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Diffuse Large B-Cell Lymphomas

Last update: 08/16/2010

TOPICS
 
Overview | Prognosis | Treatment | Monitoring | Clinical Trials
 Subtypes: Primary Mediastinal B-Cell | CNS involvementPrimary Splenic

TOPIC SEARCH: PubMed: Diagnosis | Review | Therapies | Prognosis | Refractory

Therapies:  ASCO | Medscape (free login req.) | FDA | Web

Overview

ABOUT Lymphomas

Overview of genes and cancer

Lymphoma is a cancer

About Lymphoma - general

Characteristics of NHL:
  Cell type | Histology | Grading | Staging

 Ann Arbor Staging 
 Extranodal notations  

 Diagnosis 

Host/tumor
interaction

Lymphatic System

Risk Factors

Staging

Statistics

Symptoms
 
Transformation

 
Guidelines at diagnosis
    

 
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Diffuse Large B-Cell Lymphomas (DLBCL)

A cancer of b-cells (lymphocytes) that normally reside in the lymphatic system.  

The word "diffuse" describes the cell pattern. B-cells arise from the bone marrow and mature or differentiate into many cell types that tend to migrate to different areas of the body.

What is lymphoma? See Lymphoma simplified.

Initial presentation: DLBCL typically presents as a nodal or extranodal (outside the lymphatic system) mass with fast tumour growth associated with systemic symptoms, such as sweats, fatigue, and fever. In about 40% of cases, these lymphomas appear in areas outside lymph nodes, including digestive tract, skin, bone, thyroid, and testes. 

Staging: Staging refers to the how widespread the disease is. Imaging tests (CT MRI, PET, Gallium) and bone marrow biopsies are commonly done to estimate this.  See Staging for more detail.

Also see About Transformation

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Is it DLBCL or Burkitt's? 

C-MYC Rearrangements are Frequent in Aggressive Mature B-Cell Lymphoma with Atypical Morphology  ijcep.com  pdf 

"To avoid under- or over-treatment of the patients, it is critical to distinguish Burkitt's lymphoma (BL) from DLBCL when encountering these aggressive mature B-cell lymphomas with atypical morphology. Since diagnosis of BL requires strict criteria (CD10+, BCL6+, close to a 100% proliferation index and IG-MYC), many cases that do not meet all these criteria were diagnosed as DLBCL, and therefore would not receive the benefit of intensified chemotherapy. More recent studies suggest that some of those DLBCL cases indeed had the molecular signatures of BL and over 10% of those molecular BL did not harbor any detectable C-MYC translocations". 

Question: Can you test for bone marrow involvement with PCR?

"Another key questions was whether molecular staging could increase the prognostic value of histopathological staging. Patients with positive IgR in PB/BM but without morphologically detectable Bone Marrow (BM) involvement indeed had a significantly poorer OAS than patients with positive BM histology"  nature.com/leu/journal 

Subtypes of Diffuse Large Cell lymphoma

bullet Diffuse Large B-Cell  (most common)
 
bullet Diffuse Mixed Cell 
PubMed abstracts: ReviewTherapyDiagnosis
 
bullet Immunoblastic Lymphoma 
 
bullet Primary Mediastinal B-Cell Lymphoma (see below)
 
bullet Primary Splenic Lymphoma (see below)
 
bullet Angiocentric  Lymphoma - Pulmonary B-Cell

Key Resources:

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About DLBCL:  asheducationbook.org
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Diffuse Large B-Cell Lymphoma  http://bit.ly/DLBCL-friedberg
Jonathan W. Friedberg, M.D., M.M.Sc.* (2009)
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Medscape (free login req.)
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Cancer.gov
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Diffuse large B-cell lymphoma: a heterogeneous group of non-Hodgkin lymphomas comprising several distinct clinicopathological entities -  nature.com full/

"These studies analyzed DLBCL by their gene expression profile, provided further information on some of the variants of DLBCL listed in the WHO classification and stressed the impact of the site of origin of these tumors. This review summarizes these recent data and explores their impact on the recognition of new clinicopathological lymphoma entities."


