THE ROLE OF

BENDAMUSTINE RITUXIMAB
IN NON HODGKIN
LYMPHOMA
History of Bendamustine
■ The alkylating agent bendamustine was first synthesized in 1963 in Jena,
in the former German Democratic Republic (East Germany),
■ The first use of bendamustine was in 1969 to treat MM.
■ Bendamustine was not studied systematically in clinical trials in patients
until the 1990s, after German reunification
■ Bendamustine was approved by the FDA for the treatment of CLL on March
20, 2008, and on October 31, 2008, for the treatment of indolent B-cell
NHL in patients whose disease progressed during or within 6 months of
treatment with rituximab or a rituximab-containing regimen
Tageja N, Nagi J. Bendamustine: something old, something new. Cancer Chemother Pharmacol. 2010;66:413-423.

Apostolopoulos C, Castellanl L, Stebbing J, et al. Bendamustine as a model for the activity of alkylating agents. Future Oncol.
2008;4:323-332.
 2008 Estimated US Cancer Cases*
Men Women
720,280 679,510

Prostate 33% 31% Breast

Lung & bronchus 13% 12% Lung & bronchus
Colon & rectum 10% 11% Colon & rectum
Urinary bladder 6% 6% Uterine corpus
Melanoma of skin 5% 4% Non-Hodgkin
lymphoma
Non-Hodgkin 4%
lymphoma 4% Melanoma of skin
Kidney 3% 3% Thyroid
Oral cavity 3% 3% Ovary
Leukemia 3% 2% Urinary bladder
Pancreas 2% 2% Pancreas
All Other Sites 18% 22% All Other Sites
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
Source: American Cancer Society, 2008.
 Age at Diagnosis for Hodgkin’s and
Non-Hodgkin’s Lymphoma
120
~56,390 NHL cases/y
100 ~7,350 HD cases/y

NHL
Cases/100,000

80

60

40

20
Hodgkin’s
0
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85

Age at diagnosis (y)

Data for diagnoses from 1997 to 2001.
At: http://seer.cancer.gov. Accessed March 23, 2005.
 Hodgkin’s Disease/Lymphoma
In the Beginning
First described in 1832 by Dr. Thomas Hodgkin

Neoplasm of B lymphocytes – large pleomorphic prominent

nucleolus in a halo - Hodgkin cells

Reed-Sternberg cell – binucleate Hodgkin cell with owl eye

appearance

Classification:
Classical Hodgkin’s
Nodular sclerosis – low grade
Mixed cellularity
Lymphocyte rich classical 1798-1866
Lymphocyte depleted. – high grade

Nodular lymphocyte-rich Hodgkin’s

Reed-Sternberg Cells
 Hodgkin’s Disease/Lymphoma
In the Beginning
n Accounts for ~ 30% of all malignant lymphomas

n Composed of two different disease entities:

Lymphocyte-predominant Hodgkin’s (LPHD), making up

~ 5% of cases

Classical HD, representing ~ 95% of all HDs.

A common factor of both HD types is that neoplastic

cells constitute only a small minority of the cells in
the affected tissue, often corresponding to < 2% of
the total tumor
Non-Hodgkin’s Lymphoma
 Histologic Classification of
Non-Hodgkin’s Lymphomas
1. Rappaport - 1966
2. Lukes and Collins - 1974
3. Kiel - 1974
3. Dorfman - 1974
4. Bennet et al., - 1974
5. Lennert - 1974
6. WHO - 1976
7. Working Formulation - 1982
8. REAL - 1994
9. WHO - 1999
 Non-Hodgkin’s Lymphoma
Rappaport Classification
Nodular (follicular) Diffuse

Indolent Aggressive

Small cell Large cell

Non-Hodgkin’s Lymphoma
Rappaport Classification

n Small cell, follicular

n Small cell, diffuse
n Large cell, follicular
n Large cell, diffuse
 Non-Hodgkin’s Lymphoma
Lukes-Collins & Kiel Classifications

n Lukes-Collins System – US
n Kiel System – Europe

n Differentiation of B-cell and T-cell lymphomas

 Non-Hodgkin’s Lymphoma
Working Classification
n Developed in 1980’s
n NCI Investigators reviewed Rappaport, Lukes-Collins, and Kiel
systems
n n=1175

n Goal was to clarify… now a new system!

