Hodgkins Disease

and
Non-Hodgkins
Lymphoma
Harold M. Chung, MD
Associate Professor of Medicine
VCU Medical Center MCV Hospitals
Bone Marrow Transplantation Program

November 8, 2011
Why Men Cant Be Babysitters
 Agenda
Discuss Hodgkins Disease

Discuss Non-Hodgkins Lymphoma

Classification Systems

Treatment Options
 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.
 2008 Estimated US Cancer Deaths*
Men Women
291,270 273,560
Lung & bronchus 31% 26% Lung & bronchus
Colon & rectum 10% 15% Breast
Prostate 9% 10% Colon & rectum
Pancreas 6% 6% Pancreas
Leukemia 4% 6% Ovary
Liver & intrahepatic 4% 4% Leukemia
bile duct 3% Non-Hodgkin
Esophagus 4% lymphoma
Non-Hodgkin 3% 3% Uterine corpus
lymphoma 2% Multiple myeloma
Urinary bladder 3% 2% Brain/ONS
Kidney 3% 23% All other sites
All other sites 23%
ONS=Other nervous system.
Source: American Cancer Society, 2008.
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 T-cell lymphoma*
(+ villous lymphocytes)*
Subcutaneous panniculitis-like T-cell lymphoma*
Hairy cell leukemia
Mycosis fungoides/Szary 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 Hodgkins Lymphoma (Hodgkins Disease)
Primary effusion lymphoma Nodular lymphocyte predominance Hodgkins lymphoma
Burkitts lymphoma/Burkitt cell leukemia
Classic Hodgkins lymphoma
T and NK-Cell Neoplasms
Nodular sclerosis Hodgkins lymphoma (grades 1 and 2)
Precursor T-cell neoplasm
Precursor T-lymphoblastic leukemia/lymphoma Lymphocyte-rich classic Hodgkins lymphoma
(precursor T-acute lymphoblastic leukemia Mixed cellularity Hodgkins lymphoma
Lymphocyte depletion Hodgkins 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
Includes the so-called Burkitt-like lymphomas
* Provisional entities in the REAL classification
** Formerly known as intestinal T-cell lymphoma
# Formerly know as angiocentric lymphoma
Hematopoietic System
 B cell malignancies

Lymph node, Lymph node,

lymph, blood, lymph, blood,
Bone marrow Bone marrow
bone marrow bone marrow

Progressive B lymphocyte maturation

Lymphoid stem cell Maturing B cell Mature B cell Plasma cell

many stages

Pre-B acute lympho- B cell lymphoma Chronic lympho- Multiple myeloma

cytic leukemia
blastic leukemia
Boys Need Parents
 Hodgkins 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 Hodgkins
Nodular sclerosis low grade
Mixed cellularity
Lymphocyte rich classical 1798-1866
Lymphocyte depleted. high grade

Nodular lymphocyte-rich Hodgkins

 Hodgkins Disease/Lymphoma
In the Beginning
Bimodal age distribution
first peak between 2nd - 3rd decade of life
second peak between 5th - 6th decade of life

Male: Female 2:1 in kids, adults almost equal M:F

Mixed cellularity (MC) Hodgkins Disease is more

common at younger ages

More common in immune deficiency patients

 Hodgkins Disease/Lymphoma
In the Beginning
Accounts for ~ 30% of all malignant lymphomas

Composed of two different disease entities:

Lymphocyte-predominant Hodgkins (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
 Hodgkins Disease/Lymphoma
In the Beginning
Fatal disease with 90% of untreated patients dying
within 2 to 3 years

With chemotherapy, >80% of patients suffering from

HD are cured.

Pathogenesis of HD is still largely unknown.

HD nearly always arises and disseminates in lymph

nodes
 Hodgkins Disease/Lymphoma
Interest tidbits

Pel-Ebstein Fevers

Pain with alcohol consumption

 Hodgkins Disease/Lymphoma
Clinical Presentation
Nontender lymph nodes enlargement (localized)
neck and supraclavicular area
mediastinal adenopathy
other (abdominal, extranodal disease)
systemic symptoms (B symptoms)
fever
night sweats
unexplained weight loss (10% per 6 months)
other symptoms
fatigue, weakness, pruritus
cough , chest pain, shortness of breath, vena cava
syndrome
abdominal pain, bowel disturbances, ascites
bone pain
 Hodgkins Disease/Lymphoma
Clinical Presentation
SIGNS & SYMPTOMS % OF PATIENTS
Lymphadenopathy 90
Mediastinal mass 60
B symptoms 30
Fever, weight loss, night sweats
Hepatosplenomegaly 25