Prognosis

Prognosis/
LymphoChip Findings
Germinal center B cell-like (GCB) has a more favorable response to standard therapies
Activated B cell-like (ABC) 
less responsive; pts should consider investigational treatments.
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Prognosis: With the arrival of new tests that determine the molecular characteristics of the lymphoma it's now possible to better determine the odds (or prognosis) of treatment. However, there are many factors that determine response, including age, general health, how widespread the disease is, LDH levels, etc.

Complete response rate: Most of the literature indicates that about 60% to 76% of DLBCL patients can achieve a complete response to Rituxan-based combination chemotherapy. 

"The rate of complete response was significantly higher in the group that received CHOP plus rituximab than in the group that received CHOP alone (76 percent vs. 63 percent, P=0.005). With a median follow-up of two years, event-free and overall survival times were significantly higher in the CHOP-plus-rituximab group (P<0.001 and P=0.007, respectively)." 

References:
  1. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002 Jan 24;346(4):235-42. PMID: 11807147  PubMed

    The addition of rituximab to the CHOP regimen increases the complete-response rate and prolongs event-free and overall survival in elderly patients with diffuse large-B-cell lymphoma, without a clinically significant increase in toxicity.
  2. International prognostic index-based outcomes for diffuse large B-cell lymphomas. Cancer. 2002 Jun 15;94(12):3083-8. PMID: 12115338  PubMed
  3. Expression of a single gene, BCL-6, strongly predicts survival in patients with diffuse large B-cell lymphoma. Blood. 2001 Aug 15;98(4):945-51. PMID: 11493437  PubMed
  4. A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med. 1993 Sep 30;329(14):987-94. PMID: 8141877  PubMed
  5. Rearrangement of the bcl-6 Gene as a Prognostic Marker in Diffuse Large-Cell Lymphoma  JAMA 7_19_94
  6. Significance of CD10 expression  Medscape (requires login)
  7. Genes pointing the way in lymphoma prognosis  cap.org  Sep 2002
  8. The Modified International Prognostic Index (IPX) can predict the outcome of localized primary intestinal lymphoma of both extranodal Marginal Zone B-Cell and Diffuse Large-B-Cell Histologies.  International Extranodal Lymphoma Study Group (IELSG) British Journal of Haematology, 2002, 118, 218–228   PDF | PDF Help
  9. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning  nature.com  full  

    We analyzed the expression of 6,817 genes in diagnostic tumor specimens from DLBCL patients who received (CHOP)-based chemotherapy ...  The model also effectively delineated patients within specific IPI risk categories who were likely to be cured or to die of their disease. 
  10. Response to Second-line Therapy Defines the Potential for Cure in Patients with Recurrent Diffuse Large B-cell Lymphoma: Implications for the Development of Novel Therapeutic Strategies  http://www.medscape.com/viewarticle/723577

     


Subtypes

Primary Splenic Lymphoma

 

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Primary Splenic Lymphoma

"Primary splenic lymphoma (PSL) is rare with a reported incidence of less than 1%. Diffuse large cell pathology has been reported in 22-33% of the cases and is felt to have a poor outcome. ... Seven of the nine patients remained in remission from 1 to 19 years. Splenectomy followed by combination chemotherapy, results in excellent long-term survival in PSL." [1]
 

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Postsplenectomy Therapy in Diffuse Large B-cell Lymphoma? - Medscape (free login req.)
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Primary splenic lymphoma: report of 10 cases using the REAL classification.
 
Cancer Invest. 2002;20(5-6):749-53. PMID: 12197231   PubMed
DLBC Lymphoma with CNS involvement

Also see: 
CNS Lymphomas

 

 

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DLBC Lymphoma with CNS involvement

TOPIC SEARCH PubMed: Review | Therapies
 ASCO | Medscape | WEB

"Primary CNS lymphomas (PCNSL), until recently representing about 1% of all brain tumors, show dramatically increased incidence both in high-risk groups (immunocompromised, AIDS) and in the general population. They are extranodal diffuse non-Hodgkin's lymphomas, the morphology and classification of which are identical to those of systemic lymphomas, although PCNSL show different biological behavior and diagnosis according to the New Working Formulation and updated Kiel classification may be difficult. The majority are large B cell variants of high-grade malignancy; low-grade subtypes and T cell lymphomas are rare."[1]