n No consideration to B-cell or T-cell typing
n Goal was to group lymphomas according to aggressiveness
(low, intermediate, high)
 Non-Hodgkin’s Lymphoma
Working Classification
n Low Grade
n Small Lymphocytic
n Follicular small-cleaved cell
n Follicular mixed small-cleaved and large cell
n Intermediate Grade
n Follicular large cell
n Diffuse small cleaved cell
n Diffuse mixed small and large cell
n Diffuse large cell
n High Grade
n Large cell immunoblastic
n Lymphoblastic
n Small non-cleaved cell (Burkitt's and non-Burkitt's type)
 Hodgkin Non Hodgkin Lymphoma
Lymphoma

Classical HL Indolent Aggressive Highly

(NS, MC, LR, Aggressive
LD)
B cell B cell B cell
Nodular Follicular DLBCL Pre-B
lymphocyte SLL/CLL FLg3 and tFL lymphoblastic
Predominant Marginal zone Mantle cell Burkitt
(NLPHL) LP (WM) Primary effusion

T/NK cell T/NK cell T/NK cell

Mycosis fungoides ALCL Pre-T
Sezary syndrome Angioimmunoblastic lymphoblastic
Primary cut ALCL Subq panniculitis-like
Blastic NK
Extnanodal NK/T
nasal
Enteropathy-type
Hepatosplenic
Multiple
PTCL nos
Myeloma
 Non-Hodgkin’s Lymphoma
REAL Classification
n Revised European-American Lymphoma
n Mid 1990’s – International Lymphoma Study Group
(informal group of hematopathologists)

n Using immunophenotype, cytogenetics, molecular

diagnostics
n Reclassified lymphomas by diagnostic criteria and not by
risk categories
 Non-Hodgkin’s Lymphoma
WHO Classification
n Bruce Cheson, MD and the NCI International
Working Group reported in January 1999
n Adopted in 2001, Revised in 2008

n Discredited the Working (non-REAL) Classification

n Based on REAL (Non-working) Classification

Cheson et al. J Clin Oncol. 1999 Apr;17(4):1244

 WHO/REAL Classification of Lymphoid Neoplasms
B-Cell Neoplasms
Mature (peripheral) T neoplasms
Precursor B-cell neoplasm
T-cell chronic lymphocytic leukemia / small
Precursor B-lymphoblastic leukemia/lymphoma lymphocytic lymphoma
(precursor B-acute lymphoblastic leukemia) T-cell prolymphocytic leukemia
Mature (peripheral) B-neoplasms T-cell granular lymphocytic leukemiaII
B-cell chronic lymphocytic leukemia / small lymphocytic Aggressive NK leukemia
lymphoma Adult T-cell lymphoma/leukemia (HTLV-1+)
B-cell prolymphocytic leukemia Extranodal NK/T-cell lymphoma, nasal type#
Lymphoplasmacytic lymphoma‡ Enteropathy-like T-cell lymphoma**
Splenic marginal zone B-cell lymphoma Hepatosplenic γδ T-cell lymphoma*
(+ villous lymphocytes)*
Subcutaneous panniculitis-like T-cell lymphoma*
Hairy cell leukemia
Mycosis fungoides/Sézary syndrome
Plasma cell myeloma/plasmacytoma
Extranodal marginal zone B-cell lymphoma of MALT type Anaplastic large cell lymphoma, T/null cell,
Nodal marginal zone B-cell lymphoma primary cutaneous type
(+ monocytoid B cells)* Peripheral T-cell lymphoma, not otherwise characterized
Follicular lymphoma Angioimmunoblastic T-cell lymphoma
Mantle cell lymphoma Anaplastic large cell lymphoma, T/null cell,
Diffuse large B-cell lymphoma primary systemic type
Mediastinal large B-cell lymphoma Hodgkin’s Lymphoma (Hodgkin’s Disease)
Primary effusion lymphoma† Nodular lymphocyte predominance Hodgkin’s lymphoma
Burkitt’s lymphoma/Burkitt cell leukemia§ Classic Hodgkin’s lymphoma
T and NK-Cell Neoplasms
Nodular sclerosis Hodgkin’s lymphoma (grades 1 and 2)
Precursor T-cell neoplasm
Precursor T-lymphoblastic leukemia/lymphoma Lymphocyte-rich classic Hodgkin’s lymphoma
(precursor T-acute lymphoblastic leukemia Mixed cellularity Hodgkin’s lymphoma
Lymphocyte depletion Hodgkin’s lymphoma
‡ Formerly known as lymphoplasmacytoid lymphoma or immunocytoma
IIEntities formally grouped under the heading large granular lymphocyte †Not described in REAL classification
leukemia of T- and NK-cell types §
* Provisional entities in the REAL classification Includes the so-called Burkitt-like lymphomas
** Formerly known as intestinal T-cell lymphoma
# Formerly know as angiocentric lymphoma
 Non-Hodgkin’s Lymphoma
n 30ish histologic subtypes
n B cell (85%), T cell, NK cell

