It is a complex topic which is really still in its infancy. Every day they are discovering new information.
DLBC is usually treated with R-CHOP (CHOP with Rituxan) chemotherapy or other Doxorubicin containing regimens. Many patients will be cured using this chemotherapy regimen. A "cure" is generally defined as 5 year disease free survival. The aggressive nature of DLBC means that if it has not relapsed within 5 years it is statistically highly unlikely that it ever will. In fact the vast majority of relapses occur within the first 2 years following treatment. While a relapse after 5 years is unlikely it does occur in a small subset of patients.
For years there was on-going debate about the best schedule of R-CHOP. The most common schedules were R-CHOP-21 meaning treatments are given 21 days apart, and R-CHOP-14 where cycles are 14 days apart. Studies seemed to show that by intensifying the regimen to 14 days there were better results. One of the first studies to address this issue was the RICOVER-60 trial which clearly demonstrated that six cycles of R-CHOP-14 was superior to 6 or 8 cycles of CHOP-21 (no Rituxan) and superior to 8 cycles of R-CHOP-21. Therefore in Europe where this study was performed, six R-CHOP-14 became the new standard (with or without radiation as needed) Here are the results of the RICOVER-60 trial published in February 2008.
Now at last the results of a study comparing R-CHOP14 to R-CHOP-21 have been published. These results have been long awaited because the addition of Rituxan confused the issue when the RICOVER-60 study was published. We needed a study that compared R-CHOP-14 to R-CHOP-21 to see if that intensified regimen was truly superior when you compared them head to head. The results are that R-CHOP-14 is NOT superior to R-CHOP-21. The study was first published at the ASCO 2011 annual meeting, and updated in the Journal Lancet in September 2013.
Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles
It is confusing keeping all these studies straight. The next study from December 2010 puts it into perspective. It is from the reknown haematologist Michael Pfreundschuh of the German High-Grade Non-Hodgkin Lymphoma Study Group. It examines how he approaches the treatment of elderly patients with DLBC. Note that the treatment approach for younger patients may often be more aggressive due to their better health status.
Perhaps the next question to ask is if these results for elderly patients (over 60) also apply to younger patients. In the study above Dr. Pfreundshuh notes that he does not consider 60 to be elderly but rather around 75, and perhaps even older than that if the person is in otherwise good health. A persons performance status is what determines their age rather than the number of years they have lived.
Even with R-CHOP being the current Gold Standard, there is still no consensus on the optimal frontline treatment for all DLBC patients. There are many genetic features, risk factors and other factors that influence the outcome for each patient. Below is a link to an excellent Medscape article that reviews the current knowledge, ongoing studies and future directions for DLBC treatment.
Another treatment regimen that is gaining in popularity is DA-EPOCH-R. (The DA means Dose Adjusted). This regimen has the same drugs as R-CHOP but with the addition of Etoposide. The dose adjustment allows the doctors to tailor the drug doses to the patient to achieve optimum efficacy while keeping the toxicity in check. Where this particular protocol is showing the most promise is for those patients with higher risk factors and poorer prognosis DLBC. Below is one recent study regarding this protocol
One of the more important risks of treatment with R-CHOP is the cardiotoxicity from the Doxorubicin. There are many ongoing studies using different drugs to replace Doxorubicin. Pixantrone is getting a lot of attention. Some of the other anthracyclines are showing promise, by having equal efficacy, but lower cardiac toxicity. Here is one recent but small study about Amrubicin, which had no cardiac toxicity.
This next study replaces the doxorubicin with Gemcitabine and has very good results.
De Novo Treatment of Diffuse Large B-Cell Lymphoma With Rituximab, Cyclophosphamide, Vincristine, Gemcitabine, and Prednisolone in Patients With Cardiac Comorbidity: A United Kingdom National Cancer Research Institute Trial
CNS involvement is not common but it does occur with DLBC. Of greater concern is the risk of having a relapse with central nervous system involvement. To prevent this from happening some physicians will give high risk patients CNS prophylaxis treatment. Usually that will be high dose Methotrexate, or ARA-C. Here is a recent study that examines how to treat CNS relapse of DLBC.
Of greater concern however is, how high is the risk of CNS relapse, and is it necessary to give this additional treatment in the absence of evidence there is any CNS involvement at diagnosis. Below is one study that looks at the issue of CNS relapse and whether CNS prophylaxis is necessary for newly diagnosed high risk patients.
Here is a letter to the editor from another expert in the field with his comments on the above study.
Some patients present with very high risk disease. There is no concensus on how these patients should be treated, but chemotherapy (with Rituxan) followed immediately by an SCT is one option. The study below looks very promising. In this study they treat with R-ABCBP followed by an autologous stem cell transplant. At 4 years the survival in this high risk group is an impressive 76%
One of the hardest groups to treat are the very elderly since they often cannot tolerate the doses of chemotherapy normally used. Bendamustine has been gaining widespread use in follicular lymphoma. Below is one of the first studies of using Bendamustine and Rituxan for elderly patients over 80 with diffuse large B-cell lymphoma. The results are quite excellent and quite surprising.
Relapses are unlikely to occur after two years of remission. But unlikely does not mean impossible and doctors generally don't use the cure word until 5 years of remission. Even after 5 years rare relapses do occur. Often a relapse this late is considered a whole new case of lymphoma and not really a relapse. Only a biopsy can really distinguish whether this is true. The study below discusses the characteristics and prognosis of relapses past the 5 year point.