Clinical Trial Search: With CNS involvement
 

  1. Primary central nervous system lymphomas--an update.
    J Cancer Res Clin Oncol. 1992;119(1):7-27. Review. PMID: 1400570
  2. Long-term remission of primary central nervous system lymphoma by intensified methotrexate chemotherapy. J Neurooncol. 2003 May;63(1):87-95. PMID: 12814260
  3. Addition of Systemic High-Dose Methotrexate to Intrathecal Chemotherapy for Central Nervous System Prophylaxis Substantially Reduces CNS Recurrence Rates in Patients with at-Risk Aggressive Lymphoma: A Historically Controlled Prospective Study

    http://ash.confex.com/ash/2008/webprogram/Paper4036.html

    Monday, December 8, 2008

    n = 85 pts with newly diagnosed aggressive NHL with CNS risk factors such as multiple extranodal sites and elevated LDH
DLBC Lymphoma with testicular involvement

 

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DLBC Lymphoma with testis involvement

TOPIC SEARCH PubMed: Review | Therapies  WEB

"Advanced stage, elevated serum LDH, B-symptoms, and high IPI are poor prognostic markers. R-CHOP based chemotherapy with intrathecal chemotherapy and scrotal RT is associated with an improved OS."[1]

Clinical Trial Search: With CNS involvement
 

  1. Outcome of patients with diffuse large B-cell lymphoma of the testis by era of treatment: the M. D. Anderson Cancer Center experience. http://www.ncbi.nlm.nih.gov/pubmed/20443676 

   
Treatment

Treatment
Also see:

Questions for your doctor
 - Patients Against Lymphoma
General, Treatment & Side Effects, and Tests

Treatment overview
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TOPIC SEARCH PubMed:
 Review | Therapies | Radiotherapy | Refractory | Relapsed | ASCO | Medscape | FDA | WEB


Overview

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Background articles
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NEW Diffuse Large B-Cell Lymphoma  http://bit.ly/DLBCL-friedberg
Jonathan W. Friedberg, M.D., M.M.Sc.* (2009)
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How I treat patients with diffuse large B-cell lymphoma,  
James O. Armitage MD  
bloodjournal.hematologylibrary.org
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About DLBCL:  asheducationbook.org
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Medscape (free login req.)
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Treatment of Non-Hodgkin's Lymphoma: Next Steps  Medscape.com 2004 (free login req.) Review of progress for Follicular, SLL, Diffuse Large Cell, and Mantle Cell.
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Treatment of Elderly  PAL
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Monoclonal Antibodies in Aggressive, De Novo, or Relapsed Lymphomas  Medscape (free login req.)
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Role of Radiation Therapy in Localized Aggressive Lymphoma  jco.ascopubs.org (2007, editorial)

First Primary Treatment

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Adult Non-Hodgkin’s Lymphoma ~ Best Practice  Cancer.gov  
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"Dose-densing" is the practice of shorting the cycle time between infusions of treatment (14 vs 21 days) with the goal of increasing efficacy.
 
R-CHOP-14 in patients with diffuse large B-cell lymphoma: feasibility and preliminary efficacy. Leuk Lymphoma. 2005 Apr;46(4):541-7.  PMID: 16019482 | Related articles
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Combination chemotherapy with adriamycin, cyclophosphamide, vincristine, methotrexate, etoposide and dexamethasone (ACOMED) followed by involved field radiotherapy induces high remission rates and durable long-term survival in patients with aggressive malignant non-Hodgkin's lymphomas: long-term follow-up of a pilot study. Leuk Lymphoma. 2005 Dec;46(12):1729-34. PMID: 16353313

