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Lymphoma overview
1. Lymphoma Overview
John Gerecitano, M.D., Ph.D.
The following material is intended for MSKCC internal medicine housestaff teaching purposes only. The
presentation may not be copies or disseminated. The slides were updated for the LibGuide in 2012-2013.
2. Incidence of Cancer in the United States*
Prostate 29%
Lung and bronchus 15%
Colon and rectum 10%
Urinary bladder 7%
Non-Hodgkin’s lymphoma 4%
Melanoma of the skin 4%
Kidney and renal pelvis 4%
Leukemia 3%
Oral cavity and pharynx 3%
Pancreas 2%
All other sites 19%
Women
678,060
Men
766,860
26% Breast
15% Lung and bronchus
11% Colon and rectum
6% Uterine corpus
4% Non-Hodgkin’s lymphoma
4% Melanoma of the skin
4% Thyroid
3% Ovary
3% Kidney and renal pelvis
3% Leukemia
21% All other sites
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary
bladder. Estimated for 2007.
American Cancer Society. Cancer Facts & Figures 2007. Atlanta, GA: American Cancer Society; 2007.
3. Clinical Course
and REAL/WHO Classification of NHL
*RITUXAN® (Rituximab) is approved for the bolded subtypes. Other subtypes are not approved RITUXAN indications.
Armitage JO, Weisenburger DD. J Clin Oncol. 1998;16:2780-2795; Harris NL et al. Ann Oncol. 1999;10:1419-1432; Hiddemann W et al. Blood.
1996;88:4085-4089; Horning SJ. Blood. 1994;83:881-884; Liu Q et al. J Clin Oncol. 2006;24:1582-1589; Fisher RI et al. N Engl J Med.
1993;328:1002-1006; Skarin AT, Dorfman DM. CA Cancer J Clin. 1997;47:351-372.
FL*PTCL
22%
Indolent
(low grade)
Aggressive
(intermediate grade)
Very aggressive
(high grade)
• Slowly progressive
• 5-year OS ≤95%
• Rapid clinical course
• 5-year OS ≤50%
• Grows rapidly
• Survival 0.5-2 years
31%
6%
2%
2%
6%
2%
2%
6%
5%
16%
Grades I, II- Indolent
Grade III- Agressive
11. Staging (the Modern way)
• CT Scan
• PET Scan (for aggressive lymphomas)
• Bone Marrow Biopsy
12. Ann Arbor Staging System for Hodgkin's Disease and
Non-Hodgkin's Lymphoma
Stage I Stage II Stage III Stage IV
Adapted from Skarin. Dana-Farber Cancer Institute Atlas of
Diagnostic Oncology. 1991; with permission.
14. Diffuse Large B Cell Lymphoma
• Potentially curable at any age
• R-CHOP is standard chemotherapy
• PET scanning is important in monitoring response
• Role of IF-RT?
• Autologous transplantation is potentially curative at relapse; role
in upfront Rx?
• Mini-allotransplantation is a promising salvage therapy in
selected cases
15. National High Priority Lymphoma Study: Progression-
Free Survival
Adapted from Fisher. N Engl J Med. 1993;328:1002.
Patients(%)
Years After Randomization
100
80
60
40
20
0
0 1 2 3 4 5 6
CHOP
m-BACOD
ProMACE-CytaBOM
MACOP-B
16. International Prognostic Index (IPI)
Patients of all ages Risk factors
Age > 60 years
Performance status (PS) 2-4
Lactate dehydrogenase (LDH) level Elevated
Extranodal involvement > 1 site
Stage (Ann Arbor) III–IV
Patients 60 years (age-adjusted)
PS 2-4
LDH Elevated
Stage III–IV
Shipp. N Engl J Med. 1993;329:987.
17. Age-Adjusted IPI:
Overall Survival by Risk Strata (age≤60)
HI (30%) = 3
H (15%) = 4-5
LI (40%) = 2
L (15%) = 0-1
100
75
50
25
0
0 2 4 6 8 10
Patients(%)
Year
Adapted from Shipp. N Engl J Med. 1993;329:987.
18. CD20:
A Target for Lymphoma Therapy
CD20:
• Is a transmembrane protein expressed
by 95% of mature B-cell NHLs, but is
absent in stem cells, plasma cells, and
cells of other lineages
• Is a stable target that is not shed,
modulated, or internalized upon antibody
binding
• May be involved in regulation of
intracellular calcium levels
• May be involved in regulation of the cell
cycle and apoptosis
Einfeld DA et al. EMBO J. 1988;7:711-717.
