1. Non-Hodgkin’s Lymphoma
Epidemiology, Disease and Staging

2. Haematopoietic Malignancies
Myeloproliferative diseases
Leukaemias
Malignant lymphomas
chronic myeloid leukaemia (CML)
Acute myeloid leukaemia (AML)
Hodgkin’s lymphoma
Polycythemia vera (PV)
Chronic myeloid leukaemia (CML)
Non-hodgkin’s lymphoma (NHL)
Idiopathic myelofibrosis (MF)
Acute lymphatic leukaemia (ALL)
Burkitt's lymphoma
cutaneous T-cell lymphoma (CTCL)
Essential thrombocythemia (ET)
Chronic lymphatic leukaemia (CLL)
hairy cell leukaemia (HCL)

3. Haematopoietic Malignancies
Myeloproliferative diseases
Leukaemias
Malignant lymphomas
Family of chronic neoplastic diseases
Due to a clonal disorder arising at the level of the pluripotent stem cell
Characterised by abnormal proliferation of 1 or more blood cell lines
Neoplastic disease of a haematopoietic precursor cell
Characterised by replacement of normal bone marrow
Often infiltration into other organs
Malignant clones suppress normal cell formation
Neoplastic disease of lymphatic tissue
Originates in lymph node or spleen
Hodgkin’s (15%)
non-Hodgkin’s (85%)

4. The Lymphatic System

5. Lymphatic Tissue
Lymph nodes, spleen, liver, skin and the respiratory, GI and GTU tract
Lymphocytes undergo further proliferation and differentiation in lymphoid tissue
B-lymphocytes
tend to reside in lymph nodes & spleen
T-lymphocytes
tend to circulate throughout the lymphatic system

6. Lymph Node - normal histology
afferent lymphatic vessel
capsule C
cortex
follicle (mainly B-cells) - germinal centre - mantle zone
paracortex
medulla
artery
efferent lymphatic vessel
vein

7. Hodgkin’s Lymphoma 15% of lymphomas
First described by Thomas Hodgkin in 1832
Originally had a very poor prognosis (<10% survival at 5 years)
Improved staging techniques and understanding of the pattern of spread helps direct management
Now curable in over 70% of cases through the use of radiotherapy and chemotherapy

8. Non-Hodgkin’s Lymphoma (NHL): Definition and Indication
A heterogeneous group of B- and T-cell malignancies that are diverse in cellular origin, morphology, cytogenetic abnormalities, response to treatment, and prognosis
Defining non-Hodgkin’s lymphoma (NHL) has been a consistent challenge for clinicians.51,83 NHL describes a heterogeneous group of malignancies of B or T lymphocytes that generally originate in the lymph nodes. Lymphomas are differentiated by a range of cellular, morphologic, and molecular features.
NHL is the sixth most frequent malignancy in the United Kingdom.
The incidence of NHL is increasing at a rate of 5% to 8% per year.

9. Non-Hodgkin’s Lymphoma (NHL)
85% of lymphomas
6th major cause of cancer deaths yearly Heterogeneous group of malignant diseases arising from lymphoid tissue
lymph nodes, spleen
Various immune cell types
principally B-cells derivation (>85%)
T-cells derivation
Histiocytes (very rarely)
Various stages of differentiation and maturation

10. NHL Incidence Incidence of 13.3/100,000 per year (Aust)
Predominates in the years age group
most common neoplasm in the age group
Incidence is rising
150% growth over the past 30 years
increasing by 4% annually since 1970’s
Mortality rate is also rising
2% rise per year
third highest rise, exceeded only by lung cancer in women and malignant melanoma

11. NHL Incidence Increases with age Slight male predominance overall
implications
Slight male predominance overall
Striking male predominance for several subtypes
Incidence of certain subtypes varies greatly around the world
Burkitt’s Lymphoma in African children
T-cell type more common in Japan

12. Estimated Incidence of NHL in the Year 2000 (Worldwide)
North America
South Central Asia
Eastern Europe
Southeast Asia
Northern Europe
Western Africa
Northern Africa
Australia/New Zealand
Caribbean
Melanesia
With 60,000 new cases, North America had the highest estimated incidence of lymphoma in the world for the year 2000.
Micronesia
10,000
20,000
30,000
40,000
50,000
60,000

