1. NHL Board Review
Brad Kahl, MD
1/20/04

2. NHL: Outline Epidemiology Classification Prognostic Factors
Treatment Principles
Disease by disease breakdown

3. NHL: Epidemiology Most common hematologic malignancy incidence rising
54,000 new cases annually
6th leading cause of cancer death (women)
5th in men
incidence rising
overall incidence up by 73% since 1973
“epidemic”
2nd most rapidly rising malignancy 3

4. Estimated New Cancer Cases
Estimated New Cancer Cases*: 10 Leading Sites, by Sex, United States, 2003
Prostate 33%
Lung & bronchus 14%
Colon & rectum 11%
Urinary bladder 6%
Melanoma of skin 4%
Non-Hodgkin’s 4% lymphoma
Kidney 3%
Oral cavity 3%
Leukemia 3%
Pancreas 2%
All other sites 17%
32% Breast
12% Lung & bronchus
11% Colon & rectum
6% Uterine corpus
4% Ovary
4% Non-Hodgkin’s lymphoma
3% Melanoma of skin
3% Thyroid
2% Pancreas
2% Urinary bladder
20% All other sites
Key Point: NHL is a common cancer, accounting for 4% of all new cases.
NHL is the sixth most common newly diagnosed cancer in the United States, accounting for 4% of all new cases.1
It is estimated that in 2003 there will be 53,400 new cases of NHL and 23,400 deaths due to NHL.1,2
It is distributed equally among men and women, with 53% of cases in men and 47% in women.1
Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, CA Cancer J Clin. 2003;53:5–26.
American Cancer Society. Cancer Facts and Figures Atlanta, Ga: American Cancer Society; 2003.
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Jemal et al. CA Cancer J Clin. 2003;53:5-26.

5. Incidence of NHL Is Increasing, Especially in the Elderly (60 Years)
SEER NHL incidence by age, 1975–1977 and 1998–2000 (male, all races)
140
120
1998–2000
1975–1977
100
No. per 100,000 80 60
Key Point: The incidence of NHL is increasing, especially in the elderly.
NHL is a growing problem, especially in elderly patients (>60 years), as shown above in the graph of SEER data.
An increase in the incidence of NHL is seen in almost all age groups in the 20 years from 1975–1977 to 1998–2000, with the highest increase in persons older than 60 years.1
NHL accounts for more than 80% of the lymphomas diagnosed in the United States (53,400 of the estimated 61,000 new cases of lymphoma in 2003).2
The probability of the development of NHL in men increases from 1 in 218 at ages 40–59 to 1 in 80 at ages 60–79 and in women from 1 in 316 to 1 in 101 in the same age ranges.2
Ries LAG, Eisner MP, Kosary CL, et al, eds. SEER Cancer Statistics Review, , National Cancer Institute. Bethesda, Md,
American Cancer Society. Cancer Facts and Figures Atlanta, Ga: American Cancer Society; 2003. 40 20 5
5–9
85
10–14
15–19
20–24
25–29
30–34
35–39
40–44
45–49
50–54
55–59
60–64
65–69
70–74
75–79
80–84
Age at diagnosis (years)
Ries et al (eds). SEER Cancer Statistics Review, National Cancer Institute. Bethesda, Md,

6. NHL: Epidemiology Why the increase? Other environmental factors
Increase noted mostly in farming states
MN #1, WI #7 NHL incidence
possible role of herbicides, insecticides, etc.
Other environmental factors
hair dye-very weak association
radiation-no association 9

7. NHL: Epidemiology Other risk factors immunodeficiency states
AIDS, post-transplant, genetic
Chronic immune stimulation/activation
autoimmune diseases
Sjogrens
Sprue
infections
H. pylori, EBV, HHV-8 10