Press OW et al. Blood. 1987;69:584-591.
Riley JK, Sliwkowski MX. Semin Oncol. 2000;27(suppl 12):17-24.
Tedder TF et al. Proc Natl Acad Sci U S A. 1988;85:208-223.
Tedder TF, Engel P. Immunol Today. 1994;15:450-454.
19. Antigen Expression During
B-Cell Development
Bone Marrow Periphery (Spleen, Lymph Node)
Pro-B Pre-B Immature B Mature B GC BMature B
Memory B
Plasma Cell
CD19 + + + + + + + –
CD10 + + +/– – – + – –
CD20 – – –/+ + + ++ + –
CD38 ++ ++ + + + ++ + ++
CD22 – – + + + + ? –
CD52 +
Activated B-cells
ALL=acute lymphoblastic leukemia; CLL=chronic lymphocytic leukemia, PLL=prolymphocytic leukemia;
FL=follicular lymphoma; DLBCL=diffuse large B-cell lymphoma; HCL=hairy cell leukemia; WM=Waldenström’s macroglobulinemia;
MM=multiple myeloma.
Jaffe ES et al, eds. World Health Organization Classification of Tumours. 2001; Hale G et al.
Tissue Antigens. 1990;35:118-127; Freeman GJ et al. J Immunol. 1989;143:2714-2722.
Plasmablast
WM MM
ALL CLL, PLL
Burkitt’s, FL, DLBCL, HCL
20. Rituximab:
An Anti-CD20 Monoclonal Antibody
• Genetically engineered chimeric
murine/human antibody
– Variable light- and heavy-chain
regions from murine anti-CD20
antibody
– Linked to human IgG1 and κ
constant regions
• First FDA-approved monoclonal
antibody for treatment of cancer in
the United States
– Approved November 1997
Rituxan [package insert]. South San Francisco, CA; Genentech, Inc; 2006.
Pescovitz MD. Am J Transplant. 2006;6:859-866.
Rituxan
21. 0
20
40
60
80
100
Years
1 2 3 4 5 60
CHOP (n=197)
R-CHOP (n=202)
%Surviving
*Data on file. Genentech, Inc.
Feugier P et al. J Clin Oncol. 2005;23:4117-4126.
Median 5-Year Follow-Up
First-Line R-CHOP vs CHOP
in DLBCL: Overall Survival (cont’d)
P=.0073
HR=0.68* (95% CI, 0.51-0.90)
32% risk reduction
22. First-Line R-CHOP vs CHOP
in DLBCL: Survival Summary
CHOP R-CHOP
Median EFS 1.1 years 2.9 years
OS at 2 years 58% 69%
OS at 5 years 46% 58%
Rituxan [package insert]. South San Francisco, CA: Genentech, Inc.; 2006.
25. Clinical Course
and REAL/WHO Classification of NHL
*RITUXAN® (Rituximab) is approved for the bolded subtypes. Other subtypes are not approved RITUXAN indications.
Armitage JO, Weisenburger DD. J Clin Oncol. 1998;16:2780-2795; Harris NL et al. Ann Oncol. 1999;10:1419-1432; Hiddemann W et al. Blood.
1996;88:4085-4089; Horning SJ. Blood. 1994;83:881-884; Liu Q et al. J Clin Oncol. 2006;24:1582-1589; Fisher RI et al. N Engl J Med.
1993;328:1002-1006; Skarin AT, Dorfman DM. CA Cancer J Clin. 1997;47:351-372.
FL*PTCL
22%
Indolent
(low grade)
Aggressive
(intermediate grade)
Very aggressive
(high grade)
• Slowly progressive
• 5-year OS ≤95%
• Rapid clinical course
• 5-year OS ≤50%
• Grows rapidly
• Survival 0.5-2 years
31%
6%
2%
2%
6%
2%
2%
6%
5%
16%
Grades I, II- Indolent
Grade III- Agressive
29. Follicular NHL
• Characteristics
– 80% to 90% disseminated at
diagnosis (lymph nodes,
spleen, bone marrow,
peripheral blood)
– Small B lymphocytes
– t(14:18) 90% of cases
– Relatively long median
survival
– Sensitive to chemotherapy
and RT
– Incurable with conventional
therapies (possible cures
with allo SCT)
• Histologic transformation
– Occurs in 30% to 40% of
patients
– Accompanied by new
symptoms, rapid
progression, elevated LDH,
increased activity on PET
– Generally poor prognosis
32. Follicular Lymphoma Histology
• Numbers of centroblasts (large cells) increase with grade
• Criteria for grading*
– Grade 1: 0-5 centroblasts/hpf; centrocytes predominate
– Grade 2: 6-15 centroblasts/hpf
– Grade 3: >15 centroblasts/hpf; centroblasts predominate
Grade 1 Grade 2 Grade 3
* These images do not reflect individual high power fields.
