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Types of Lymphoma >
Diffuse Large
B-Cell Lymphomas
Last update:
08/16/2010
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TOPICS
Overview
| Prognosis | Treatment
| Monitoring | Clinical Trials
Subtypes: Primary Mediastinal B-Cell
| CNS involvement | Primary Splenic
 TOPIC SEARCH: PubMed: Diagnosis
| Review
| Therapies
| Prognosis
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Therapies: ASCO |
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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".
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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
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Diffuse Large B-Cell (most common)
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Diffuse Mixed Cell
PubMed abstracts: Review
| Therapy
| Diagnosis
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Immunoblastic Lymphoma
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Primary Mediastinal B-Cell Lymphoma (see below)
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Primary Splenic Lymphoma (see below)
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Angiocentric Lymphoma - Pulmonary B-Cell |
Key Resources:
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Prognosis
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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:
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.
International
prognostic index-based outcomes for diffuse large B-cell
lymphomas.
Cancer. 2002 Jun 15;94(12):3083-8. PMID: 12115338 PubMed
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
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
Rearrangement of the bcl-6 Gene as a Prognostic Marker in
Diffuse Large-Cell Lymphoma JAMA
7_19_94
Significance
of CD10 expression Medscape (requires login)
Genes pointing the way in lymphoma prognosis
cap.org
Sep 2002
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
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.
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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
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Subtypes
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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
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DLBC
Lymphoma with CNS involvement
Also see:
CNS Lymphomas
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DLBC
Lymphoma with CNS involvement
TOPIC
SEARCH PubMed: Review
| Therapies
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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
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Primary central nervous system lymphomas--an update.
J Cancer Res Clin Oncol. 1992;119(1):7-27. Review. PMID:
1400570
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Long-term remission of primary central nervous system lymphoma
by intensified methotrexate chemotherapy. J Neurooncol. 2003
May;63(1):87-95. PMID:
12814260
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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
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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
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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
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Treatment
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TOPIC
SEARCH PubMed:
Review
| Therapies
| Radiotherapy
| Refractory |
Relapsed
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ASCO | Medscape
| FDA
| WEB
Overview
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Background articles
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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
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Role of Radiation Therapy in Localized
Aggressive Lymphoma
jco.ascopubs.org (2007, editorial)
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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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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
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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."
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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
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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
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Clinical Trials
Also see our NHL treatment-specific links to
ClinicalTrials.gov
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ClinicalTrials.gov
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