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Diffuse Large B-Cell Lymphomas

Last update: 06/11/2014

TOPICS
 
Overview | In the News | Workup | Prognosis | Treatment | Relapsed | Novel Investigational |
 Monitoring | Clinical Trials | Key Resources
 
 Subtypes: Primary Mediastinal B-Cell | CNS involvementPrimary Splenic 

Double Hit - an emerging molecular subtype

TOPIC SEARCH - PubMedDiagnosis | Review | Therapies | Prognosis | Refractory
 

Overview

ABOUT Lymphomas

Lymphoma Overview

Lymphatic System

Lymphoma Simplified

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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"Lymphoma is a blood cell cancer.  The effected cells are called lymphocytes, a type of white blood cell that helps protect us from infection."

Diffuse Large B-Cell Lymphomas (DLBCL) is the most common type of lymphoma.  It has an aggressive (fast growing) behavior and is treated at diagnosis with curative intent. 

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.  See also What is lymphoma?

Initial presentation: DLBCL typically presents as a nodal or extranodal mass (outside the lymphatic system)  with fast tumor 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. 


Workup (adapted from NCCN Guidelines)

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Calculate International Prognostic Index (IPI)

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Staging tests:
 
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CT of Chest/abdominal/pelvic with contrast of diagnostic quality

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Unilateral or bilateral bone marrow biopsy (1-2 cm) + aspirate to document clinical stage I_II disease

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PET-CT scan

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Useful in select cases:
 
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Lumbar puncture if involvement in following sites:
 
paranasal sinus,
testicular,
epidural,
bone marrow with large cell lymphoma,
HIV lymphoma, or
> 2 extranodal sites
 

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CT or MRI of neck and head
 

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Physical exam:
 
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Attention to node-bearing areas, including Waldeyer's ring

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Examine size of liver and spleen

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Performance status

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B symptoms
 

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Labs and tests:
 
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CBC, differential, platelets,

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Beta-2-microglobulin

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LDH

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Comprehensive metabolic panel

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Uric acid

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Hepatitis B testing

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MUGA scan / echocardiogram" 
(prior to anthracycline-based therapy)

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Useful in select cases:
 
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HIV test
 

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Treatment, age and gender specific:
 
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Discuss fertility issues

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Pregnancy testing in women of child-bearing age if chemo is planned


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.

 

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

 

Question: Should radiation be given to involved areas when PET positive after treatment?

FDG-PET Scan Guided Consolidative Radiation Therapy Optimizes Outcome In Patients with Advanced-Stage Diffuse Large B-Cell Lymphoma (DLBCL) with Residual Abnormalities on CT Scan Following R-CHOP ash.confex.com/ash/2010l

 

DLBCL: Preventive Therapy (Prophylaxis)
for CNS Involvement - When and How? 

bullet See new subtopic PAL


Double-hit lymphoma

PubMed Topic Search  

Curr Opin Hem, 2012; Biology of Double-Hit B Cell Lymphomas http://1.usa.gov/1lrhT4o

COMMENT:  This section of the paper suggests that there is considerable uncertainty about the clinical meaning of the "double-hit" finding. Importantly, it doesn't predict outcomes in individual cases even if the association with poorer outcomes is ever validated.

SNIP:

Among patients with double-hit lymphomas, few prognostic variables have been identified consistently across studies. As in DLBCL without double-hit lesions, the International Prognostic Index (IPI), LDH, extent of extranodal disease, and performance status are informative regarding prognosis [2,11*].

Several studies have found that in MYC/BCL2 double-hit lymphoma, non-DLBCL morphology portends shorter survival than DLBCL morphology [2,8], while another found no association between survival and morphology [11*],

There is similar inconsistency regarding the prognostic importance of BCL2 protein expression, non-IG/MYC translocations, and history of indolent lymphoma [2,11*,27*],

Several small series suggest that lymphomas bearing three (MYC/BCL2/BCL6) or four (MYC/BCL2/BCL6/CCND1) concurrent rearrangements may fare even worse than double-hit lymphomas, but with small numbers and lack of uniform treatment protocols, it is difficult to draw conclusions regarding definitive differences in clinical outcomes [18,20].