13. Estimated Incidence of NHL (US)
60,000
45,000
Estimated Annual Incidence
30,000
~4% compound annual increase in incidence
15,000
NHL is a heterogeneous group of B- and T-cell malignancies with diverse growth patterns and responses to therapy. Although some types of NHL are among the most common childhood cancers, more than 95% of cases occur in adults.40
The annual report of cancer statistics, issued by the American Cancer Society, estimates that 56,200 new cases of NHL will be diagnosed in the United States in the year NHL currently ranks fifth and sixth for newly diagnosed cancers among men and women, respectively, and it accounts for 5% of all cancer-related deaths in the United States.
The incidence of NHL in the United States and worldwide over the last 15 years has increased by approximately 4% annually, despite the decline in age-adjusted incidence rates for all cancers combined.40 NHL is one of the most rapidly rising cancers; its incidence has doubled since the early 1970s. Potential explanations for the increased incidence of NHL include infectious agents, congenital and acquired immunodeficiency syndromes, environmental exposure, and genetic factors.
1980
1985
1990
1995
2000
Year
Adapted from Greenlee et al. CA Cancer J Clin. 2001;51:15.

14. Revised European-American Lymphoma (REAL) Classification: B-Cell Neoplasms
Indolent
Aggressive
Very Aggressive
CLL/SLL
Lymphoplasmacytic/ IMC/WM
HCL
Splenic marginal zone lymphoma
MZL
- Extranodal (MALT)
- Nodal
Follicle center lymphoma, follicular, grade I-II
PLL
Plasmacytoma/ Multiple myeloma
MCL
Follicle centre lymphoma, follicular, grade III
DLCL
Primary mediastinal large B-cell lymphoma
High-grade B-cell lymphoma/Burkitt’s-like
Precursor B-lymphoblastic lymphoma/ Leukemia
Burkitt’s lymphoma/ B-cell acute leukemia
Plasma cell leukemia
Since Gall and Mallory proposed the first lymphoma classification in 1942, several systems have emerged as potentially more effective tools for diagnostic and prognostic purposes.82
In the last 10 years, increased understanding about NHL resulted in the recognition of new entities and refinement of previously recognized disease categories. A new clinical classification system was needed to accommodate these changes (eg, MCL and MALT lymphoma).
In 1994, the International Lymphoma Study Group proposed a new classification of hematologic malignancies, widely known as the Revised European American Lymphoma (REAL) Classification.51
Hiddemann. Blood. 1996;88:4085.
CLL = chronic lymphocytic leukemia; SLL = small lymphocytic lymphoma; IMC = immunocytoma; WM = Waldenström’s macroglobulinemia; HCL = hairy cell leukemia; MZL = marginal zone lymphoma; MALT = mucosa-associated lymphoid tissue; PLL = prolymphocytic leukemia; MCL = mantle cell lymphoma; DLCL = diffuse large B-cell lymphoma.
MZL = marginal zone lymphoma.

15. World Health Organization (WHO) Classification of Lymphoid Neoplasms: B-Cell Neoplasms
Precursor B-cell neoplasm
Precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia)
Mature (peripheral) B-cell neoplasms
B-cell CLL/SLL
B-cell PLL
Lymphoplasmacytic lymphoma
Plasmacytoma, plasma cell myeloma
HCL
Marginal zone B-cell lymphoma
Marginal zone B-cell lymphoma of MALT
Nodal marginal zone lymphoma (+/- monocytoid B-cells)
Splenic marginal zone B-cell lymphoma FL
Grade 1, 0-5 centroblasts/hpf
Grade 2, 6-15 centroblasts/hpf
Grade 3, >15 centroblasts/hpf
3a, >15 centroblasts, but centrocytes still present
3b, centroblasts from solid sheets with no residual centrocytes
Variants
Cutaneous follicle center
MCL
DLCL
Mediastinal (thymic) large B-cell lymphoma
Intravascular lymphoma
Primary effusion lymphoma
Burkitt’s lymphoma/Burkitt cell leukemia
The REAL classification was updated by the World Health Organization (WHO) in The modified REAL classification is based on morphology and cell lineage, and it includes B-cell neoplasms, T-cell neoplasms, and Hodgkin’s disease. Within each category, disorders are defined as indolent, aggressive, or very aggressive, based on the clinical course of each disease entity.57
Jaffe et al. Ann Oncol. 1998;9 (suppl 5):S25.
FL = follicular lymphoma; CLL = chronic lymphocytic leukemia; SLL = small lymphocytic lymphoma; HCL = hairy cell leukemia; MALT = mucosa-associated lymphoid tissue; PLL = prolymphocytic leukemia; MCL = mantle cell lymphoma; DLCL = diffuse large B-cell lymphoma.