"After a median observation time of 10 years and 2 months, 16/22 (73%) patients are alive in continuous complete response without evidence of any late toxicities."
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CHOP + Rituxan is the standard of treatment [2005]  for 
Diffuse Large B-cell Lymphoma.  See CHOP+R
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Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy. 
Blood. 2002 Apr 15;99(8):2685-93. PMID: 11929754  PubMed
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Rationale for Consolidation to Improve Progression-Free Survival in Patients with Non-Hodgkin's Lymphoma: A Review of the Evidence Full text:   http://bit.ly/2ttiY3 
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CHOP-R + bortezomib (Velcade) as initial therapy for diffuse large B-cell lymphoma (DLBCL). http://bit.ly/9ifYVY
 
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Rituxan maintenance for DLBCL following CHOP-R ?  
ASCO 2007  http://bit.ly/1SkdJX

Maintenance rituximab (MR) compared to observation (OBS) after R-CHOP or CHOP in older patients (pts) with diffuse large B-cell lymphoma (DLBCL): An Intergroup E4494/C9793 update.

MR after CHOP, but not after R-CHOP, significantly prolongs TTF, but fails to prolong OS, possibly due to a delayed pattern of relapse and/or the efficacy of rituximab in the salvage setting. 

As 6-yr FFS declined to <50% among R-CHOP responders, with or without MR, there is a need for more effective treatment strategies in older DLBCL pts.
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Clinical trials in ClinicalTrials.gov
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Newly diagnosed or untreated
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Excluding bone marrow transplants 

Relapsed / Recurrent Diffuse Large B-Cell Lymphoma

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Adult, Aggressive, Recurrent Non-Hodgkin’s Lymphoma
Standard of Care  Cancer.gov  
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Treatment for Refractory Disease  PAL
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Multicenter study of i.v. Bu/Cy/E as conditioning regimen for autologous stem cell transplantation in patients with non-Hodgkin's lymphoma. Bone Marrow Transplant. 2007 Sep 10; PMID: 17846602  

In conclusion, the conditioning regimen of i.v. Bu/Cy/E was well tolerated and seemed to be effective in patients with aggressive NHL
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NEW Second SCT for lymphoma patients who relapse after autotransplantation: another autograft or switch to allograft? 
Freytes CO, Lazarus HM. Bone Marrow Transplant. 2009 Aug 24.
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Mitoxantrone, carboplatin, cytosine arabinoside, and methylprednisolone followed by autologous peripheral blood stem cell transplantation (MiCMA): a salvage regimen for patients with refractory or recurrent non-Hodgkin lymphoma. Cancer. 2006 Feb 15;106(4):859-66. PMID: 16419074
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Autologous bone marrow transplantation in B-cell non-Hodgkin's lymphoma: very low treatment-related mortality in 100 patients in sensitive relapse. J Clin Oncol 8 (5): 784-91, 1990.  PUBMED
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Reduced-intensity allogeneic stem cell transplantation for diffuse large B-cell lymphoma: Clinical evidence of a graft-versus-lymphoma effect. ASCO 2006

Conclusions: The clinical observations of sustained CR/CRu after withdrawal of immune suppression and DLI suggest that a GVL effect exists against DLBC. RI alloSCT should be considered as a treatment option for pts with primary refractory and relapsed DLBC.
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High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-Hodgkin's lymphoma. J Clin Oncol 11 (10): 1846-51, 1993.  PUBMED
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BEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin's lymphoma. J Clin Oncol 13 (3): 588-95, 1995.  PUBMED
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Salvage therapy for relapsed diffuse large B-cell lymphoma remains poor, except for those patients who have chemotherapy-responsive disease and are candidates for high-dose therapy. 

Preliminary results with a new "standard dose" salvage regimen were presented. Using a combination of rituximab, gemcitabine, and oxaliplatin, (R-GEMOX) an overall response rate of 88% (42% complete responses) was obtained in a small group of 24 patients.[18] With short follow-up, most of the patients remained in remission. This regimen, using "newer" chemotherapeutic agents with presumably less cross-resistance, is of interest, and further results and follow-up are awaited.