Question: I've never heard the term Myc-positive and Double Hit Nhl....what are they?

Comment: These are features of the tumor (genetic or molecular abnormalities) associated with higher risk lymphoma - mainly for aggressive NHL. At this time we're not aware of how this finding would influence the approach to initial treatment or the approach when a Complete Response (CR) is not achieved with regular treatment. 

Discussions are under way if this finding should be the basis for selecting patients for the study of novel approaches to initial treatment of DLBCL - such as by adding targeted agents to R-CHOP or upfront SCT.

 

Question: 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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Key Resources on DLBCL:

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Background on DLBCL
Ash Education Book.org

Medscape (free login req.)
Cancer.gov
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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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Best Practice and Research in Clinical Haematology: Diffuse large B Cell lymphoma: How can we cure more patients in 2012?
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Best Practice and Research in Clinical Haematology: Relapses, treatments and new drugs
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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."

Topics:

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

 


In the News:

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Blood, 2013:
Determining Cell-Of-Origin Subtypes (ABC versus GCB)
In Diffuse Large B-Cell Lymphoma Using Gene Expression Profiling On Formalin-Fixed Paraffin-Embedded Tissue – An L.L.M.P.P. Project http://bit.ly/1kIs3RL
 
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HemOnc Today 2014:
R-CHOP plus radiation improved outcomes in bulky B-cell lymphoma http://bit.ly/1cJKpyq

Comment: Important finding described here … arguably, according to Dr. Kahl, practice-changing. (Karl)
 
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Encouraging report for DLBCL - MNT 2013:
Patients with non-Hodgkin lymphomas resistant to treatment benefit from drug-antibody pair http://bit.ly/18IETHK

"To date, the trial has enrolled 62 patients with B-cell lymphomas, including 44 diagnosed with DLBCL. Most the patients were no longer responding to previous therapy, and 23 percent had never responded to any treatment.
 
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ASH 2012: compiled abstracts by PAL
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ASCO 2012: Diffuse Large B-cell Lymphoma abstracts
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DLBCL and Burkitt - Best Practice and Research in Clinical Haematology: New insights into the biology of molecular subtypes of diffuse large B-cell lymphoma and Burkitt lymphoma
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OncLive: New Directions in Relapsed / Refractory Diffuse Large B-cell Lymphoma  

"the Bruton’s tyrosine kinase inhibitor PCI-32765 was tested in 8 patients with relapsed or refractory ABC DLBCL. The results showed that 2 patients achieved complete response for 11+ and 5 months, respectively; 3 patients achieved stable disease for 4, 2, and 2 months, respectively; and 3 patients had progressive disease. The drug was generally well tolerated across the patient population."

See for more on this kinase inhibitors
Cancer: Limited-stage diffuse large B-cell lymphoma treated with abbreviated systemic therapy and different types of consolidation radiotherapy
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Trial of interest - Relapsed DLBCL - Navitoclax (ABT-263 - a BCL-2 inhibitor) in Addition to Bendamustine and Rituximab (NAVIGATE trial)

