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

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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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