Lymphoma Therapy

Updated and Simplified:

An Overview of Current

Concepts

Daryl Tan

Consultant,

Department of Haematology

Singapore General Hospital

Adj Assictant Professor,

Duke-NUS GMS

Overview- Advances in Lymphoma

Therapy

• Advances in understading of Disease biology

• Advances in Prognostication

– Identification of important biological and clinical biomarkers

• Novel modalities in treatment

Overview-Advances in Lymphoma Therapy

• Advances in understading of Disease biology

• Advances in Prognostication

– Identification of important biological and clinical biomarkers

• Novel modalities in treatment

– Immunotherapy

– Targeted therapy

– Radioimmunotherapy

– Proteasome inhibition

– Others

Multiple myeloma

Ontogeny of B-Lymphoid Neoplasm

WHO classification of the mature B-cell, T-cell, and NK-cell NHLs (2008)

Immunophenotyping

Lymphoid Differentiation

Anti-CD20

Antibody

(Rituximab)

Each Defined by Own Unique Molecular Features

and Addiction

Each Defined by Own Unique Molecular Features

and Addiction -that can be targeted by drugs

• Advances in understading of Disease biology

• Advances in Prognostication

– Identification of important biological and clinical biomarkers

• Novel modalities in treatment

– Immunotherapy

– Targeted therapy

– Radioimmunotherapy

– Proteasome inhibition

– Others

Overview-Advances in Lymphoma Therapy

WHO Classification of Lymphoid Neoplasms

by Degree of Aggressiveness

The Indolent diseases

B-cell neoplasms

• Small lymphocytic lymphoma/B-cell chronic

lymphocytic leukemia

• Lymphoplasmacytic lymphoma (±

Waldenstrom's macroglobulinemia)

• Multiple Myeloma

• Follicular lymphoma (grade I and II)

• Hairy cell leukemia

• Marginal zone B-cell lymphoma

• Mantle cell lymphoma

T-cell neoplasms

• T-cell large granular lymphocyte leukemia

• Mycosis fungoides

• T-cell prolymphocytic leukemia

• Natural killer cell large granular lymphocyte

leukemia

The Aggressive diseases B-cell neoplasms

• Follicular lymphoma (grade III)

• Diffuse large B-cell lymphoma

• Mantle cell lymphoma

T-cell neoplasms

• Peripheral T-cell lymphoma

• Natural killer cell neoplasms

• Anaplastic large cell lymphoma, T/null cell

Hodgkin’s Lymphoma

The Highly Aggressive diseases

B-cell neoplasms

• Burkitt's lymphoma/ leukaemia

• Precursor B lymphoblastic

leukemia/lymphoma

T-cell neoplasms

• Adult T-cell lymphoma/leukemia

• Precursor T lymphoblastic

leukemia/lymphoma

Aggressiveness

Evolution of Chemotherapy Over the Decades

• 1940s: Nitrogen mustard

• 1950s: Alkylating agents (cyclophosphamide, chlorambucil, melphalan)

Antimetabolites (methotrexate)

• 1960s: Vinca alkaloids (vincristine, vinblastine)

• 1970s: Anthrracyclines (adriamycin), CHOP regime

Bleomycin,

Cisplatin

• 1980s: Etoposide,

Carboplatin

• 1990s: Purine Analogues (cytarabine, fludarabine)

Conventional

Cytotoxic

Chemotherapy

Traditional Principle of Treatment

Indolent

CVP

C=cyclophosphamide, V=vincristine, P=prednisolone,

Traditional Principle of Treatment

Aggressive

CHOP

Indolent

CVP

C=cyclophosphamide, V=vincristine, P=prednisolone,H=adriamycin,

Traditional Principle of Treatment

Highly Aggressive

Aggressive

Acute lymphoblastic leukaemia Protocols

(Induction/ Consolidation/ Maintainance)

CHOP

Indolent

CVP

Evolution of Chemotherapy Over the Years

• 1940s: Nitrogen mustard

• 1950s: Alkylating agents (cyclophosphamide, chlorambucil, melphalan)

Antimetabolites (methotrexate)

• 1960s: Vinca alkaloids (vincristine, vinblastine)