16. Modified Ann Arbor Staging of NHL
Stage I Involvement of a single lymph node region
Stage II Involvement of 2 lymph node regions on the same side of the diaphragm
Stage III Involvement of lymph node regions on both sides of the diaphragm
Stage IV Multifocal involvement of 1 extralymphatic sites ± associated lymph nodes or isolated extralymphatic organ involvement with distant nodal involvement
Although it was originally designed for staging Hodgkin’s disease, the modified Ann Arbor staging system is also commonly used to define the extent of disease in NHL.83 However, this system does not address certain prognostic or therapeutic issues known to be important in NHL, such as bulky disease (lesion >10 cm in diameter).
Each of the stages is further subdivided
“A” – patients without B symptoms
“B” – patients with B symptoms (unexplained weight loss, sweats, high fever, or pruritis)
“E” – extranodal lymphoid malignancies; a symbol for the specific site may also be used: nodes (N), spleen (S), liver (H), pleura (P), lung (L), bone (O), bone marrow (M), skin (D)
The Non-Hodgkin’s Lymphoma Pathologic Classification Project. Cancer. 1982;49:2112.

17. Staging of NHL

18. Staging of NHL

20. Follicular non-Hodgkin’s Lymphoma
Classification and survival

21. Classification of Indolent NHL: International Working Formulation (IWF)
% of NHL Median Class Patients Survival (y)
A. Small lymphocytic
B. Follicular, predominantly small cleaved cell
C. Follicular, mixed small and large cell
D. Follicular, predominantly large cell
According to the International Working Formulation (IWF), there are 3 classes of indolent NHL (A, B, and C).82
These classes of indolent NHL are commonly grouped with follicular, predominantly large cell lymphoma (IWF class D) as “indolent lymphomas” due to similarities in disease characteristics and prognosis.
The median survival rate of patients with indolent lymphoma ranges from 3 to 7+ years.
As is shown in the slide, the majority of patients with indolent lymphoma have follicular, predominantly small cleaved cell NHL.
Follicular, mixed small and large cell NHL is the next most common class.
Follicular, predominantly large cell NHL and small lymphocytic NHL are less common.
The Non-Hodgkin’s Lymphoma Pathologic Classification Project. Cancer. 1982;49:2112.

22. Survival of Patients with Indolent Lymphoma: The Stanford Experience, 1960-1996
100 80 60
Patients (%) 40 20
Actuarial survival curves for patients with indolent NHL treated at Stanford University from 1960 to 1976, 1976 to 1987, and 1987 to 1996 are essentially indistinguishable, which shows that the widespread use of single-agent or multiagent chemotherapy or combined modality therapy has not had a significant impact on the natural course of the disease.54 5 10 15 20 25 30
Year
Adapted from Horning. Semin Oncol. 1993;20(5 suppl 5):75.

23. 1998-2000 CHOP + monoclonal antibody therapy
SWOG Finding: New treatment options have changed the natural history of follicular lymphoma1
91%
79%
69%
Overall survival (%)
Adapted from ref 1
CHOP + non-specific immunostimulants
ProMACE – MOPP + Interferon
CHOP + monoclonal antibody therapy
Impact of new treatment options on the natural history of follicular lymphoma determined by SWOG via retrospective analysis of three sequential treatment approaches :Fisher et al Blood 2004;104 Abstract 583

24. Follicular Lymphoma: Overall Survival
100 80
IPI 0/1 60
Overall Survival (%)
IPI 2/3 40 20
A retrospective evaluation of the REAL classification was conducted by the International Lymphoma Study Group. Nine institutions provided 200 consecutive cases of previously untreated patients with NHL that were representative of the region during the period between January 1, 1988, and December 31, In total, 1403 cases were examined.3 The International Prognostic Index (IPI) was used to stratify patients, and outcome was measured using failure-free survival and OS.
For patients with FL, overall rates were distinctly different among the various IPI risk groups. Five-year OS rates ranged from ~12% in the high-risk group (IPI 4–5) to ~87% in the low-risk group (IPI 0–1).3
P<0.001
IPI 4/5 1 2 3 4 5 6 7 8
Year
Adapted from Armitage and Weisenburger. J Clin Oncol. 1998;16:2780.

