What is Lymphoma?
Lymphoma Disease Management
• Non-Hodgkin’s Lymphoma
Overview and Principles of Therapy
Owen A. O’Connor, M.D., Ph.D. Director, Lymphoid Development and Malignancy Program Herbert Irving Comprehensive Cancer Center Chief, Lymphoma Service The New York Presbyterian Hospital Columbia University Medical Center
• Hodgkin’s Disease
– Typically presents with a clonal expansion of lymphocytes in lymph nodes
– Lymph nodes are involved with the characteristic ReedSternberg cells
– Different lymphomas arise from B, T, and NK cells
– Evidence suggest origin from a post germinal center B cell
– 85% off allll lymphomas l h in i the th US are derived from B cells
– Estimated 7,500 new cases
– Estimated 55,000 new cases
– Peak of incidence in the 3rd and 4th decades of life
– Indolent lymphomas account for approximately 40% of new diagnoses
– Vast majority of patients can be cured with current therapy
– Aggressive lymphomas account for 60% of presentations
REAL Classification of NHL Subtypes
Lymphoma Overview and Principles of Therapy
Most Lymphomas Are Relatively Rare Other, 16%
• Non-Hodgkin’s Lymphoma
Burkitts-Like ~ 2%
– Epidemiology
Lymphoblastic ~ 2%
DLBCL, 31%
Anaplastic LCL~ 2%
– Classification/Staging g g
Mediastinal LBCL~ 2%
– Indolent Lymphoma
MALT~ 5%
– Aggressive Lymphoma
PTCL~ 6%
MCL~ 6%
• Hodgkin’s Disease – Not Today
FL, 22%
SLL/CLL, 6%
• New Approaches to Therapy – Not Today Armitage JO, Weisenburger DD. J Clin Oncol. 1998;16:2780-2795.
The Ontogeny of Lymphoid Neoplasm’s is Complex and Heterogeneous V(D)J Recombination
Immature B-cells
IgV hypermutation
Naive B-cells
Ig isotype switch
Germinal Center B-cells
Memory B-cells
B-CLL Plasma cells Bone Marrow
ALL
Germinal Center
MCL BL FL DLBCL
Characteristics of the 13 Most Common Entities Subtype
Ag
Mantle
WHO/REAL Classification of Lymphoma
DLCL FL SLL/CLL MCL PTCL MZL (MALT) Mediastinal LCL ALCL LL (T/B) Burkitt-like MZL (Nodal) SLL, PL BL TOTAL
Frequency (%)
Immunophenotype
Molecular Lesions
31 22 6 6 6 5 2 2 2 2 1 1 60 years
PS
≥2
LDH
>Normal
Low
Extranodal sites
≥2
Stage
III-IV
Number of Factors Present
5-year DFS (%)
5-year OS (%)
0-1
70
73
Low/Intermediate
2
50
51
High/Intermediate
3
49
43
4-5 4 5
40
26
Risk Group
High
High
1.0
Level of gene expression Low
Germinal-center B-cell–like
Type 3
Probability
• • • • •
Indolent Lymphoma
Activated B-cell–like
Genes
Aggressive Lymphoma
Prognostic Subgroups in de novo DLBCL Based on Ontogeny
Germinal-center B-cell–like
0.5
Type 3 Activated B-cell–like 0.0
0
2
4
6
8
10
Overall survival (years)
Rosenwald A et al. N Engl J Med. 2002;346:1937-1947.
Lymphoma Overview and Principles of Therapy
• Non-Hodgkin’s Lymphoma – Epidemiology – Classification/Staging g g – Indolent Lymphoma
Age-Adjusted
Age-Adjusted Factor
Number of Factors Present
5-year OS Age>60 (%)
5-year OS Age≤60 (%)
Low
0
56
83
Low/Intermediate
1
44
69
High/Intermediate
2
37
46
High
3
21
32
Adverse
PS
≥2
LDH
>Normal
Stage
III-IV
Risk Group
– Aggressive Lymphoma • Hodgkin’s Disease • New Approaches to Therapy
The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med. 1993;329:987-994.
