Post on 25-Dec-2015
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
– 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
Estimated New Cancer Cases*:
10 Leading Sites, by Sex, United States, 200332% 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
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%
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Jemal et al. Jemal et al. CA Cancer J Clin.CA Cancer J Clin. 2003;53:5-26. 2003;53:5-26.
Incidence of NHL Is Increasing,
Especially in the Elderly (60 Years)SEER NHL incidence by age, 1975SEER NHL incidence by age, 1975––1977 and 19981977 and 1998–2000–2000 (male, all races) (male, all races)
Ries et al (eds). SEER Cancer Statistics Review, 1975-2000. National Cancer Institute. Bethesda, Md, http://seer.cancer.gov/csr/1975_2000, 2003.
Age at diagnosis (years)Age at diagnosis (years)
00
2020
4040
6060
8080
100100
120120
140140 55 55 –– 99
1010 ––
1414
1515 ––
1919
2020 ––
2424
2525 ––
2929
3030 ––
3434
3535 ––
3939
4040 ––
4444
4545 ––
4949
5050 ––
5454
5555 ––
5959
6060 ––
6464
6565 ––
6969
7070 ––
7474
7575 ––
7979
8080 ––
8484
858
5
19981998––2000200019751975––19771977
No. perNo. per100,000100,000
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
• 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
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…)
Cancer. 1982;49:2112.
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
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 Risk factors Age > 60 yearsPerformance status (PS) 2-4Lactate dehydrogenase (LDH) level Elevated Extranodal involvement > 1 siteStage (Ann Arbor) III–IV
Patients 60 years (age-adjusted)PS 2-4LDH ElevatedStage III–IV
Shipp. N Engl J Med. 1993;329:987.
IPI Risk Strata
All ages Low (L) 0-1Low-intermediate (LI) 2High-intermediate (HI) 3High (H) 4-5
Age-adjusted L 0LI 1HI 2H 3
RiskFactorsRisk Group
Shipp. Blood. 1994;83:1165.
IPI: Overall Survival by Risk Strata
Adapted from Shipp. N Engl J Med. 1993;329:987.
100
75
50
25
0
0 2 4 6 8 10
H
HILI
L
Pa
tie
nts
(%
)
Year
Age-Adjusted IPI: Overall Survival by Risk Strata
HI
H
LI
L
100
75
50
25
0
0 2 4 6 8 10
Pa
tie
nts
(%
)
Year
Adapted from Shipp. N Engl J Med. 1993;329:987.
Follicular Lymphoma (FL) : Overall Survival
Adapted from Armitage. J Clin Oncol. 1998;16:2780.
Year
8
IPI 0/1
IPI 2/3
IPI 4/5
100
Ov
era
ll S
urv
iva
l (%
)
0 2 5 6 73 41
P < 0.001
60
40
20
0
80
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 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 Peterson, JCO 2003
ProM-MOPP 500 83% 47% 3.2 yrs Fisher, JCO 2000
Fludarabine 101 84% 47% 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 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
Adapted from Fisher. N Engl J Med. 1993;328:1002.
Pa
tie
nts
(%
)
Years After Randomization
100
80
60
40
20
00 1 2 3 4 5 6
CHOPm-BACODProMACE-CytaBOMMACOP-B
Diffuse Large B-Cell Lymphoma (DLCL): Overall Survival
Pa
tie
nts
(%
)
Year
Adapted from Armitage. J Clin Oncol. 1998;16:2780.
100
60
40
20
0
0 2 5 6 7 83 41
80
IPI 0-1
IPI 2-3
IPI 4-5
P < 0.001
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 non-
malignant 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 survivalBCL-2 expression vs survival
R. Gascoyne et al, Blood 90:244, 1997R. 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/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
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