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

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

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

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%
NonHodgkin’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% NonHodgkin’s lymphoma
3% Melanoma of skin
3% Thyroid
2% Pancreas
2% Urinary bladder
20% All other sites
*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.

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
40
20
0
Age at diagnosis (years)
Ries et al (eds). SEER Cancer Statistics Review, 1975-2000 . National Cancer Institute.
Bethesda, Md, http://seer.cancer.gov/csr/1975_2000, 2003.

NHL: Epidemiology

Why the increase?
– 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

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

Revised European-American Lymphoma
(REAL) Classification: B-Cell Neoplasms
Indolent Aggressive Very Aggressive
• CLL/SLL
• Lymphoplasmacytic/
IMC/WM
• HCL
• Splenic marginal zone lymphoma
• Marginal zone lymphoma
– Extranodal (MALT)
– Nodal
• Follicle center lymphoma, follicular, grade I-II
• PLL
• Plasmacytoma/
Multiple myeloma
• MCL
• DLCL
• Primary mediastinal large
B-cell lymphoma
• Follicle center lymphoma, follicular, grade III
• Precursor
B-lymphoblastic lymphoma/Leukemia
• Burkitt’s lymphoma/
B-cell acute leukemia
• Burkitt’s-like
• Plasma cell leukemia
Hiddemann. Blood.
1996;88:4085.

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…)

Modified Ann Arbor Staging of NHL
Stage I
Stage II
Involvement of a single lymph node region
Involvement of

2 lymph node regions on the same side of the diaphragm
Stage III
Stage IV
Cancer.
1982;49:2112.
Involvement of lymph node regions on both sides of the diaphragm
Multifocal involvement of

1 extralymphatic sites ± associated lymph nodes or isolated extralymphatic organ involvement with distant nodal involvement

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

International Prognostic Index (IPI)
Patients of all ages
Age
Risk factors
> 60 years
Performance status (PS) 2-4
Lactate dehydrogenase (LDH) level Elevated
Extranodal involvement
Stage (Ann Arbor)
> 1 site
III –IV
Patients

60 years (age-adjusted)
PS
LDH
Stage
2-4
Elevated
III
–IV
Shipp. N Engl J Med. 1993;329:987.

All ages
IPI Risk Strata
Risk Group
Low (L)
Low-intermediate (LI)
High-intermediate (HI)
High (H)
Risk
Factors
0-1
2
3
4-5
Age-adjusted L
LI
HI
H
Shipp. Blood. 1994;83:1165.
2
3
0
1

IPI: Overall Survival by Risk Strata
100
75
50
25
0
0 2 4
Adapted from Shipp. N Engl J Med.
1993;329:987.
Year
6 8
HI
L
LI
H
10

Age-Adjusted IPI:
Overall Survival by Risk Strata
100
75
50
25
0
0 2 4
Adapted from Shipp. N Engl J Med.
1993;329:987.
Year
6 8
L
LI
HI
H
10

Follicular Lymphoma (FL) :
Overall Survival
100
80
60
40
20
P < 0.001
0
0 1 2 3
Adapted from Armitage. J Clin Oncol.
1998;16:2780.
4
Year
5 6
IPI 4/5
7
IPI 0/1
IPI 2/3
8

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

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

Indolent NHL: chlorambucil vs W&W

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
Chl-P (pulse) 77 78% 34% 2.5 yrs
CVP (which?)
Peterson, JCO 2003
Baldini, JCO 2003
(Await E1496)
CHOP (B) 109 93% 60% 3.6 yrs
ProM-MOPP 500 83% 47% 3.2 yrs
Fludarabine
FN
FND
ATT
101
78
73
69
84%
94%
98%
97%
47%
44%
79%
87%
3.0 yrs
2.7 yrs
3.5 yrs
5.0 yrs
Peterson, JCO 2003
Fisher, JCO 2000
Zinzani, JCO 2000
Velasquez, JCO 2003
Tsimberidou, Blood 2002
Tsimberidou, Blood 2002

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

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

National High Priority Lymphoma
Study: Progression-Free Survival
100
80
CHOP m-BACOD
ProMACE-CytaBOM
MACOP-B
60
40
20
0
0 1 2 3 4
Years After Randomization
5
Adapted from Fisher. N Engl J Med.
1993;328:1002.
6

Diffuse Large B-Cell Lymphoma
(DLCL): Overall Survival
100
80
60
40
20
P < 0.001
0
0 1 2 3
Adapted from Armitage. J Clin Oncol.
1998;16:2780.
4
Year
5 6 7
IPI 0-1
IPI 4-5
IPI 2-3
8

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

NHL: Elderly

Indolent histology
– 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

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

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

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

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

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

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, 1996 DFS

Gascoyne et al. Blood 90:244, 1997 DFS, OS

Kramer et al. Blood 92:3152, 1998 DFS, OS

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

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)

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+

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

T-Cell NHL

Will lack B cell antigens
– 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

Small Lymphocytic Lymphoma

Distinction with CLL is arbitrary
– > 5000/mm 3 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

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