Calculate International Prognostic Index (IPI)

Staging tests:
 

	CT of Chest/abdominal/pelvic with contrast of diagnostic quality
	Unilateral or bilateral bone marrow biopsy (1-2 cm) + aspirate to document clinical stage I_II disease
	PET-CT scan
	Useful in select cases:   Lumbar puncture if involvement in following sites:   paranasal sinus, testicular, epidural, bone marrow with large cell lymphoma, HIV lymphoma, or > 2 extranodal sites   CT or MRI of neck and head

Physical exam:
 

	Attention to node-bearing areas, including Waldeyer's ring
	Examine size of liver and spleen
	Performance status
	B symptoms

Labs and tests:
 

	CBC, differential, platelets,
	Beta-2-microglobulin
	LDH
	Comprehensive metabolic panel
	Uric acid
	Hepatitis B testing
	MUGA scan / echocardiogram"  (prior to anthracycline-based therapy)
	Useful in select cases:   HIV test

Treatment, age and gender specific:
 

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

2017: Clinical Controversies of Double-Hit Lymphoma
http://bit.ly/2qoLfex  an excellent review

Outcomes of Patients With Double-Hit Lymphoma
Who Achieve First Complete Remission ascopubs.org

Medscape 2014 with video and text:
Double-Hit Lymphomas Explained, With Surprising (and encouraging)
EPOCH-R Data, and more  
 

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].

Background on DLBCL

Diffuse Large B-Cell Lymphoma  http://bit.ly/DLBCL-friedberg
Jonathan W. Friedberg, M.D., M.M.Sc.* (2009)

Best Practice and Research in Clinical Haematology: Diffuse large B Cell lymphoma: How can we cure more patients in 2012?

Best Practice and Research in Clinical Haematology: Relapses, treatments and new drugs

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."

Outcomes in treatment-refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study http://bit.ly/2ub9obZ 

Unmet need clearly defined.

"refractory DLBCL, which, for this study, was defined as progressive disease or stable disease as best response at any point during chemotherapy (>4 cycles of first-line or 2 cycles of later-line therapy) or relapsed =12 months of autologous stem cell transplantation."
 

Suboptimal dosing of rituximab in male and female patients with DLBCL. - PubMed - NCBI http://bit.ly/2kPfE34

2016, JCO: Continued Risk of Relapse Independent of Treatment Modality in Limited-Stage Diffuse Large B-Cell Lymphoma: Final and Long-Term Analysis of Southwest Oncology Group Study S8736 http://bit.ly/29BJaFW 
 

DLBCL patients who are event-free at 24 months after treatment
have a normal life expectancy. http://1.usa.gov/1UHvDb8 

Alvarez et al. CLML 2014 (informs practice)
What Determines Therapeutic Choices for Elderly DLBCL Pts? [Portugal]  http://ow.ly/Rv5PF 

CONCLUSION:  This was the first characterization of the clinical care of elderly Portuguese patients with DLBCL. We showed that R-CHOP is effective even in patients > 79 years, emphasizing that treatment decisions based on age alone can compromise treatment efficacy and outcome in fit patients.
 

2015, technical:
Blood Cancer Journal - Whole-exome analysis reveals novel somatic genomic alterations associated with outcome in immunochemotherapy-treated diffuse large B-cell lymphoma http://bit.ly/1JHlxB1 (full paper)

In summary, we provide the first data using WES to identify somatic genomic alterations in immunochemotherapy-treated DLBCL tumors that are associated with failure to achieve EFS24, identifying those patients who have treatment-resistant and aggressive disease. Although these novel targets require replication and functional validation, the results are provocative and supported by prior work. We biologically validate the potential impact of deletions in SLC22A16 at 6q21 and future biological analysis of additional CNAs and mutations is warranted.
 

Double-hit lymphoma

2015 Educational Book | Meeting Library 2015 http://bit.ly/1EVzM2s

Agents with Differential Single Agent and in Combination of XR-CHOP Activity in DLBCL Subtypes meetinglibrary.asco.org 2015: http://bit.ly/1RJeP3K

Double-hit Lymphoma: Table of Induction Therapy and Outcome From meetinglibrary.asco.org, 2015: http://bit.ly/1JpVHoP
 

2014: Dunleavy, Wilson on
Molecular Subtypes of Diffuse Large B-Cell Lymphoma | Cancer Network http://bit.ly/1zIfRSE   Login Required

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
 

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)
 

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.
 

ASH 2012: compiled abstracts by PAL

ASCO 2012: Diffuse Large B-cell Lymphoma abstracts

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

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 inhibitorsCancer: Limited-stage diffuse large B-cell lymphoma treated with abbreviated systemic therapy and different types of consolidation radiotherapy

Trial of interest - Relapsed DLBCL - Navitoclax (ABT-263 - a BCL-2 inhibitor) in Addition to Bendamustine and Rituximab (NAVIGATE trial)

Recent report on Navitoclax

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.