www.medscape.com


El-Gnaoui T, Joly B, Dupuis J, et al. Rituximab, gemcitabine and oxaliplatin (R-GEMOX): a promising regimen for refractory/relapsed B-cell lymphoma. Proc Am Soc Clin Oncol. 2004;23:578. Abstract 6592.
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Outcomes: Two Studies Demonstrate REVLIMID (R) (lenalidomide) Activity In Patients With Relapsed/Refractory Aggressive Non-Hodgkin's Lymphoma  medilexicon.com 

"The data from these studies are encouraging in that they show an impressive response to REVLIMID in relapsed/refractory, aggressive NHL," said John Leonard, M.D., The Richard T. Silver Distinguished Professor of Hematology Medical Oncology at Weill Cornell Medical College. "These data justify a wide exploration of REVLIMID in a variety of lymphoma settings both alone and in combination, and warrant a detailed assessment of which patients can particularly benefit."
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Response to Second-line Therapy Defines the Potential for Cure in Patients with Recurrent Diffuse Large B-cell Lymphoma: Implications for the Development of Novel Therapeutic Strategies  http://www.medscape.com/viewarticle/723577

"Because the prospect for cure in these patients is remote with standard strategies, management should include a frank discussion of the goals of care, including issues of the toxicity of therapy and quality of life. No clear indication exists that palliative approaches are inferior to further intensive approaches in this setting. This fact may make a comfort-directed or investigational strategy more acceptable to some patients, because they do not risk losing the chance for a cure by choosing an alternative to established standard chemotherapy regimens."
 
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Clinical Trials for relapsed DLBCL  ClinicalTrials.gov
All recurrent
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With stem cell transplant | Bexxar + Stem cell transplant
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Studies recruiting for DLBCL, not eligible for transplant http://bit.ly/aVbuVF  (by request)
Monitoring DLBCL

"Most relapses for patients with aggressive lymphoma are found because of symptoms, new physical findings or abnormal laboratory tests such as LDH or sedimentation rate." 4

Monitoring after first remission:

"Routine imaging of patients with aggressive lymphoma in complete remission is standard practice in most of the United States. The timing (i.e. every 6 months or every year), the duration (i.e. usually for 3–5 years) and the type of image performed (i.e. CT scan, PET scan or both) vary among clinicians." 4

Dr. Armitage writes: "Follow up visits include interval history, careful physical examination, and laboratory studies including a complete blood count, chemistry screen, and serum Lactate Dehydrogenase (LHD). 

Once a complete remission is documented I would do no more images in the absence of some abnormality hinting at relapse or at the patient’s request. I know it is standard care in much of the U.S. to do routine images in complete remission, but this approach cannot be supported with data. 

There is no convincing evidence that routine images in remission accomplish their goal of improving survival by finding early relapse although this could be tested in a prospective trial. While there is at best minimal evidence that routine images in remission could improve survival,(3) it is certain that they are expensive. 

Whether these studies make a patient less anxious because a negative test is reassuring, or make them more anxious by reminding them that they should be afraid of relapsing, is a point that could be argued. However, given the specificity and sensitivity of the tests, and the chances of relapse at any particular point in time, it can be shown that abnormal findings on routine images are much more likely (i.e. >80% of the time) to represent false positives and lead to inappropriate further evaluation, or, even worse, instituting inappropriate therapy.(4) Most patients who are going to relapse will do so in the first two of three years." 

  1. Armitage, MD, Mar 14, 2007 How I treat patients with diffuse large B-Cell lymphoma
  2. Cheson, et al. Role of Positron Emission Tomography in Lymphoma
  3. Surveillance imaging during remission identifies a group of patients with more favorable aggressive NHL at time of relapse: a retrospective analysis of a uniformly-treated patient population. Ann Oncol. 2006 Jun;17(6):909-13. Epub 2006 May 3. PMID: 16672295 
  4. Is there a place for routine imaging for patients in complete remission from aggressive lymphoma? Ann Oncol. 2006 Jun;17(6):883-4. PMID: 16707741 

 

Clinical Trials
Also see our NHL treatment-specific links to  ClinicalTrials.gov 

 

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ClinicalTrials.gov searches by:

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Lymphoma subtype
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Other criteria such as age, stage, phase, refractory
 
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For all medical concerns,  you should always consult your doctor. 
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