If a relapse occurs a more potent salvage therapy will be used. In most cases if the patient is under 70 and in good general health a Stem Cell Transplant will be the treatment of choice for a relapse. Stem Cell transplants are highly effective and can cure a significant percentage of patients who undergo them. The patients who had a good response to their initial therapy are the ones who are most likely to have a good outcome from a stem cell transplant. There are two basic types of Stem Cell Transplant.
- Allogeneic - where someone else is the donor. This type has a very high probability of curing the patient, but is also very risky. About 20-30% of patients die during this procedure.
- Autologous - where the patient donates their own stem cells. This type is very safe (2% death rate) but does not produce the high rate of cures that allogeneic transplants to.
Not everyone is a candidate for a stem cell transplant. Other treatment options are available with varying degrees of success. For a list of alternative treatments to SCT click on the relapsed DLBC menu choice at the top left of this page.
Recent research has identified two distinct types of DLBC. Using modern techniques such as DNA Microarray analysis, and Flow Cytometry, researchers have discovered that DLBC can be divided into Germinal B-Cell (GBC) and Activated B-Cell (ABC) types of diffuse large B-cell lymphoma. Previously it was believed that the GBC variant had a more very favourable prognosis than the ABC variant. Most as more studies are done, they are discovering that there are many genetic features which may play a much more important role in the overall prognosis. You can read some of these studies below.
It still remains a challenge for researchers and doctors to find ways to use this information to develop treatments that make use of the knowledge and help boost the survival rate for those with poor prognostic indicators. It is hoped that in the future they will be able to tailor the treatment to the subtype. Here is a list of medical studies on this subject.
Bcl-2 but not FOXP1, is an adverse risk factor in
immunochemotherapy-treated non-germinal center diffuse
large B-cell lymphomas
Evaluation of immunophenotype in diffuse large B-cell
lymphoma and its impact on prognosis.
morphology but not the immunohistochemical GCB/non-GCB
classifier predicts outcome in diffuse large B-cell
lymphoma in the RICOVER-60 trial of the DSHNHL
Prognostic significance of CD44 expression in diffuse
large B cell lymphoma of activated and germinal centre B
cell-like types: a tissue microarray analysis of 90
Distinct types of diffuse large B-cell lymphoma
identified by gene expression profiling.
Immunohistochemical expression patterns of germinal
center and activation B-cell markers correlate with
prognosis in diffuse large B-cell lymphoma.
Gene expression profiling of diffuse large B-cell
Immunophenotype as prognostic factor for diffuse large
B-cell lymphoma in patients undergoing clinical
- Double hit lymphoma: the MD Anderson Cancer Center clinical experience.
There are also a number of questions that don't have any cut and dry answers regarding DLBC. For example is a mid treatment PET scan necessary? Is it necessary to screen for Hepatitis in low risk patients being treated with Rituxan?, When should CNS prophylaxis be used? What about Lenalidomide use?
Double hit lymphoma refers to those whose DLBC has two adverse genetic mutations. They have both the MYC and the BCL2 mutation. This double mutation type of DLBC is more difficult to treat and and a less favourable outcome. Read some of the articles below for more information about this.
Growing Importance of MYC/BCL2 Immunohistochemistry in
Diffuse Large B-Cell Lymphomas
Immunohistochemical Double-Hit Score Is a Strong
Predictor of Outcome in Patients With Diffuse Large
B-Cell Lymphoma Treated With Rituximab Plus
Cyclophosphamide, Doxorubicin, Vincristine, and
of Myc, but not pSTAT3, is an adverse prognostic factor
for diffuse large B-cell lymphoma treated with
status in concert with BCL2 and BCL6 expression predicts
outcome in diffuse large B-cell lymphoma
- This next article is a peer review of the article
- MYC, BCL2, BCL6 in DLBCL: impact for clinics in the future?
Another variant of DLBC is T-cell/Histiocyte - Rich B-cell Lymphoma. Despite the name this not a T-cell lymphoma, but a form of DLBC. It derives its name from the fact that the tumour environment is populated by a high percentage (over 50%) of normal healthy T-cells. The links below takes you to an excellent article on this type of NHL
A general overview of the features of T-cell histiocyte rich
B-cell lymphoma from Haematologica
Biology, Diagnosis and Management of T-cell Histiocyte-Rich
T-cell rich B-cell lymphoma from Blood Journal
T-cell/histiocyte-rich large B-cell lymphoma displays a
heterogeneity similar to diffuse large B-cell lymphoma: a
clinicopathologic, immunohistochemical, and molecular study
of 30 cases
- T-cell-rich B-cell lymphoma. Analysis of clinical features, response to treatment, survival and comparison with diffuse large B-cell lymphoma
To read more about diffuse large b-cell lymphoma check out the following links.
(Note, follow the links on the left side of this page for additional information since it is all categorized.) Because this type of lymphoma is the most common type there is an abundance of information about it on the Internet. But for the average person who is looking for treatment options the best place to look is likely going to the be American Society of Hematology) ASH abstracts. These abstracts represent the ground breaking work of the worlds leading haematologists as presented at their annual convention