Recent report on Navitoclax
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Blood: The interim 18-FDG-PET/CT failed to predict the outcome in diffuse large B-cell lymphoma patients treated at the diagnosis with rituximab-CHOP.
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Brit J Hem: The addition of rituximab reduces the incidence of secondary central nervous system involvement in patients with diffuse large B-cell lymphoma
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Cancer Chemo and Pharmacology: Addition of rituximab to reduced-dose CHOP chemotherapy is feasible for elderly patients with diffuse large B-cell lymphoma
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Annals of Oncology: R-CHOEP-14 improves overall survival in young high-risk patients with DLBCL compared with R-CHOP-14. A population-based investigation from the Danish Lymphoma Group
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ASH Education Book 2011:  Relapsed/Refractory Diffuse Large B-Cell
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JCO: Study Gives Slight Edge to R-DHAP for B-Cell Lymphoma Subtype- From Journal of Clinical Oncology
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J Cancer Research, Clinical Onc: How to determine post-RCHOP therapy for risk-tailored adult patients with diffuse large B-cell lymphoma, addition of maintenance rituximab or observation: multicenter experience
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Leuk Lymphoma: Pilot trial of yttrium-90 ((90)Y)-ibritumomab tiuxetan (Zevalin) consolidation following R-CHOP chemotherapy in patients with limited-stage, bulky DLBCL
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Cancer: Lack of benefit of central nervous system prophylaxis for diffuse large B-cell lymphoma in the rituximab era
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Blood: Epratuzumab with R-CHOP in patients with previously untreated DLBCL
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The Lancet: CHOP-like therapy with or without rituximab in young patients with good-prognosis DLBCL: 6-year results - (MInT) Group
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BJH: Biweekly R-COMP-14 in elderly patients with poor-risk DLBCL and moderate to high ‘life threat’ impact cardiopathy
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Blood: How I treat patients with
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Improving Outcomes for Patients with Diffuse Large B-cell Lymphoma
Flowers, Rajni, Sinha, Vose

 


Prognosis

A prognosis is NOT a prediction - it's an estimate of risk. 
It may tell you what curve you are on, but not where you are on the curve.

Prognosis
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.
Return to top

 

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

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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

"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
Return to top

TOPIC SEARCH PubMed:
Review | Therapies | Radiotherapy | Refractory | Relapsed

Overview

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Background articles
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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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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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Report: Dose Intensive R-ACVBP vs Standard R-CHOP In Younger Patients with DLBCL http://bit.ly/heJlx2
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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
Outcomes as of this writing (2014)
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About 40% of patients with DLBCL fail to respond to initial therapy or relapse
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Auto transplant (Standard of Care) cures about 48% of patients with chemotherapy-sensitive relapse 1,2
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Following ASCT in the relapse setting, about 70% of relapses occur in the first 12 months 1,2
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ABC (Activated B-cell) subtype patients do less well at the time of diagnosis and may be overrepresented at relapse
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Agents that target subtype-specific pathobiology may improve outcomes in combination with conditioning and during the high-risk period following ASCT.

1: Gisselbrecht et al, JCO 2012; 2: Vose et al, JCO 2013


Adding radiotherapy after R-chemo?

The decision to add radiotherapy for this indication seems to be based on individual risk factors, such as stage, areas of involvement, degree of bulk, perhaps LDH at diagnosis, and response to induction chemo. I suppose age is a factor, because the risk of radiotherapy decreases with age. (Reasons to consult an experts who have first-hand information about your case for a second opinion, not patients!)

NCCN guidelines, based on risk factors list protocols as
R-CHOP x 3 +RT (with radiotherapy)
R-CHOP x 6 +-RT (with or without radiotherapy)

Here's a fairly recent report on this question - that could help in the discussion with your
doctors:

JCO, 2010:
Benefit of Consolidative Radiation Therapy in Patients With DLBCL Treated With R-CHOP
http://171.66.121.246/content/28/27/4170.full

"Of 469 patients, 190 (40.5%) had stage I or II disease and 279 (59.5%) had stage III or IV disease, 327 (70%) had at least six cycles of R-CHOP, and 142 (30.2%) had involved-field RT (dose, 30 to 39.6 Gy) after complete response to chemotherapy.

Although radiation therapy (RT) was the first curative therapy for aggressive lymphomas, whether it continues to have a role in the treatment of DLBCL is controversial, with some studies supporting its use and others not. Four randomized trials were unable to conclusively determine the benefit of RT for patients with DLBCL

Our findings (with this caveat: retrospective study, single center) indicate that even in the era of R-CHOP chemotherapy, the use of RT was associated with significant improvements in OS and PFS for all patients with DLBCL. The benefit was seen in both univariate and multivariate analysis, across all disease stages and regardless of disease bulk. Although both the type and number of chemotherapy cycles administered varied somewhat, most patients (84%) received what is considered to be the current standard of care. Moreover, RT in all cases was delivered only to involved fields and not to adjacent uninvolved lymph node stations; this was done to minimize unnecessary toxicity."