9. Revised European-American Lymphoma (REAL) Classification: B-Cell Neoplasms
Indolent
CLL/SLL
Lymphoplasmacytic/ IMC/WM
HCL
Splenic marginal zone lymphoma
Marginal zone lymphoma
Extranodal (MALT)
Nodal
Follicle center lymphoma, follicular, grade I-II
Aggressive
PLL
Plasmacytoma/ Multiple myeloma
MCL
DLCL
Primary mediastinal large B-cell lymphoma
Follicle center lymphoma, follicular, grade III
Very Aggressive
Precursor B-lymphoblastic lymphoma/Leukemia
Burkitt’s lymphoma/ B-cell acute leukemia
Burkitt’s-like
Plasma cell leukemia
Since Gall and Mallory proposed the first lymphoma classification in 1942, several systems have emerged as potentially more effective tools for diagnosis and prognostic purposes.2
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.3 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.
CLL = chronic lymphocytic leukemia; SLL = small lymphocytic lymphoma; IMC = immunocytoma; WM = Waldenström’s macroglobulinemia; HCL = hairy cell leukemia; MALT = mucosa-associated lymphoid tissue; PLL = prolymphocytic leukemia; MCL = mantle cell lymphoma; DLCL = diffuse large B-cell lymphoma.
Hiddemann. Blood. 1996;88:4085.

10. NHL: Approach to the Patient
Staging evaluation
History and PE
Routine blood work
CBC, diff, plts, electrolytes, BUN, Cr, LFT’s, uric acid, LDH, B2M, HIV
CT scans chest/abd/pelvis
Bone marrow evaluation
Other studies as indicated (lumbar puncture, MRI, PET, etc…)

11. 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.5 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)
Cancer. 1982;49:2112.

12. Modified Ann Arbor Staging of NHL
“E” designation for extranodal disease
B symptoms
recurrent drenching night sweats during previous month
unexplained, persistent, or recurrent fever with temps above 38 C during the previous month
unexplained weight loss of more than 10% of the body weight during the previous 6 months
Criteria for bulk
10 cm nodal mass
mediastinal mass > 1/3 thorax diameter

13. International Prognostic Index (IPI)
Patients of all ages Risk factors Age > 60 years Performance status (PS) Lactate dehydrogenase (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 > 2,000 patients with aggressive NHL was conducted between the years 1982 and
Objective characteristics independently associated with survival included age, performance status (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.

14. IPI Risk Strata Risk Factors Risk Group
All ages Low (L) Low-intermediate (LI) High-intermediate (HI) High (H) 4-5
Age-adjusted L LI HI 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.7
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.

15. IPI: Overall Survival by Risk Strata
100 75
Patients (%) 50 L LI
Each of the four 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.6 25 HI H 2 4 6 8 10
Year
Adapted from Shipp. N Engl J Med. 1993;329:987.

16. Age-Adjusted IPI: Overall Survival by Risk Strata
100 L 75 LI
Patients (%) 50 HI
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.6 25 H 2 4 6 8 10
Year
Adapted from Shipp. N Engl J Med. 1993;329:987.

17. Follicular Lymphoma (FL) : Overall Survival
100 80
IPI 0/1 60
Overall Survival (%)
IPI 2/3 40
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.7 The International Prognostic Index (IPI) was used to stratify patients, and outcome was measured using failure-free survival and overall survival.
For patients with FL, overall survival rates were distinctly different among the various IPI risk groups. Five-year overall survival rates ranged from ~ 12% in the high-risk group (IPI 4–5) to ~ 87% in the low-risk group (IPI 0–1).7 20
P < 0.001
IPI 4/5 1 2 3 4 5 6 7 8
Year
Adapted from Armitage. J Clin Oncol. 1998;16:2780.