Most commonly involved lymph nodes are the

cervical and supraclavicular in 75%
Bone marrow is involved in 5% of patients
Reed-Sternberg Cells
CD 30 Immunostain
 Hodgkins Disease/Lymphoma
Clinical Presentation
Stage Definition

I Involvement of a single lymph node region (I) or of a single extralymphatic organ or site (IE)

II Involvement of two or more lymph node regions on the same side of the diaphragm (II) or
localized involvement of an extralymphatic organ or site and one or more lymph node
regions on the same side of the diaphragm (IIE)

III Involvement of lymph node regions on both sides of the diaphragm (III) which may be
accompanied by involvement of the spleen (IIIS) or by localized involvement of an
extralymphatic organ or site (IIIE) or both (IIISE)

IV Diffuse or disseminated involvement of one or more extra lymphatic organs or tissues with
or without associated lymph node involvement

B symptoms: fever > 38C for three consecutive days, drenching night sweats or unexplained loss 10% or more of
weight the preceding 6 months
 Hodgkins Disease/Lymphoma
Treatment

Unfavorable prognostic factors:

- Stage IIIB, IV
- B symptoms
- Bulky disease
- High ESR >50
 Hodgkins Disease/Lymphoma
Treatment
Long term effects of treatment should be
taken into consideration:
- Treatment-related second neoplasms
(i.e. AML, NHL and breast cancer)
- Infertility
- Growth consideration
- Long-term organ dysfunction (i.e.,
thyroid, heart, lung)
 Hodgkins Disease/Lymphoma
Treatment
Adolescent patients who have achieved
maximum growth can be treated as adult
patients

Chemotherapy alone protocols for

localized disease has been used in
developing countries with some success

Lobo-Sanahuja F: Medical and Pediatric Oncology 22(6);1994

Hodgkins Disease/Lymphoma
Treatment
With appropriate treatment about 85% of
patients with Hodgkins disease are curable

I A,B Radiation Therapy

II A Combination Chemo +
Radiotherapy
IIB; IIIA,B; IVA,B Combination Chemo
(+/- radiotherapy)
 Hodgkins Disease/Lymphoma
Treatment
Radiation therapy (35-40 Gy) 80-90% RC
Mantle field
Paraaortic field
Pelvic field

Combination chemotherapy
ABVD 80% RC
BEACOPP 90% RC
Hodgkins Disease/Lymphoma
Treatment Progress
 ABVD vs
MOPP vs
MOPP/ABVD
Failure-free survival

Canellos et al,
NEJM, 2002
Overall survival
Hodgkins Disease/Lymphoma
Treatment
Almost no MDS/AML (at 15 years 1.0%)
(Valagussa 86)

Oligospermia 50% complete recovery

Median FSH in normal range (Viviani 85)

Bleomycin-related pulmonary toxicity ~1/3

have reduced PFT but recover in 3 months;
~20% omit Bleomycin.
 Cancer and Leukemia Group B 8251 and 8952:
Recurrent Hodgkin's Disease by Treatment

Canellos, G. P. et al. J Clin Oncol; 22:1532-1533 2004

Hodgkins Disease/Lymphoma Advanced Stage
ABVD vs MEC vs Stanford V
Hodgkins Disease/Lymphoma
Actual Treatment Progress
100 IIIIIIIIIIIIIIIIIIIIII
IIIIIIIIIIIIII
IIII IIIIII
IIIIII IIIIIIII
IIIIII IIIIIIIII
IIIIIII IIIIIIIIIIIIII
IIIIII IIIIIIIIII
IIIIIII IIIIIIIIIIIIIIIIIIIIIIIII
IIIIIII IIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
IIIIIII IIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
IIIIIII IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIII IIIII III IIII IIII III
PROBABILITY (%)

80 IIIIIIIIII
IIIIIIIIII
IIIIIIII
IIIIIIIII
IIIIIIII
IIIIIIIIIII
IIIIIIIII
IIIIIII
IIIIIIIII
IIIIIIIII
IIIIIIIIIII
IIIIIIIIII
IIIIIIIIII
IIIIIII
60 IIIIIIII
IIIIIIII
IIIIIII
IIIIIIIIIII
IIIIIIIIII
IIIIIIII
IIII
III
II
IIIIIIIIIIII
IIIIII
IIIIIIIII
40 IIIII
IIIIIIII II
III IIIII II
Expected Survival I II
III
I HD Survival I IIII III

20 I Observed Survival

0
0 5 10 15 20 25 30 35
YEARS
Stanford, Hoppe et al
Causes of Death among 2733 Patients
with Hodgkins Disease/Lymphoma