Relapsed Diffuse Large B-Cell Lymphoma

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* Jonathan W. Friedberg, 2011, Hematology:
Relapsed/Refractory Diffuse Large B-Cell Lymphoma http://bit.ly/LBJJP7

* Sud, Friedberg, 2010:
Salvage therapy for relapsed or refractory diffuse large B-cell lymphoma: impact of prior rituximab http://bit.ly/LBKgRm
 
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Adult, Aggressive, Recurrent Non-Hodgkin’s Lymphoma
Standard of Care  Cancer.gov  
Salvage Therapy with stem cell transplant
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haematologica.org, 2008
R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO study  http://www.haematologica.org/content/93/12/1829.full

Clin Oncol. 2010
Salvage Regimens With Autologous Transplantation for Relapsed Large B-Cell Lymphoma in the Rituximab Era http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664033/?report=classic

Mediterr J Hematol Infect Dis. 2012
Autologous stem cell transplantation for aggressive lymphomas. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507533/ 

J Clin Oncol. 2013
Phase III randomized study of rituximab/carmustine, etoposide, cytarabine, and melphalan (BEAM) compared with iodine-131 tositumomab/BEAM with autologous hematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: results from the BMT CTN 0401 trial.
http://www.ncbi.nlm.nih.gov/pubmed/?term=CTN 0401

2007 Sep 10;
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 TransplantPMID: 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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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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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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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
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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 DLBCL  ClinicalTrials.gov
Untreated | Relapsed  | Excluding Stem Cell Transplant (rescue) 
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With stem cell transplant | Bexxar + Stem cell transplant


Stem Cell Transplant in Recurrent DLBCL

Comments:  Cancer.gov indicates that high dose therapy with autologous stem cell rescue is the standard of care (as of Jan 2012).  NCCN notes that allogeneic (from donor) SCT is indicated only in select cases, such as when there are mobilization failures (inability to harvest stem cells) or persistent bone marrow involvement.

The following reports suggest also that autologous SCT is the standard of care for initial relapse of DLBCL for those eligible for high dose therapy. But that an allogeneic SCT can succeed in those who relapse following an auto SCT.

Reports:
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DLBL, relapsed - BjH, 2007: Non-myeloablative (mini) allogeneic stem cell transplantation for relapsed diffuse large B-cell lymphoma: a multicentre experience http://bit.ly/wKWvXQ 

"Patients with DLBCL who relapse after, or are ineligible for, autologous HCT have a poor prognosis with conventional therapy. This study provides evidence that non-myeloablative allogeneic HCT is an effective salvage therapy which can produce long-term disease-free survival in a subset of these patients. Given that virtually none of these patients would be expected to achieve durable disease-free survival with conventional therapy, the rate of PFS seen after non-myeloablative allogeneic HCT is encouraging and provides proof of the principle that immunological GVL effects alone can control DLBCL in some cases."
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DLBCL, relapsed - Biology of Blood and Marrow Transplantation:
Low Nonrelapse Mortality and Prolonged Long-Term Survival after Reduced-Intensity Allogeneic Stem Cell Transplantation for Relapsed or Refractory Diffuse Large B Cell Lymphoma


"Sixty-eight patients (median age: 48 years) were transplanted from October 1998 to January 2007. They had received a median of 2 regimens of therapy prior to allogeneic SCT, and 54 (79%) had already undergone SCT. Prior to transplantation, 32 patients (47%) were in complete remission (CR)."
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Aggressive, Recurrent Adult Non-Hodgkin Lymphoma, Cancer.gov