18. NHL: Approach to the Patient
Approach dictated mainly by histology
reliable hematopathology crucial
Approach also influenced by:
stage
prognostic factors
co-morbidities 17

19. Treatment Strategies for Indolent NHL
Stage I-II Disease
“Watchful waiting”
Radiation
Stage III-IV Disease
“Watchful waiting”
Purine analogs
Alkylating agents
Combination chemotherapy
MoAbs (conjugated and unconjugated)
Chemotherapy + MoAbs
Intensive chemotherapy + autologous/allogeneic bone marrow (BM) or peripheral blood (PB) transplantation
In many patients with early (stage I-II) or advanced (stage III-IV) lymphoma, treatment is deferred until systemic disease or tumor burden develops (“watchful waiting”).8
Patients with stage I-II disease most commonly undergo “watchful waiting” or receive radiation.
Because patients with advanced-stage, low-grade NHL have high relapse rates and are rarely cured with current therapies, there is considerable controversy about how to treat these patients. The most common therapies include purine analogs (ie, Fludara® [fludarabine]), alkylating agents (eg, cyclophosphamide, chlorambucil), combination chemotherapy (eg, CHOP, CVP, FND), unconjugated monoclonal antibodies (MoAbs) (eg, Rituxan® [rituximab]), and intensive chemotherapy + autologous/allogeneic bone marrow (BM) or peripheral blood (PB) transplantation. In addition, investigational studies are evaluating the efficacy of radio-conjugated MoAbs (eg, Zevalin™ [90y-ibritumomab], Bexxar™ [131I-tositumomab]) for indolent NHL.

20. Indolent NHL: chlorambucil vs W&W

21. Indolent NHL: What are reasonable first line therapies?
Therapy #
ORR CR
Median PFS
Reference
Chlorambucil
158
90%
63% ?
Ardeshna, Lancet 2003
Cytoxan (daily)
119
89%
66%
4.2 yrs
Peterson, JCO 2003
Chl-P (pulse) 77
78%
34%
2.5 yrs
Baldini, JCO 2003
CVP (which?)
(Await E1496)
CHOP (B)
109
93%
60%
3.6 yrs
ProM-MOPP
500
83%
47%
3.2 yrs
Fisher, JCO 2000
Fludarabine
101
84%
3.0 yrs
Zinzani, JCO 2000 FN 78
94%
44%
2.7 yrs
Velasquez, JCO 2003
FND 73
98%
79%
3.5 yrs
Tsimberidou, Blood 2002
ATT 69
97%
87%
5.0 yrs

22. NHL: Approach to the Patient
Indolent NHL: guiding treatment principle
early treatment does not prolong overall survival
When to treat?
constitutional symptoms
compromise of a vital organ by compression or infiltration, particularly the bone marrow
bulky adenopathy
rapid progression
evidence of transformation

23. NHL: Approach to the Patient
Aggressive NHL: treatment approach
Stage I-II: combined modality therapy
R-CHOP chemotherapy x 3 + IF radiotherapy
Consider more chemo if bulky, high LDH, stage II
Stage III-IV (also bulky stage II)
R-CHOP chemotherapy x 6-8 cycles
Great lesson in clinical trials

24. National High Priority Lymphoma Study: Progression-Free Survival
100
CHOP
m-BACOD 80
ProMACE-CytaBOM
MACOP-B 60
Patients (%) 40
The efficacy of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), 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).8
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.8
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.8
Eligible patients (N = 899) were stratified by prognostic factors and randomized into four treatment groups to receive 1) CHOP, 2) m-BACOD, 3) ProMACE-CytaBOM, or 4) 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).8
These results established CHOP as the standard of care for patients with aggressive NHL. 20 1 2 3 4 5 6
Years After Randomization
Adapted from Fisher. N Engl J Med. 1993;328:1002.

25. Diffuse Large B-Cell Lymphoma (DLCL): Overall Survival
100 80
IPI 0-1 60
Patients (%) 40
IPI 2-3
A retrospective evaluation of the REAL classification was conducted by the International Lymphoma Study Group.9 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 overall survival.
The most frequently occurring NHL was the aggressive subtype, DLCL. Overall survival rates were distinctly different between the various IPI risk groups. Five-year overall survival rates ranged from 20% in the high-risk group to 70% in the low-risk group.9
IPI 4-5 20
P < 0.001 1 2 3 4 5 6 7 8
Year
Adapted from Armitage. J Clin Oncol. 1998;16:2780.