25. Aggressive non-Hodgkin’s Lymphoma
Classification and Survival

26. Years After Radomization
National High-Priority Lymphoma Study: Overall survival for aggressive lymphoma
100
CHOP
m-BACOD 80
ProMACE-CytaBOM
MACOP-B 60
Patients (%) 40 20
The efficacy of CHOP, a first-generation combination chemotherapy regimen, was demonstrated for lymphoma in the 1970s and 1980s. Patients achieved high response (45%–53%) and long-term survival rates (30%–37% 5 years).28
Single-institution studies conducted in the 1980s suggested that 55%–65% of patients with intermediate- or high-grade NHL might be cured by more complex, third-generation regimens.28
In the 1980s, the Southwest Oncology Group (SWOG) and the Eastern Cooperative Oncology Group (ECOG) conducted a prospective, randomized, phase III trial (NHPLS) to compare the relative efficacy of CHOP and several third-generation combination chemotherapy regimens in patients with aggressive NHL.28
Eligible patients (N=899) were stratified by prognostic factors and randomized into 4 treatment groups to receive CHOP, m-BACOD, ProMACE-CytaBOM, or MACOP-B.
At 3 years post-treatment, 44% of all patients were alive and disease-free without significant differences among the 4 treatment arms. Patients treated with CHOP, however, had fewer fatal toxic reactions (P=0.09).26
These results established CHOP as the standard of care for patients with aggressive NHL. 1 2 3 4 5 6
Years After Radomization
Fisher et al. N Engl J Med. 1993;328:1002.

27. International Prognostic Index (IPI)
Patients of all ages Risk Factors Age >60 years PS LDH level Elevated Extranodal involvement >1 site Stage (Ann Arbor) III-IV
Patients 60 years (age-adjusted) PS LDH Elevated Stage III-IV
To identify prognostic factors for survival, an international study involving >2000 patients with aggressive NHL was conducted between the years 1982 and
Objective characteristics independently associated with survival included age, PS, serum LDH level, number of extranodal disease sites, and disease stage (Ann Arbor). For younger patients (60 years), clinical features predictive of survival were PS, LDH, and stage.
Shipp. N Engl J Med. 1993;329:987.

28. IPI Risk Strata Risk Factors Risk Group
All ages Low (L) Low-intermediate (LI) 2 High-intermediate (HI) 3 High (H) 4-5
Age-adjusted L 0 LI 1 HI 2 H 3
Because the relative risk associated with each prognostic factor is similar, the survival probability is simply calculated by adding the number of prognostic factors present at diagnosis.
The relative risk for death in patients with each possible number of prognostic factors was determined, and patients with similar relative risk (low [L], low-intermediate [LI], high-intermediate [HI], or high [H] risk) were identified.107
An age-adjusted model was also developed because of significant differences in treatment options and clinical outcomes for younger (60) vs older (>60) patients.
Shipp. Blood. 1994;83:1165.

29. IPI: Overall Survival by Risk Strata
100 75 L
Patients (%) 50 LI HI 25
Each of the 4 risk groups in the International NHL Prognostic Factors Project exhibited a distinct 5-year survival pattern ranging from 26% in the high-risk group to 73% in the low-risk group.56 H 2 4 6 8 10
Year
Adapted from Shipp. N Engl J Med. 1993;329:987.

30. Age-Adjusted IPI: Overall Survival by Risk Strata
100 L 75 LI
Patients (%) 50 HI 25 H
A similar pattern of survival was evident among younger patients (60) with 5-year survival rates ranging from 32% in the high-risk group to 83% in the low-risk group.56 2 4 6 8 10
Year
Adapted from Shipp. N Engl J Med. 1993;329:987.

31. DLCL: Overall Survival
100 80
IPI 0-1 60
Patients (%) 40
IPI 2-3
IPI 4-5 20
A retrospective evaluation of the REAL classification was conducted by the International Lymphoma Study Group.3 Nine institutions provided 200 consecutive cases of previously untreated patients with NHL that were representative of the region during the period between January 1, 1988, and December 31, In total, 1403 cases were examined. The IPI was used to stratify patients, and outcome was measured using failure-free survival and OS.
The most frequently occurring NHL was the aggressive subtype, DLCL. Overall survival rates were distinctly different between the various IPI risk groups. Five-year OS rates ranged from 20% in the high-risk group to 70% in the low-risk group.3
P<0.001 1 2 3 4 5 6 7 8
Year
Adapted from Armitage and Weisenburger. J Clin Oncol. 1998;16:2780.