"In a prospective randomized study, known as the EORTC-PARMA trial, 215 patients in first or second relapse of aggressive lymphoma, younger than 60 years, and with no bone marrow or central nervous system involvement, were given two cycles of intensive combination chemotherapy. The 109 patients who responded were randomly assigned to receive four more cycles of chemotherapy and involved-field radiation therapy (IF-XRT) versus autologous BMT followed by IF-XRT. With a 5-year median follow-up, the event-free survival was significantly improved with transplantation (46% vs. 12%). Overall survival (OS) was also significantly better with transplantation (53% vs. 32%).[7][Level of evidence: 1iiA] Salvage BMT was unsuccessful for patients on the nontransplant arm whose disease relapsed.
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The International Prognostic Index Correlates to Survival in Patients With Aggressive Lymphoma in Relapse: Analysis of the PARMA Trial 

"The results presented here show that the IPI at the date of relapse enables us to distinguish patients with a very different response rate to the DHAP regimen and a different survival. The proportion of patients in each risk group was comparable to that reported in the initial report of the IPI.18 However, it must be noted that the PARMA trial selected a population of favorable patients without BM or CNS involvement."
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DLBCL, relapsed - Annals of Oncology ,1999: International Consensus Conference on high-dose therapy with stem-cell transplantation in aggressive non-Hodgkin's lymphomas: Report of the jury*

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Novel Approaches to DLBCL in Relapse Setting

Here we will list approved and investigational agents that appear to have promise in the relapse setting as an alternative or "bridge" to high-dose therapy with stem cell rescue.

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Investigational approaches to high dose therapy with stem cell rescue
given with curative intent:

Stem Cell transplant studies

> (standard of care for relapsed DLBCL for eligible patients)  Reports
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Potentially curative but also high risk:

anti-CD-19 directed (CART19) engineered t-cells 
 
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  (adoptive immunotherapy)   Reports
 
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Immune modulating agent showing good activity in DLBCL:

Lenalidomide (Revlimid / CC 5013)

>
 (Immune-modulating / direct) Reports
 
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Early, investigational immune consolidation following standard treatment:

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nti-PD-1 antibody (CT-011 (pidilizumab) OR BMS-936558)
 
>  (inhibiting Immune checkpoint blockade)  Reports
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Appears to be most active in the Activated B- Cell (ABC) subtype of DLBCL:

Btk-inhibitor (PCI-32765
/ ibrutinib)
 >  (targeting the b-cell receptor pathway)
Reports
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Bispecific antibody
BiTe ( Blinatumomab | MT103)  >
Reports
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Panobinostat (LBH589) > Reports
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anti-CD19 + maytansinoi (SAR3419)  > Reports
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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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"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

 

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Monitoring aggressive lymphoma 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

In the News

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Onclive: Follow-Up Scans Do Little to Detect Relapse of Diffuse Large B-Cell Lymphoma http://bit.ly/105ODYv

Sixty-eight percent of patients had symptoms at the time of relapse, 55% had abnormal blood tests, and 42% had an abnormal physical exam finding. Notably, only eight relapses were detected through a planned surveillance scan before symptoms appeared—equivalent to just 1.5%.

Comment: A second question is if there is benefit to finding a relapse early - if doing so improves the chance to cure with second line therapy. It may turn out that sensitivity to treatment is more important than the stage at which the relapse was detected.

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 
  5. Value of serum beta 2 microglobulin as an indicator of early relapse in diffuse large cell lymphoma  ncbi.nlm.nih.gov

 

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

 

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ClinicalTrials.gov searches

Rationale for participation in clinical trials:

DLBCL is potentially curable with R-CHOP, but roughly 40% of patients either do not respond to treatment or relapse after achieving remission (Coiffier. Blood 2010). Further those who do not respond to R-CHOP have a long-term survival of only 20% (Gisselbrecht, J Clin Oncol 2010).

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Clinical Trials for DLBCL  ClinicalTrials.gov
Untreated | Relapsed  | Excluding Stem Cell Transplant (rescue) 
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With stem cell transplant | Bexxar + Stem cell transplant
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State or Country
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Other criteria such as age, stage, phase, refractory
 
Disclaimer:  The information on Lymphomation.org is not intended to be a substitute for 
professional medical advice or to replace your relationship with a physician.
For all medical concerns,  you should always consult your doctor. 
Patients Against Lymphoma, Copyright © 2004,  All Rights Reserved.