• 1970s: Anthrracyclines (adriamycin), CHOP

Bleomycin,

Cisplatin

• 1980s: Etoposide,

Carboplatin

• 1990s: Purine Analogues (cytarabine, fludarabine)

• From 2000 :

1. Conventional Chemotherapy

2. Immunotherapy

3. Radioimmunotherapy

4. Epigenetic targeting

5. Proteasome inhibition

6. Immunomodulation

7. Other targeted drugs

1. Conventional Cytotoxic Chemotherapy

Aggressive

Diffuse large B- Cell Lymphoma

Fisher R, Gaynor et al. NEJM 1993;328:1002

Aggressive

DLBCL

Immunotherapy

Diffuse Large B-Cell Lymphoma : R-CHOP

R-CHOP

CHOP

Diffuse Large B-Cell Lymphoma : R-CHOP

R-CHOP

CHOP

Cell Signaling in ABC-type DLBCL

Upregulation

of NFKB

pathway

Proteasome

Inhibition

2004 Nobel Prize in Chemistry

"for the discovery of ubiquitin-mediated protein degradation”

Bortezomib

Inhibitor of the Proteasome

Inhibition of the

proteasome prevents

the degradation of

intracellular proteins,

affecting multiple

signaling cascades

within cell.

Proteasome

Bortezomib

Ubiquitin Protein

Bortezomib

Inhibitor of the Proteasome

Inhibition of the

proteasome prevents

the degradation of

intracellular proteins,

affecting multiple

signaling cascades

within cell.

Proteasome

Bortezomib

Ubiquitin Protein

Objectives Primary • Overall CR rate (PET negative)

Secondary

• Overall Response rate ( CR + PR) • 1 & 2 Year PFS • Duration of response • Safety • QOL/PRO • Biomarker

R

A

N

D

O

M

I

Z

E

R-CHOP Cyclophosphamide 750 mg/m2 day 1

Doxorubicin 50mg/m2 day 1

Vincristine 1.4mg/m2 (max 2mg) day 1

Prednisolone 100mg/m2 days 1-5

Rituximab 375mg/m2 day 1

1:1 randomization

Stratify by IPI

82 pts per arm

VR-CAP Cyclophosphamide 750 mg/m2 day 1

Doxorubicin 50mg/m2 day 1

VELCADE 1.3mg/m2 D 1, 4, 8 and 11

Prednisolone 100mg/m2 days 1-5

Rituximab 375mg/m2 day 1

Treatment: 6 cycles (21-day)

Phase II Study:

Objectives & Design NCT01040871

Indolent

Follicular Lymphoma

Survival of patients with Indolent Lymphoma:

the Stanford experience, 1960–1993

Horning S, Semin Oncol 1993;20(5 Suppl. 5):75

Pati

en

ts (

%)

Year

1987-1993

1976-1986

1960-1975

100

60

40

20

0

80

0 5 10 15 20 25 30

1960-1975

1976-1986

1987-1992

1987-1996

1997-2003

1976-1986

1960-1975

Tan D, Horning S et al: Blood 110:3428A, 2007

Survival of patients with Indolent Lymphoma:

the Stanford experience, 1960–2003

1997-2003

1976-1986

1960-1975

Closing the gap: A comparison of observed

versus expected survival in follicular lymphoma

Tan D, Rosenberg SA, et al. J Clin Oncol 2008;26:8535

Expected Normal Survival

1987-1996

TTTF

Randomized Trials of R-Chemo vs Chemo alone

CHVP-IFN

R-CHVP-IFN

R-MCP

Phase 3 Trial of Bendamustine + Rituximab vs R-CHOP in

First-Line Indolent and Mantle Cell Lymphomas:

Final Results

(N=549)

N=260

N=253

Rummel et al ASH 2009 Abstract #405

Alkylation

moiety

Benzimidazole ring

Phase 3 Trialof Bendamustine + Rituximab vs R-CHOP in

First-Line Indolent Lymphomas:

Final Results

BR R-CHOP R-CHOP R-CHOP BR BR

Median f/u: 32 mths

BR R-

CHOP

p-

value

PFS

(mths)

54.8 34.8 0.0002

TTNT

(mths)