n Histologic subtype dictates the approach to the patient

n Median age at diagnosis 60

n Often widespread disease at diagnosis
n Wide variation in outcome
n Some cases rapidly fatal

n Some cases readily curable

n Some cases incurable but patient can live for many years with good quality of life
 WHO Classification:
B-Cell Malignancies
Precursor B-cell neoplasm
• Precursor B-lymphoblastic leukemia/lymphoma

Mature (peripheral) B-cell neoplasms

• B-cell chronic lymphocytic leukemia/ • Hairy cell leukemia
small lymphocytic lymphoma • Plasma-cell myeloma/
• B-cell prolymphocytic leukemia plasmacytoma
• Lymphoplasmacytic lymphoma • Follicular lymphoma
• Splenic marginal-zone B-cell lymphoma • Mantle-cell lymphoma
• Nodal marginal-zone lymphoma • Diffuse large B-cell lymphoma
• Extranodal marginal-zone B-cell (DLBCL)
lymphoma, mucosa-associated • Burkitt's lymphoma/Burkitt's cell
lymphoid tissue (MALT) type leukemia
• Blastic NK-cell leukemia
Harris NL et al. J Clin Oncol. 1999;17:3835-3849.
 WHO Classification:
T-Cell Malignancies
Precursor T-cell neoplasm
• Precursor T-lymphoblastic leukemia/lymphoma

Mature (peripheral) T-cell neoplasms

• T-cell prolymphocytic leukemia
• T-cell granular lymphocytic leukemia
• Aggressive NK-cell leukemia
• Adult T-cell lymphoma/leukemia (HTLV1+)
• Extranodal NK/T-cell lymphoma, nasal type
• Enteropathy-type T-cell lymphoma
• Hepatosplenic gamma-delta T-cell
lymphoma
• Subcutaneous panniculitis-like T-cell
lymphoma
• Mycosis fungoides/Sézary syndrome
• Primary cutaneous anaplastic large cell
lymphoma, T/null cell
• Peripheral T-cell lymphoma, unspecified
• Angioimmunoblastic T-cell lymphoma
• Primary systemic anaplastic large cell
lymphoma, T/null cell
• Blastic NK lymphoma

Harris NL et al. J Clin Oncol. 1999;17:3835-3849.