26. NHL: Approach to the Patient
Role for Stem Cell Transplantation (auto)
Aggressive NHL
clear benefit when used for aggressive NHL in first relapse in appropriately selected patients
1/3 of these patients can be cured by SCT
Indolent NHL
no convincing evidence that patients are cured
CUP trial suggests survival advantage for ASCT

27. NHL: Elderly Indolent histology Aggressive histologies
usual principles apply
Aggressive histologies
trials have consistently shown that prophylactic dose reductions/delays/omissions result in inferior outcomes
PS predicts outcome rather than chronological age
routine use of growth factors reduces FN and infections, does not improve survival. NCCN guidelines recommends routine use in patients over age 70 treated with CHOP.
R-CHOP superior to CHOP in GELA trial for DLBCL

33. DLBCL Actually a heterogenous group 3 subtypes by microarray
Germinal center B cell like
Activated peripheral blood B cell like
Type 3

34. DNA Microarray Alizadah et al, Nature,2000:403;503
examined gene expression profiles in DLCL tumor samples
compared to profiles of non- malignant B cells
noted emergence of patterns

35. DNA Microarray Alizadah et al, Nature,2000:403;503
Reviewed clinical outcome data
Gene expression profiles had prognostic value
Added to IPI

36. DNA Microarray Rosenwald et al. NEJM 2002:346;1937

37. DNA Microarray Rosenwald et al. NEJM 2002:346;1937

38. Biologic Factors Bcl-2 Predictive Power in DLBCL
Hermine et al. Blood 87:265, 1996 DFS, OS
Kramer et al. JCO 14:2131, 1996 DFS
Hill et al. Blood 88:1046, DFS
Gascoyne et al. Blood 90:244, 1997 DFS, OS
Kramer et al. Blood 92:3152, 1998 DFS, OS

39. BCL-2 expression vs survival R. Gascoyne et al, Blood 90:244, 1997

40. Biology Summary
Microarray studies indicate 3 distinct subtypes of DLBCL based upon gene expression profile
Challenge is to better understand the intracellular derangements unique to each subtype so that new targeted therapies can be developed
Develop easily applicable lab techniques to distinguish the different biological entities (morphology does not do it)

43. Follicular Center Cell NHL
3 Grades
Grade 1: 0-5 centoblasts/HPF
Grade 2: 6-15 centroblasts/HPF
Grade 3: > 15 centroblasts/HPF
3a: no sheets of large cells
3b: sheets of large cells
Characterized by t(14;18)
Overexpression of bcl-2
Flow cytometry: CD10+

46. MALT Lymphoma arises in tissue normally devoid of lymphoid tissue
Stomach, lungs, orbit, skin, breast, salivary glands
Gastric MALT unique due to high association with H. pylori
Often regresses after H. pylori eradication therapy
t(11;18) predicts non response to H pylori therapy

50. T-Cell NHL Will lack B cell antigens Should have T cell markers
CD20, sIg
Should have T cell markers
CD3+, CD4+ or CD8+
Harder to tell if clonal
Can’t do simple kappa/lamda
Can look for clonal T cell receptor gene rearrangements with molecular studies

53. Small Lymphocytic Lymphoma
Distinction with CLL is arbitrary
> 5000/mm3 circulating lymphs
Characteristic flow pattern
CD5+, dim CD20+, CD23+, dim sIg
Can be confused with MCL
Similar morphology
CD5+, CD20+, CD23-, bright sIg
Frequent GI tract involvement
Lymphomatous polyposis

61. Anaplastic large cell (T cell)
CD30+ (Ki-1 positive)
If CD20+, then DLBCL
3 types
Cutaneous
Distinguish from lymphomatoid papulosis
Systemic ALK+
t(2;5) characteristic
Systemic ALK-
Poor prognosis