Not

reached

40.7 0.0002

OS ND ND NS

Rummel et al ASH 2009 Abstract #405

B-Cell Lymphomas Express Several Antigens that can be Targeted

B Cell

Blinatumomab

Epratuzumab/

Inotuzumab

Lumiliximab

Dacetuzumab/

HCD122

Galiximab

Idiotype

Vaccination

B-Cell Lymphomas Express Several Antigens that can be Targeted

B Cell

Blinatumomab

Epratuzumab/

Inotuzumab

Lumiliximab

Dacetuzumab/

HCD122

Galiximab

Idiotype

Vaccination

RadioImmunotherapy

Novel Targeted Approach for Lymphoma Tx

Highly Aggressive Lymphoma

Lymphoblastic Lymphoma

Burkitt’s Lymphoma

INDUCTION

CONSOLIDATION MAINTENANCE

Qu

ality

of

Rem

issio

n (

CR

Rate

)

Remission Duration

Step 3:

Prevent relapse

by maintaining

best response

Step 1:

Reduce tumor

load and induce

initial response

Goals of therapy over a patient’s course of treatment

Step 2:

Maximize response by

rapidly improving quality

of response to induction

Treatment Algorithm of Acute Lymphoblastic

Leukamia

INDUCTION

CONSOLIDATION MAINTENANCE

•Combination chemo- or

immunochemotherapy

•Steroids

• Auto-SCT

• Radiolabeled immunotherapy

•Immunotherapy

•Immunomodulation

Qu

ality

of

Rem

issio

n (

CR

Rate

)

Remission Duration

Step 3:

Prevent relapse

by maintaining

best response

Step 1:

Reduce tumor

load and induce

initial response

Goals of therapy over a patient’s course of treatment

Step 2:

Maximize response by

rapidly improving quality

of response to induction

Treatment Algorithm of Lymphoma in Era of Novel

Therapy

Historical Perspectives

1832 : Sir Thomas Hodgkin described Hodgkin’s Disease

1863 : Virchow > Lymphosarcoma

1871 : Billroth > Malignant Lymphoma

1900 : Carl Sternberg + Dorothy Reed described

the Reed Sternberg cell

1958 : Dennis Burkitt > Burkitt’s lymphoma

1956 : Rappaport Classification

1967 : Ann Arbor > Lymphomas are Neoplastic

counterparts of normal B and T cells development

1974 : European Kiel classification

American Luke-Collins classification

1982 : Working formulation

1994 : REAL classification

2001 : WHO classification

2000 Onwards :

Rapid Advances in Therapeutics

Immuno-

pathology

Immuno- therapy

Histopathology Cytotoxic

Chemotherapy

Clinical Radiotherapy

Rx Dx

Targeted Therapy Gene Expression

Profiling

Molecular Genetics

Treating Lymphoma

Cytotoxic Chemo

Immunotherapy

Targeted Therapy

Tan Ah Kow The Near Future…….

Rx: CHOP + anti CD XX + agent C + agent X

Thank You

Feasibility:

CHOP-Ontak

Pralatrexate consol

Ann Arbor Staging

INDUCTION

CONSOLIDATION MAINTENANCE

•Combination chemo- or

immunochemotherapy

•Steroids

• Auto-SCT

• Radiolabeled immunotherapy

•Immunotherapy

•Immunomodulation

Qu

ality

of

Rem

issio

n (

CR

Rate

)

Remission Duration

Step 3:

Prevent relapse

by maintaining

best response

Step 1:

Reduce tumor

load and induce

initial response

Goals of therapy over a patient’s course of treatment

Step 2:

Maximize response by

rapidly improving quality

of response to induction

Treatment Algorithm of Lymphoma in Era of

Novel Therapy

RELAPSE

Overview-Advances in Lymphoma Therapy

• Advances in understading of Disease biology

• Advances in Prognostication

– Identification of important biological and clinical biomarkers

• Novel modalities in treatment

– Immunotherapy

– Targeted therapy

– Radioimmunotherapy

– Proteasome inhibition

– Others

Chronic Lymphocytic Leukaemia/ Small

Lymphocytic Lymphoma: FISH

Rosenwald et al NEJM 2002

Immunotherapy