International Prognostic Index Predicts Overall Survival – What is Biological Basis?
Trends in Cancer Mortality, 1991-1995 U.S. Cancer Mortality, All Ages
Percentt Survival
100 80
All sites -2.6 Lung -1.5 Breast (women) -6.3 Prostate -6.2 Colorectal -5.4 Ovary -4.8 Cervix Uteri -9.7 Bladder -1.5 Oral -9.6 Lymphatic 3.8 Leukemias -1.9 Other -0.9
L
60
LI
40
HI H
20 0 0
2
4 Years
6
8
10
-10
-8
-6
-4
-2
0
2
4
Percent change, 1991-1995 N Engl J Med.1993;329:987.
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Non-Hodgkin’s Lymphoma: SEER Incidence by Age
WORLD HEALTH ORGANIZATION (WHO) T-CELL LYMPHOMA CLASSIFICATION A Whole Different Lecture
1973-1975 vs 1993-1995; All Races, Male
Precursor T/NK Neoplasms 140
1973-1975 19731993--1995 1993
120 Rate per 1100,000
Precursor T lymphoblastic leukemia/lymphoma Blastic NK lymphoma
Peripheral T/NK Neoplasms
100 80 60 40 20 > 85
80--84 80
75--79 75
70--74 70
65--69 65
60--64 60
55--59 55
50--54 50
45--49 45
40--44 40
35--39 35
30--34 30
25--29 25
20--24 20
15--19 15
10--14 10
10 cm or 1/3 thoracic diameter – E: Extra-nodal extension of disease
• New Approaches to Therapy
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Follicular Lymphoma
Lymphoma Overview and Principles of Therapy
• Non-Hodgkin’s Lymphoma
H&E
CD20
CD10
CD3
CD 10+, CD 19+, CD 20+, CD 22+, LCA+,, κ/λ clonal excess
– Epidemiology – Classification/Staging g g – Indolent Lymphoma – Aggressive Lymphoma
CD 3 -, CD 5 -, CD 15 -, CD 30 -
• Hodgkin’s Disease • New Approaches to Therapy
FL: Reproducibility of Grading
CLINICAL MANAGEMENT OF FOLLICULAR LYMPHOMA In Patients With An Indication for Therapy
Berard Criteria
Indolent NHL In Need of Treatment Chemotherapy
Transplantation
Biological Specific p
Alkylator Rx CVP/CHOP Chlorambucil
Purine Analog Rx Fludarabine
Autologous
Antibody Rx Rituximab R-CHOP/R-CVP R-Flu (R & all combos w / R) Radioimmuno Rx Vaccines
FND Flu /
Allogeneic
Grade 2
Grade 3
Mixed
Large Cell
15
72%
61%
60%
Large Cells Per High Power Field
CyFlu
Expert Concordance
Non-Specific
Investigational
Grade 1 Small Cleaved
Interferon
Indolent B-Cell Lymphoma
Follicular Lymphoma
Survival by Era • Molecular 100
1987-1996 (N=668) 1976-1987 (N=513) 1960-1976 (N=195)
80
– t(14;18) translocation – BCL2 is overexpressed – BCL2 is anti-apoptotic
• Clinical
Probability 60 (%)
40 20 0 0
5
10
15
Time (y) Courtesy of Sandra J. Horning, MD.
