1. Improving Outcomes for Patients with Diffuse Large B-Cell Lymphoma
Journal conference
Improving Outcomes for Patients
with Diffuse Large B-Cell Lymphoma
CA CANCER J CLIN 2010;60:393–408
Christopher R. Flowers, MD, MS1; Rajni Sinha, MD, MRCP2;
Julie M. Vose, MD3
R3 Jae Ryung Shin/ Prof. Hwi Jung Yun

2. Introduction Epidemiology DLBCL Risk Factors
- Dietary, Genetic, Environmental, Clinical Conditions
Clinical Presentation
Clinical Prognostic Factors
- PET Scanning as a Prognostic Indicator in DLBCL
Histological Features and Pathological Classification
Biological Prognostic Factors
DLBCL Treatment and Outcomes
- First-Line Treatment
- Salvage Treatment for Patients With Relapsed DLBCL
- Novel Therapies for DLBCL

3. Epidemiology
NHL increased dramatically from the 1970s until the middle of the 1990s
- estimated 65,540 new cases expected in the United States in 2010
- increase of 3% to 4% per year in incident cases of lymphoma
From 1992 to 2006, the age-adjusted incidence rate for DLBCL increased approximately 1% per year
Several factors have contributed to this increased incidence including
- more sensitive methods for identifying diagnostic cases
- Improvements in cancer reporting for hematological malignancies
- changes in the classification systems used for lymphoid malignancies
- increase in HIV-associated lymphomas

4. Epidemiology
DLBCL occurred in both sexes, across racial categories, all age
- the median age is in the seventh decade
Males have a 1.5-fold higher incidence of DLBCL
There are significant racial differences in DLBCL incidence
- white Americans: age-adjusted incidence of 7.36 per 100,000
- black Americans: an incidence of 4.88
- mixed categories of American Indians, Alaska Natives,
and Asian/Pacific Islanders have an incidence of 5.59
Some factors that influence the risk of lymphoma
- genetics
- comorbid diseases or their treatments (notably immunosuppression)
- environmental factors such as ultraviolet radiation, pesticides,
hair dyes, and diet

5. DLBCL Risk Factors
Higher total flavonoid intake was associated with a 47% risk reduction in NHL when comparing the highest quartile of intake to the lowest, with similar risk reduction seen for DLBCL, odds ratio (OR), 0.39; 95% CI,
Am J Clin Nutr. 2008;87:
Greater intake of total fruits and vegetables was associated with lower NHL risk but was not observed among patients with DLBCL
The Iowa Women’s Health Study. Int J Cancer. 2010;126:
Severe obesity (defined as BMI of 40 kg/m2) was not associated with risk of NHL overall, or most NHL subtypes, but was associated with increased risk of DLBCL (pooled OR, 1.80), which may warrant further investigation
Int J Cancer. 2008;122:

6. DLBCL Risk Factors
Genetic predisposition underlies the etiology of DLBCL and other NHLs
1) NHL risk is increased in individuals with a family history of
hematopoietic malignancy
- a first-degree relative with NHL(OR, 1.4; 95% CI, ), Hodgkin
lymphoma (OR 1.7; 95% CI, ); leukemia (OR 1.3; 95% CI, )
Blood. 2007;109:
2) Some common genetic variations
- promote B-cell survival and growth increase the risk of lymphoma
- TNF-308 G>A (OR, 1.29; 95% CI, )
- Interleukin-10, IL T>A genes (OR, 1.15; 95% CI, ),
- Both TNF-308G>A and IL T>A occurred, the OR for
developing DLBCL was 2.13
Lancet Oncol. 2006;7:27-38
Recent findings suggest that genetic polymorphisms in TNF and IL10 are associated with an increased risk of non-Hodgkin lymphoma (NHL), particularly for diffuse large B-cell lymphoma (DLBCL).

7. DLBCL Risk Factors
Proximity to industrial facilities had on developing NHL
Living within 2 miles of a lumber facility was associated with increased DLBCL risk (OR, 1.7; 95% CI, ) but did not provide strong evidence that living near manufacturing industries increases NHL risk overall
Environ Res. 2010;110:70-78
Increased recreational sun exposure was associated with decreased risk of NHL and DLBCL (pooled ORs, 0.76; 95% CI, and 0.69; 95% CI, , respectively) for the highest exposure category, but this level of sun exposure may be associated with other health risks
Int J Cancer. 2008;122:
In other studies, ultraviolet radiation, herbicides, insecticides, and oxidative dye products have also been associated with increased lymphoma risk, but debate remains concerning their relative influence on DLBCL development specifically

8. DLBCL Risk Factors
Several infectious organisms have been linked to the risk of lymphoma
- Epstein-Barr virus(EBV)
: Immunoblastic and primary central nervous system DLBCLs
- Immunodeficient patients in association with infection by HHV8
: Primary effusion lymphoma
- Helicobacter pylori, Chlamydia psittaci
: Indolent lymphomas
- HCV infection
: lymphoplasmacytic lymphoma (OR, 2.57)
marginal zone lymphoma(OR, 2.47)
DLBCL (OR, 2.24; 95% CI, )

9. DLBCL Risk Factors
Associated with a diagnosis of rheumatoid arthritis (OR, 1.4),
Sjogren syndrome (OR, 2.0), and autoimmune hemolytic anemia (OR, 3.3)
Int J Cancer. 2009; 125:
Systemic lupus erythematosus and hemolytic anemia also were associated with increased risk
Blood. 2008;111:

10. Clinical Presentation
Most patients present with a rapidly enlarging, painless, lymph node
Up to 40% of patients, the initially identified site is extranodal
- involving the skin, gastrointestinal tract, central nervous system(CNS),
lungs, genitourinary tract, or the bones.
Approximately 15% of patients present with bone marrow involvement
about one-third have B-symptoms(fever, night sweats, and weight loss)
nearly one-half have Ann Arbor system stage III/IV disease
and more than one-half have an elevated serum LDH level

11. Clinical Prognostic Factors
(IPI) remains the primary clinical tool used to predict outcome for patients with DLBCL
Revised IPI (R-IPI) grouping, 3 separate categories were defined that provided more accurate prediction of outcome

12. PET Scanning
Predicting outcomes in DLBCL is evaluating interval response to therapy
A study of 98 patients treated at the Memorial Sloan Kettering Cancer Center with DLBCL who received initial treatment with CHOP plus rituximab and risk-adapted therapy on the basis of PET scan
- 51 of 59 patients who had a negative PET scan were progression free at a median follow up of 44 months. However, among 38 patients who had a positive PET after 4 cycles and who underwent repeat biopsy, 33 were negative for DLBCL, and 26 remained progression free after consolidation therapy
J Clin Oncol. 2010;28:
Negative interim PET scan after 4 cycles of CHOP-based chemotherapy can have prognostic significance for patients with DLBCL, but positive interim PET scans need to be followed by biopsy before additional treatment is implemented

13. Pathology Recognize multiple morphologic variants
This classification system demonstrates the importance of site or clinical factors in defining variants of DLBCL

14. Biological Prognostic Factors
Gene expression analyses of DLBCL biopsy samples by using DNA microarrays
Activated (ABC-DLBCL), with a pattern of genetic expression that is similar to healthy, activated B cells, and a chromosomal translocation involving the gene bcl-6
Germinal center (GCB-DLBCL), with a pattern of genetic expression that is similar to germinal center B cells and a chromosomal translocation involving the gene bcl-2
- The GCB subtype had significantly better outcome
(3-year OS, 87% GCB vs 44% ABC; P < .001)
Clin Cancer Res. 2009;15:
Primary mediastinal B-cell lymphoma(PMBL), tends to occur in younger
patients in the anterior mediastinum with a GEP signature that
significantly overlaps with Hodgkin lymphoma cell lines

15. Initial Treatment
rituximab is thought to induce lymphoma cell lysis through complement-mediated cytolysis, antibody-dependent cell cytotoxicity, and direct induction of apoptosis. In addition, Rituximab acts synergistically with chemotherapy
CR rates were 67% in the R-CHOP14 and 75% in the R-CHOP21
The 2-year EFS, PFS, and OS were 48%, 49%, and 67% for the
R-CHOP14 compared with 61%, 63%, and 72% for R-CHOP21
But, these differences were not statistically significant
Grade 3-4 hematological toxicity was more frequent in the R-CHOP14 group
GELA, LNH03-6B trial

16. British Journal of Haematology,2006, 133, 3–18
Salvage Treatment
British Journal of Haematology,2006, 133, 3–18

17. British Journal of Haematology,2006, 133, 3–18
Salvage Treatment
British Journal of Haematology,2006, 133, 3–18

18. Novel Therapies for DLBCL
A multicenter phase 2 study of a potent inhibitor of protein kinase C beta (PKCβ), an enzyme involved in the induction of VEGF-stimulated neo-angiogenesis, enzastaurin, maintenance therapy after RCHOP administration in DLBCL patients
J Clin Oncol. 2007;25:
B-cell receptor (BCR)-mediated survival signals, can be blocked by an inhibitor of spleen tyrosine kinase (Syk), fostamatinib disodium, which induces apoptosis in B-cell lymphoma cell lines and primary tumors
Blood. 2010;115:
limit the activity of enzastaurin and Syk inhibitors to subsets of ABC-like DLBCL
A proteasome inhibitor, prevent degradation of pro-apoptotic factors, bortezomib(velcade), demonstrated single-agent activity which led to its approval for use in relapsed mantle cell lymphoma
J Clin Oncol. 2006;24:

19. Novel Therapies for DLBCL
Lenalidomide, that is used in MDS and myeloma, has been studied in patients with relapsed aggressive lymphomas and has produced responses in 5 of 26 DLBCL patients
J Clin Oncol. 2008;26:
Other antibodies targeting B-cell lymphomas
- AME-133, GA101, veltuzumab (all CD20), epratuzumab (CD22)
dacetuzumab(CD40), galiximab (CD80), lexatumumab(TRAIL)
AME-133: A Next-Generation Anti-CD20 Engineered for Enhanced Killer Function
GA-101, a third-generation, humanized and glyco-engineered anti-CD20 mAb
Veltuzumab is a monoclonal antibody which is being investigated for the treatment of non-Hodgkin's lymphoma
Epratuzumab is a humanized monoclonal antibody
Dacetuzumab (also known as SGN-40 or huS2C6) is a humanized monoclonal antibody
Galiximab is a monoclonal antibody designed for the treatment of B-cell lymphoma
Lexatumumab (also known as ETR2-ST01) is an agonistic human monoclonal antibody