Diffuse large B-cell lymphoma

 

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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 about 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 disease free for 5 years. See the section below on relapsed DLBC for more information.

The prognosis for DLBC improved significantly starting in 2000 when the monoclonal antibody Rituximab was added to the standard chemotherapy of CHOP. As reported by the LNH-98.5 report by Bertrand Coiffier et al (1) (2) the 10 year survival for elderly patients aged 60-80 increased from 27.6% to 43.5%. This includes death from all causes not just NHL so considering the age group this is quite a remarkable improvement.

While the IPI is still the most commonly used tool for estimating the prognosis, the science has evolved and is now starting to use the genetic features of the DLBC into account to more accurately determine the prognosis. For example it has been determined that a low absolute lymphocyte count at diagnosis confers a poorer prognosis in patients with DLBC.(3) (4) The loss of HLA-DR expression and immunoblastic morphology are also predictive of an adverse outcome.(5) Additional information about research into the genetic and biologic features of DLBC and how it affects the prognosis is found lower down on this page here.

There are two main variants of DLBC that are widely recognized and come with a significantly different prognosis. They are the Activated B-cell variant (ABC) with a worse prognosis and the Germinal Center B-cell variant (GCB). (6) (7) (8) While the ABC variant has historically had a worse overall prognosis there has been a lot of progress made in treating this variant to improve the prognosis so that it is nearly as favourable as the GBC variant. Continue reading below in our treatments section for more information.

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

 

Treatments

The Gold Standard treatment for DLBC is 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 (9) 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.  But it was comparing R-CHOP to CHOP so it still could not say the a cycle of 14 days was superior to the standard 21 days. Finally in 2011 a study comparing R-CHOP14 to R-CHOP-21 was published and updated in 2013. If finally showed that R-CHOP-14 is not superior to R-CHOP-21 and so the standard regimen is now 6 cycles of R-CHOP-21 (10)

It is confusing keeping all these studies straight.  To help put it into perspective you may wish to read the article below from the renown 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.

How I treat elderly patients with Diffuse Large B-Cell Lymphoma

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.

As discussed earlier the Activated B-cell (ABC) variant of DLBC has historically had a worse overall prognosis than the Germinal Center B-cell type. Work is being done to change that and a lot of progress has been made. Several clinical studies have been done where adding various other agents to the chemotherapy regimen have improved the survival of ABC patients to nearly the same as the GBC patients. Lenalidomide is one example (18). Read the review article below.

Beyond R-CHOP for lymphoma

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

A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype

Click here for a focused search of the Medline database for other studies about DA-EPOCH-R

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. A small study about Amrubicin, showed excellent results and no cardiac toxicity. (11)  Another study replaces the doxorubicin with Gemcitabine and has very good results. (12)

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, typically that will be high dose Methotrexate, or ARA-C. (13)  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. The SWOG 8516 (14) (15) study is one study that looks at the issue of CNS relapse and whether CNS prophylaxis is necessary for newly diagnosed high risk patients.

There is currently no consensus on what is the best treatment for patients who present with very high risk disease.  One option is chemotherapy followed immediately by an SCT. In one study they had a 76% survival rate at 4 years with this approach. (16)

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. There has been less study of using Bendamustine for DLBC, but in one study for the very elderly patients with a median of 85 years of age, Bendamustine and Rituxan achieved impressive results. (17)   

 

Relapsed aggressive NHL

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.

Lymphoma recurrence 5 years or more following diffuse large B-cell lymphoma: Clinical characteristics and outcome

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.  Since this mortality rate is very high the use of reduced intensity allogeneic transplants is widely used. This means they reduce the dosage of the drugs used, and rely on the donor’s immune system to assist with eradication of the lymphoma. Non-myeloablative transplants are similar. They use even lower doses of chemotherapy so that the patient’s immune system is not entirely destroyed. These two options significantly reduce the transplant related mortality down to about 5-10% or less.

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.