20
25
30
– Equal number of men and women – Uncommon in Blacks and Asians – Transformation is common – Spontaneous regress occurs in ~30% of cases
• Pathology – subtypes: Grades 1, 2, 3
4
Gastric MALT Lymphoma
Follicular Lymphoma
A curable low grade lymphoma
Histological Transformation (HT)
Disease-Free Survival
• Actuarial risk of HT is 25% to 60% at 8 years 100
– P53 mutation (~50%), translocations of c-myc (~15%) and BCL6 (~10%)
80
Proportion Surviving
• HT results from g genetic alteration of a single g cell
60 40 20
• Prognosis following HT is generally poor
N = 48 patients 0 0
12
24
36
48
60
72
84
96
Months
Indolent B Cell Lymphoma
Indolent B Cell Lymphoma
Clinical Management
Clinical Management
Indolent B Cell Lymphoma
Indolent B Cell Lymphoma
Localized
Advanced Low Tumor Burden
Advanced High Tumor Burden
Localized
Advanced Low Tumor Burden
Advanced High Tumor Burden
Involved/Extended Field Radiation
Observation
Therapy
Involved/Extended Field Radiation
Observation
Therapy
Gastric MALT Lymphoma A curable low grade lymphoma
Indolent B Cell Lymphoma: Advanced Stage Principles of Therapy
• Not curable with conventional therapy • Strong association with Heliobacter pylori infection – In 10%-50% of cases, treatment of the infection will ill resultlt iin regression i off th the llymphoma h – Remissions may take up to 6 months • Most patients who fail to respond to antibiotics can be cured with radiation therapy
• Presents in older patients who may have significant co-morbid conditions complicating therapeutic options • Observation is appropriate if there are no indications for therapy • Response duration is generally shorter with each course of therapy • Enrollment on clinical trials is recommended if feasible
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TARGETS ON B-CELLS
Indolent B Cell Lymphoma: Advanced Stage Observation in Absence of an Indication for Treatment
• Both prospective randomized and retrospective studies have:
slg CD19 DR
CD20
z Surface proteins can be targeted with:
CD22
 Active immunotherapy Â
– No survival disadvantage
Vaccines
 Passive immunotherapy
B Lymphocytes
– 3 year median progression to treatment
Â
Unmodified MAbs
Â
Conjugated MAbs
ÂRadioisotopes ÂDrugs ÂToxins  Peptides selected for binding
– Same rate of histological transformation
 Small molecules
B-Cell Life Cycle CD20 Tumor Specificity
Indolent B Cell Lymphoma Clinical Management
Blood Lymph
Bone Marrow
Indolent B Cell Lymphoma Localized
Involved/Extended Field Radiation
Advanced Low Tumor Burden
Advanced High Tumor Burden
Observation
Therapy
Pluripotent Stem Cell
Lymphoid Stem Cell
Pre-B Cell
B Cell
Activated B Cell
Plasma Cell
CD20 Antigen Expression CML
Indolent B Cell Lymphoma: Advanced Stage Clinical Management with Indication for Therapy
Precursor BB-Cell Acute Leukemias
B-Cell Lymphomas, CLL
Myeloma
B1 (CD20) Antigen Exon VI
Diagnosis of Low Grade Lymphoma Needs Treatment Chemothrapy-based
Biological-based
Extracellular Exon IV
Transplantation
Polar Groups Hydrophobic Light Region
Alkylator Based Treatment e g CVP e.g. Chlorambucil
Specific
Non-Specific
Autologous Polar Groups Cytoplasm
Purine Analogs Fludarabine FND CyFlu
Antibody-Based Rituximab Alone CHOP+Rituximab
Interferon
Allogeneic Full or Non-myeloablative
Exon V
NH3
COOH
Exon VII
Exon III
Radio-immunotherapy Tositumomab Ibritumomab Tiuxetan Exon VIII
Vaccination Mason et al. Am J Pathol. Pathol. 1990;136:1215.