 B-Cell Development
Stem cell Immature B cell Follicle-center B cell
s-IgM s-IgM/G/A
CD22 CD79a
CD79a
TdT CD22
CD21 CD10
HLA-DR bcl6 CD21
CD20 HLA-DR
HLA-DR CD34 CD20
CD19
CD19

Pre-pre–B cell Immunoblast

s-IgM/G/A
TdT
CD22
c-CD22 CD79a
c-CD79a Mature B cell CD138±
c-Ig
s-IgM & IgD CD20
HLA-DR CD19
CD79a CD19
HLA-DR
CD22 MUM1
HLA-DR CD21
Pre–B cell
CD20
CD10 TdT CD19
c-CD22 Plasma cell
c-CD79a
c-µ CD20
CD79a c-Ig CD138
CD19
HLA-DR Precursor cells PCA-1

Virgin (naïve) B cells MUM1

Germinal-center and post–germinal-center B cells
 Non-Hodgkin’s Lymphoma
Immunophenotyping
n Immunohistochemistry
n Immunofluorescence
n Flow cytometry

n Identification of CD’s (cluster determinants)

n CD5 = T cell type
n CD20 = B cell type
Non-Hodgkin’s
Lymphoma
Cluster
Determinants
Antigen Expression in B-Cell Lineage

ALL MCL, CLL Burkitts, FL, DLBCL WM MM

Stem cell Pre-B Early B Mature B Activated B Plasmacytoid B Plasma

Germinal center

Type of B cell lymphoma is a function of:

1) Where the cell was in development/maturation when it went “bad”
2) What molecular derangement occurred

Jaffe. In: Non-Hodgkin’s Lymphoma. 1997:84.

Chromosomal Translocations Commonly Associated With
Activation in B-Cell Malignancies
Oncogene Protein Translocation Disease

bcl-1 Cyclin D1 t(11;14) MCL

BCL2
bcl-2 t(14;18) FL
(antiapoptosis)

myc Transcription factor t(8;14) Burkitt’s NHL

Zinc-finger DLBCL (some

bcl-6 t(3;14)
transcription factor follicular NHL)

National Comprehensive Cancer Network. Practice Guidelines in Oncology. v.1.2005.

 Most Common NHLs
Category Frequency (%)
Diffuse large B-cell 31
Follicular 22
Marginal-zone B-cell, MALT 8
Peripheral T-cell 7
Small B-lymphocytic/CLL 7
Mantle-cell lymphoma 6
Primary mediastinal large B-cell 2
Anaplastic large T/null cell 2
High-grade B-cell, Burkitt-like 2
Marginal-zone B-cell, nodal 2
Precursor T-lymphoblastic lymphoma 2

Armitage JO, Weisenburger DD. J Clin Oncol. 1998;16:2780-2795.

 Lymphoma Biology
n Aggressive NHL
n short natural history (patients die within months if untreated)
n disease of rapid cellular proliferation
n Potentially curable with chemotherapy

n Indolent NHL
n long natural history (patients can live for many years untreated)
n disease of slow cellular accumulation
n Generally incurable with chemotherapy
 NHL: Presentation and Staging

n Aggressive NHL
n Patients likely to present with symptoms

n Indolent NHL
n Patients likely to present with painless adenopathy

n Initial workup similar to Hodgkin Lymphoma

 NHL: Approach to the Patient

n Approach dictated mainly by histology

n reliable hematopathology crucial

n Aggressive NHL
n Cure is often the goal
n Indolent NHL
n Cure is rarely the goal
n Control is the goal
 Approach to Aggressive NHL

n Patients have the potential to be cured

n Administer most effective therapy (no matter how harsh) at diagnosis

n If not cured, patients typically die within a few years of diagnosis

 Approach to Indolent NHL
n Indolent NHL: guiding treatment principle
n immediate treatment does not prolong overall survival for many patients

n When to treat?
n constitutional symptoms

n compromise of a vital organ by compression or infiltration, particularly the bone marrow

n bulky adenopathy

n rapid progression

n evidence of transformation

n Will often begin with relatively non-toxic treatments and escalate the intensity of the
therapy
 DIAGNOSIS

• Excisional/incisional biopsy
• FNA not suitable
• Core biopsy is not optimal
• Rebiopsy if nondiagnostic
• IHC,Flow cytometry,FISH, gene
arrangement
Ann Arbor Staging System for Hodgkin's Disease and Non-
Hodgkin's Lymphoma

Stage I Stage II Stage III Stage IV

Reprinted with permission. Adapted from

Skarin. Dana-Farber Cancer Institute Atlas
of Diagnostic Oncology. 1991.
THANK YOU