Warnke RA et al. Tumors of the Lymph Node and Spleen. Washington, DC: Atlas of Tumor
Pathology, Armed Forces Institute of Pathology; 1995.
Harris NL et al. Ann Oncol. 1999;10:1419-1432.
33. Comparison of Response Rates, Response Durations and Survival
Times After Treatment of Consecutive Recurrences of
Follicular Lymphoma
Johnson et al., JCO 1995;13(1):140
Treatment # Treated RR (%) Duration
(years)
Survival (years)
First 204 88 2.6 9.2
Second 110 78 1.1 4.6
Third 63 76 1.1 3.5
Fourth 37 68 0.5 1.2
34. NHL: Survival Of Patients With
Low-Grade Disease
Courtesy of Sandra J. Horning, MD.
0
20
40
60
80
100
0 5 10 15 20 25 30
Time (y)
Probability
(%)
1987-1996 (N=668)
1976-1987 (N=513)
1960-1976 (N=195)
36. Treatment of Follicular Lymphoma (Grades 1-2)
(…and other indolent lymphomas)
Modified from National Comprehensive Cancer Network. Non-Hodgkin’s lymphoma. Clinical Practice Guidelines in
Oncology – v.3. 2007. Jenkintown, PA: National Comprehensive Cancer Network; 2007.
Workup
(Staging)
Stage I-II
Stage II bulky,
or Stage III-IV
Yes Initial treatment
Treatment
indicated?
No
Observe
Progression
Indications for treatment
• Candidate for clinical trial
• Symptoms
• Threatened end-organ function
• Cytopenia secondary to lymphoma
• Bulky disease
• Patient preference
Localized
Locoregional/
extended-field
radiation
37. RT for Limited Stage Disease
Wilder et al. Int. J. Radiation Oncology Biol. Phys, 2001
38. Treatment Options for Advanced Stage
Follicular Lymphoma
Interferon
Autologous
Allogeneic
(full or non-
myeloablative)
Alkylator-based
CVP
Chlorambucil
Bendamustine
Specific Nonspecific
Purine analogs
Fludarabine
Fludarabine-based
combination
Chemotherapy-based
Antibody-based
Rituximab alone
Chemo-immunotherapy
Radioimmunotherapy
Tositumomab
Ibritumomab tiuxetan
Biologic-based Transplantation
Diagnosis of low-grade lymphoma
needs treatment
Anthracycline-based
CHOP
40. Rituximab:
An Anti-CD20 Monoclonal Antibody
• Genetically engineered chimeric
murine/human antibody
– Variable light- and heavy-chain
regions from murine anti-CD20
antibody
– Linked to human IgG1 and κ
constant regions
• First FDA-approved monoclonal
antibody for treatment of cancer in
the United States
– Approved November 1997
Rituxan [package insert]. South San Francisco, CA; Genentech, Inc; 2006.
Pescovitz MD. Am J Transplant. 2006;6:859-866.
Rituxan
41. Principles of Radioimmunotherapy
• Targeted delivery of radiation to
tumor cells
• Greater exposure of tumors vs
surrounding normal organs by
virtue of limited path length of
particle emissions and selectivity
of the carrier antibody
• Crossfire of particle emissions
• Continuous exposure of tumor
cells
• Retention of anti-tumor
mechanisms of the antibody
43. Approaches to Relapsed Patients
• Usually includes rituximab ± other agents
• Optimal regimen unknown
• Optimal duration of therapy unknown
• Activity of agents unknown in new era
• Clinical trial is the standard of care
45. Marginal Zone Lymphomas
• Gastric MALT
– Often associated with H. Pylori
– Eradication of H. Pylori can be curative in 2/3 patients
• Local RT for all others
– Patients with t(11:18), API2;MLT have more extensive dz and
worse prognosis
• Splenic MZL
– Usu dx’d based on SM and BM involvement
– Splenectomy can yield long term DFS in many patients
• Nodal MZL
– Worse prognosis, treated like advanced stage FL