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• Rituximab – Engineered derivative of IDEC--2B8 IDEC – Murine antigen binding domain – Human κ constant region – Human Ig Igγγ1 constant region – Induces apoptosis
B cell CD20 antigen
Rituximab
• CD20 antigen
External Beam Irradiation
Radioimmunotherapy
Tumor Tumor
• Effect of chimerism
– Hydrophobic, 35 kD phosphoprotein – Expressed only on B lineage cells – Important for cell cycle initiation and differentiation – Does not shed or rapidly modulate off cell surface
– – – –
t1/2 = 76 h after 1st dose t1/2 = 206 h after 4th dose Activates complement Induces antibody dependent cell--mediated cytotoxicity cell
Cytotoxic Mechanisms of Monoclonal Antibodies
Effector cells/ complement
Apoptosis
Radiation/ radionuclide
Crossfire Enhances Antibody Action
Toxin/drug
Naked Antibody
Radiolabeled Antibody
• Ibritumomab tiuxetan
RITUXIMAB CLINICAL TRIAL SUMMARY
– Murine IDECIDEC-2B8 (parent of rituximab) – MX MX--DTPA conjugated to antibody forming strong urea--type bond urea – Stable retention of 90Y
LOW GRADE LYMPHOMA Trial Phase (Author)
N
Pivotal, Phase III (McLauglin et. al)
Patient Population
166 Low grade NHL, relapsed/refractory
Regimen
Rituximab 375 mg/m2 x 4
RR
ORR 48%
RD TTP Months (median) Months 11.2
CR 6%
CD20 antigen
PR 42% Rituximab/CHOPPhase II
40
Low grade NHL, new dx or relapsed/ refractory
(Czuczman et. al)
Rituximab 375 mg/m2 x 6 CHOP x 6
ORR 95%
B cell
13+
39.1+
Ibritumomab tiuxetan
41.1
• Yttrium Yttrium--90
CR 55% PR 40%
RR
Response Rate
RD
Response Duration
ORR
Overall Response Rate
TTP
Time to tumor progression
CR
Complete reponse
PR
Partial Response
90Y
– t1/2 = 64 hours – Outpatient administration – Beta emission X90 = 5 mm
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Iodine I 131 Tositumomab
Indolent Lymphoma
Mechanism Of Action
Continuing Challenges
• Iodine I 131 tositumomab
• Define the optimal use of antibody-based therapy
- murine IgG2a anti-CD20 MAb - B-cell specific
– First line
- triggers apoptosis
– In combination with chemotherapy
- antibody-dependent antibody dependent cellular cytotoxicity
– Sequentially with chemotherapy
• Iodine-131 radioisotope - beta emission short pathlength “crossfire” effect (~1mm)
• Refine the use of high dose therapy to provide maximal benefit
- gamma emission allows individual dosimetry • Iodine I 131 tositumomab
• Develop new targeted therapy based on molecular mechanisms of lymphomagenesis
- targeted radiotherapy
RITUXIMAB v 90Y-2B8: RESPONSE TO THERAPY INTERIM ANALYSIS (n=90) Histology ORR
Rituximab N (%)
Ibritumomab p-value* N (%)
20 (43.5)
35 (79.5)
28.1-58.9%
64.2-89.7%
CR
3 (7%)
9 (21)
PR
17 (37%)
26 (59%)
0.001
Lymphoma Overview and Principles of Therapy
• Non-Hodgkin’s Lymphoma – Epidemiology – Classification/Staging g g
95% CI
– Indolent Lymphoma 0.057
– Aggressive Lymphoma • Hodgkin’s Disease
*Calculated from Cochran-Mantel-Haenszel test over histology type (A/Follicular/Transformed)
• New Approaches to Therapy
Witzig, et al., Blood, 94 (Supplement 1), Abstract 2805
Overall Survival: Large Cell Histologies + 1.0
Idiotype Rescue by Cell Fusion or Molecular Approach
Tumor Biopsy
0.9
Anaplastic large cell lymphoma
0.8
Vaccine Production
Survivval
0.7
Immunization
0.6
Diff Diffuse large l B cell ll lymphoma l h
0.5 0.4
Burkitt-Like
0.3
KLH Carrier Protein Id
Tumor Id Protein
Peripheral T cell lymphoma
0.2 0.1
Log rank test: p 1
• Low
0
BACOP
ProMACE MOPP ProMACE-MOPP
MACOP B MACOP-B
• LDH > 1 x normal
• Low-intermediate
1
MOPP
M-BACOD
ProMACE-CytaBOM
• Stage III or IV
• High-intermediate
2
• High
3
COPA-Bleo
COP-BLAM
ProMACE-MOPP 1/8
CAP-BOP
COP-BLAM III
COMLA COPA CHOP Shipp et al. N Engl J Med. 1993.