How I treat DLBC - A discussion by Dr. James Armitage The Joe Shapiro Professor of Medicine, University of Nebraska Medical Center, Omaha

 

Additional topics 

Genetic and biologic information

Below are some studies that look at how scientists are using more detailed genetic and biologic information to more accurately determine the prognosis for patients with DLBC. What is challenging is to find ways to use this information to improve the treatment options for patients with worse prognostic features.

  1. Bcl-2 but not FOXP1, is an adverse risk factor in immunochemotherapy-treated non-germinal center diffuse large B-cell lymphomas  
  2. Immunoblastic 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  

  3. Immunohistochemical expression patterns of germinal center and activation B-cell markers correlate with prognosis in diffuse large B-cell lymphoma.  

  4. Gene expression profiling of diffuse large B-cell lymphoma.  

  5. Immunophenotype as prognostic factor for diffuse large B-cell lymphoma in patients undergoing clinical risk-adapted therapy

  6. Click here to run a focused Medline search for more abstracts on this topic

  7. Front-line Therapy for Nonlocalized Diffuse Large B-cell Lymphoma: What Has Been Demonstrated and What Is Yet to Be Established

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?

Click here to read the opinions of 10 lymphoma experts on these questions.

 

Double hit lymphoma

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 has a less favourable outcome. Read some of the articles below for more information about this.

  1. Growing Importance of MYC/BCL2 Immunohistochemistry in Diffuse Large B-Cell Lymphomas
  2. Double hit lymphoma: the MD Anderson Cancer Center clinical experience.

  3. 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 Prednisone

  4. Expression of Myc, but not pSTAT3, is an adverse prognostic factor for diffuse large B-cell lymphoma treated with epratuzumab/R-CHOP

  5. MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma

This next article is a peer review of  #5 article above.

MYC, BCL2, BCL6 in DLBCL: impact for clinics in the future?  

 

T-cell rich B-cell lymphoma  

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

  1. A general overview of the features of T-cell histiocyte rich B-cell lymphoma from Haematologica
  2. Biology, Diagnosis and Management of T-cell Histiocyte-Rich DLBC

  3. T-cell rich B-cell lymphoma from Blood Journal

  4. 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

  5. T-cell-rich B-cell lymphoma. Analysis of clinical features, response to treatment, survival and comparison with diffuse large B-cell lymphoma

Further reading

Medscape page on DLBCL

National Cancer Institute aggressive NHL information

(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

 

References

  1. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte
  2. Read a peer review of the above study: A decade of R-CHOP

  3. Low absolute lymphocyte count is a poor prognostic factor in diffuse-large-B-cell-lymphoma

  4. Low absolute lymphocyte count is a poor prognostic marker in patients with diffuse large B-cell lymphoma and suggests patients' survival benefit from rituximab.

  5. Loss of HLA-DR expression and immunoblastic morphology predict adverse outcome in diffuse large B-cell lymphoma – analyses of cases from two prospective randomized clinical trials

  6. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling.

  7. Evaluation of immunophenotype in diffuse large B-cell lymphoma and its impact on prognosis.

  8. 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 cases.

  9. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60).

  10. 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

  11. Late phase II study of amrubicin in previously untreated patients with non-Hodgkin's lymphoma (NHL).

  12. 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

  13. Systemic and intrathecal chemotherapy followed by high-dose chemotherapy with autologous stem cell transplantation (HD-ASCT) for CNS relapse of aggressive lymphomas: A potentially curative approach?

  14. Natural History of CNS Relapse in Patients With Aggressive Non-Hodgkin's Lymphoma: A 20-Year Follow-Up Analysis of SWOG 8516—The Southwest Oncology Group

  15. Natural History of CNS Relapse in Aggressive Non-Hodgkin's Lymphoma: What Have We Learned?

  16. Survival impact of rituximab combined with ACVBP and upfront consolidative autotransplantation in high risk diffuse large B-cell lymphoma for GELA.

  17. Phase II study of bendamustine in combination with rituximab as first-line treatment in patients 80 years or older with aggressive B-cell lymphomas

  18. Lenalidomide Combined With R-CHOP Overcomes Negative Prognostic Impact of Non-Germinal Center B-Cell Phenotype in Newly Diagnosed Diffuse Large B-Cell Lymphoma: A Phase II Study

 

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