Brit J Hem: The addition of rituximab reduces the incidence of secondary central nervous system involvement in patients with diffuse large B-cell lymphoma

Cancer Chemo and Pharmacology: Addition of rituximab to reduced-dose CHOP chemotherapy is feasible for elderly patients with diffuse large B-cell lymphoma

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

ASH Education Book 2011:  Relapsed/Refractory Diffuse Large B-Cell

JCO: Study Gives Slight Edge to R-DHAP for B-Cell Lymphoma Subtype- From Journal of Clinical Oncology

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

Leuk Lymphoma: Pilot trial of yttrium-90 ((90)Y)-ibritumomab tiuxetan (Zevalin) consolidation following R-CHOP chemotherapy in patients with limited-stage, bulky DLBCL

Cancer: Lack of benefit of central nervous system prophylaxis for diffuse large B-cell lymphoma in the rituximab era

Blood: Epratuzumab with R-CHOP in patients with previously untreated DLBCL

The Lancet: CHOP-like therapy with or without rituximab in young patients with good-prognosis DLBCL: 6-year results - (MInT) Group

BJH: Biweekly R-COMP-14 in elderly patients with poor-risk DLBCL and moderate to high ‘life threat’ impact cardiopathy

Blood: How I treat patients with

Improving Outcomes for Patients with Diffuse Large B-cell Lymphoma
Flowers, Rajni, Sinha, Vose

Postsplenectomy Therapy in Diffuse Large B-cell Lymphoma? - Medscape (free login req.)

Primary splenic lymphoma: report of 10 cases using the REAL classification.
 
Cancer Invest. 2002;20(5-6):749-53. PMID: 12197231   PubMed

Background articles

	Diffuse Large B-Cell Lymphoma  http://bit.ly/DLBCL-friedberg Jonathan W. Friedberg, M.D., M.M.Sc.* (2009)
	How I treat patients with diffuse large B-cell lymphoma,   James O. Armitage MD   bloodjournal.hematologylibrary.org
	About DLBCL:  asheducationbook.org
	Medscape (free login req.)

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.

Treatment of Elderly  PAL

Monoclonal Antibodies in Aggressive, De Novo, or Relapsed Lymphomas  Medscape (free login req.)

Role of Radiation Therapy in Localized Aggressive Lymphoma  jco.ascopubs.org (2007, editorial)

Report: Dose Intensive R-ACVBP vs Standard R-CHOP In Younger Patients with DLBCL http://bit.ly/heJlx2

Adult Non-Hodgkin’s Lymphoma ~ Best Practice  Cancer.gov  

"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

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."

CHOP + Rituxan is the standard of treatment [2005]  for 
Diffuse Large B-cell Lymphoma.  See CHOP+R

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

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 

CHOP-R + bortezomib (Velcade) as initial therapy for diffuse large B-cell lymphoma (DLBCL). http://bit.ly/9ifYVY
 

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.

Clinical trials in ClinicalTrials.gov

About 40% of patients with DLBCL fail to respond to initial therapy or relapse

Auto transplant (Standard of Care) cures about 48% of patients with chemotherapy-sensitive relapse 1,2

Following ASCT in the relapse setting, about 70% of relapses occur in the first 12 months 1,2

ABC (Activated B-cell) subtype patients do less well at the time of diagnosis and may be overrepresented at relapse

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

Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study
http://bit.ly/2ub9obZ 
 

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
 

Adult, Aggressive, Recurrent Non-Hodgkin’s Lymphoma
Standard of Care  Cancer.gov  

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 Transplant.  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

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.

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.

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

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."
 

Clinical Trials for DLBCL  ClinicalTrials.gov

Untreated | Relapsed  | Excluding Stem Cell Transplant (rescue) 

With stem cell transplant | Bexxar + Stem cell transplant

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."

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)."

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.

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."

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*

DLBCL: Double-Hit Lymphoma
2015 Educational Book | Meeting Library 2015 http://bit.ly/1EVzM2s

Agents with Differential Single Agent and in Combination of XR-CHOP Activity in DLBCL Subtypes meetinglibrary.asco.org 2015: http://bit.ly/1RJeP3K

Double-hit Lymphoma: Table of Induction Therapy and Outcome From meetinglibrary.asco.org, 2015: http://bit.ly/1JpVHoP
 

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

Potentially curative but also high risk:

anti-CD-19 directed (CART19) engineered t-cells   
>  (adoptive immunotherapy)   Reports
 

Immune modulating agent showing good activity in DLBCL:

Lenalidomide (Revlimid / CC 5013)
>  (Immune-modulating / direct) Reports
 

Early, investigational immune consolidation following standard treatment:

Anti-PD-1 antibody (CT-011 (pidilizumab) OR BMS-936558)
 >  (inhibiting Immune checkpoint blockade)  Reports

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

Bispecific antibody
BiTe ( Blinatumomab | MT103)  > Reports

Panobinostat (LBH589) > Reports

anti-CD19 + maytansinoi (SAR3419)  > Reports

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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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.

Clinical Trials for DLBCL  ClinicalTrials.gov

Untreated | Relapsed  | Excluding Stem Cell Transplant (rescue) 

With stem cell transplant | Bexxar + Stem cell transplant

State or Country

Other criteria such as age, stage, phase, refractory