National High Priority Lymphoma Study:
International Prognostic Index
Time to Treatment Failure by Randomized Treatment Arm
Age-Adjusted Overall Survival
CHOP m-BACOD P-CytaBOM MACOP--B MACOP
80%
At Risk 225 223 233 218
Relapses or death 114 109 115 119
100
3-year estimate 41% 46% 46% 41%
80 Percent Survvival
100%
60% 40% 20%
L
60
LI
40
HI H
20
0% 0
1
2 3 Years after Randomization
4
0
5
Fisher et al. N Engl J Med. 1993;328:1002.
0
2
4 Years
6
8
10
N Engl J Med.1993;329:987.
Diffuse Large B Cell Lymphoma
International Prognostic Index Prognostic Indicators (APLES) • Risk Category
Distinct Forms Revealed by Expression Arrays • Lymphochip expression array data segregates diffuse large B cell lymphoma into two molecular entities:
Factors
• Age > 60 years
• Low
• Performance status > 1
• Low-intermediate
0 or 1 2
• LDH > 1 x normal
• High-intermediate
3
• Extranodal sites > 1
• High
– Germinal center phenotype – Activated B cell phenotype • Molecular subtype is independent of International Prognostic Index risk group
4 or 5
• Stage III or IV
Hiddemann. E. J Cancer. 1995; Jagannath et al. J Clin Oncol. 1986; Danieu et al. Cancer Res. 1986; Swan et al. J Clin Oncol 1989; Coiffier et al. J Clin Oncol. 1991; Shipp et al. N Engl J Med. 1993.
Alizadeh et al. Nature 403:503-511 (2000)
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Management of Aggressive NHL
Parma Trial: Event-free Survival
R-CHOP 55
45
CR 44
Primary Refractory 11
Cure
???
Relapse
% Event-free e Survival
100 80 60
ABMT (N = 55)
40 DHAP (N = 54)
20 0
HDT/ASCT
0 Philip et al. N Engl J Med. 1995;333:1540-1545.
15
30
45
60
75
90
Months from Inclusion
Second Line Therapy for Aggressive NHL • Ideal second line therapy
Aggressive Lymphoma
– Provides effective reduction in tumor size – Results in minimal non-hematologic toxicity
Second-line Therapy
– Effectively mobilizes stem cells into the peripheral blood
Management of Aggressive NHL
CR 44
Cure
• Passive Immunotherapy in aggressive NHL has changed the landscape
45
Primary Refractory 11
Relapse HDT/ASCT
Summary • R-CHOP remains the standard, albiet with suboptimal results, for refractory
R-CHOP 55
Therapy for Aggressive NHL
???
• High dose therapy with ASCT is superior to chemotherapy for relapsed and refractory aggressive lymphoma • A better response to second line therapy correlates with a superior outcome post ASCT • Based on intention to treat, about 30% of patients are benefited by second-line therapy with high dose chemotherapy consolidation
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Therapy for Aggressive NHL
TARGETING BCL-6 IN LYMPHOMA
Summary HDAC
• Patients with primary refractory disease, both induction failures and those achieving only a PR to first line therapy can benefit from ASCT • Second-line age-adjusted g j international p prognostic g index (saaIPI) predicts survival • Not all patients with relapsed and refractory aggressive NHL are potentially curable with this approach, particularly: – relapsed saaIPI IV
HDAC Inhibitor
Ac
HDAC
BCL6
Transcription
Ac
Ac
Ac
Ac
Ac
(ex: p21WAF1)
Growth Inhibition, Apoptosis, Differentiation Anti-tumor activity
– refractory saaIPI III/IV
Second-line Therapy of NHL
No Transcription
BCL6
The BCL6:p53 Network: A Rational Target
Avenues for New Directions
• Improved cytoreduction (RICE) • Improved HDT (TBI-Ifos-Etop)
SAHA
Ac
HDAC inhibitor
Co-repressor complex
BCL6
– Non-myeloablative alloBMT • Post P t remission i i th therapy
P
Acetylation
– Cellular therapy – Post remission chemotherapy (after transduction of stem cells with drug resistance genes) • Novel targeted therapy
Small molecules
DNA damage Ac
Sir2 inhibitor
P
p53 ETOPOSIDE
NIACINAMIDE
DEATH
Thank You The Future of Cancer Therapy Targeting the Molecular Pathways
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