Hodgkin lymphoma 383 41.2%

Secondary cancers 200 21.5%
Cardiovascular 148 15.9%
Pulmonary 41 4.4%
Infection 35 3.8%
Trauma/Suicide 16 1.7%
MDS 11 1.2%
Other/Unknown 96 10.3%
Total 930 100.0%
Stanford, Hoppe et al
 SECOND TUMORS LONG-TERM SURVIVORS OF
HODGKINS DISEASE/LYMPHOMA
(PRIMARY RT OR COMBINED MODALITY)
# pts Actuarial Incidence Median Follow-up

Princess Margaret 865 18% (20 years) 20 years

Hospital, Toronto

US Pediatric Series 1380 26.3% (30 years) 17 years

(JCO 21:4386, 2003)

Harvard/Joint Center 1319 35% (25 years) 12 years

(Blood 100:1989, 2002)

Netherlands 1253 27.7% (25 years) 14.1 years

(JCO 18:481, 2000)

NIH Survey of 32,591 21.9% (25 years) 10 years

Registries and Seer
(JCO 20:3474, 2002)
 HODGKINS DISEASE/LYMPHOMA
SALVAGE REGIMENS
Regimen Patients CR/PR to ASCT
DHAP 102 87% 60%
(dexamethasone, ara-C, cisplatin)

Mini-BEAM 89 77% 82%

(BCNU, etoposide, ara-C, melphalan; 2 series)

Dexa-BEAM 225 75% 75%

(above plus dexamethasone; 3 series)

GDP 34 62% 88%

(gemcitabine, dexamethasone, oxaloplatin)

ICE 65 84% 86%

(ifosfamide, carboplatin, etoposide)

GND 38 64% --
(gemcitabine, vinorelbine, liposomal doxorubicin)
CALGB 50203 Treatment Plan

AVG:

Doxorubicin 25mg/m2 IV d1, D15

Vinblastine 6mg/m2 IV d1, d15
Gemcitabine 1,000mg/m2 IV d1, d15
800mg/m2 if gr. 4 ANC/plt ct in 2.6 pts

Repeat every 28 days x 6 cycles

HODGKINS DISEASE/LYMPHOMA
Autologous Transplants as Primary Therapy
1996 - 2002: 7 uncontrolled trials
Event-free survival 242/337 patients 72%
Median follow-up 42-46 months (30-86 months)

2003: Prospective Randomized Trial

(JCO 21:2320, 2003)

163
83 ASCT 80 (4 more cycles ABVD)
CR 89% 92%
RFS (5 years) 88% 94%
OS (5 years) 88% 88% [no difference]
 PROBABILITY OF SURVIVAL AFTER
AUTOTRANSPLANTS FOR RELAPSED
HODGKINS DISEASE/LYMPHOMA, 1996-2001
100
CR1 (N =
226)
80
PROBABILITY, %

CR2+ (N =
733)
60

Never in remission (N = 823)

40
Relapse (N = 1,744)

20

P = 0.0001
0
0 1 2 3 4 5 6
YEARS
 ALLOTRANSPLANTATION
HODGKINS DISEASE/LYMPHOMA

EBMTR IBMTR JOHNS HOPKINS

Patients 45 100 53
Median age 29 28 28
Event-free
Survival 15% 15% 26%
Median F/U (mos.) 31 36 60
Overall Survival 25% 21% 30%
Treatment Mortality 48% 61% 43%
GVH -
Acute 63% 35% 45%
Chronic 55% 45% 17%
HODGKINS DISEASE/LYMPHOMA
Non-Myeloablative Allotransplants
7 series (2004-2008)

Total Patients = 547 (1.5 5-year follow-up)

Relapse 43-64%
PFS 18-32%
OS 28-61%
Treatment-Related Mortality 5-24%

(The majority failed autotransplantation)

HODGKINS DISEASE/LYMPHOMA
Residual Masses By PET scan
5 series (2001-present)

Total Patients 204 Relapses

PET negative 144 18 (12.5%)

after therapy

PET positive 60 35 (58.3%)

after therapy

? 40% false positive rate

 CTN 0701

Tandem Transplant

Modeled after myeloma data

High-risk Hodgkins Disease

University of Nebraska Julie Vose, MD

Monoclonal Antibodies
 MDX-060 - Anti-CD30 target
Anti-CD30 antibody
Medarex 2004 Orphan Drug Status

Hodgkins Disease/Lymphoma
Anaplastic Large Cell NHL
 SGN-35 (Seattle Genetics)

A Younes et al, N Engl J Med 2010;363:1812-21.

 Good Ideas
Cadence Pharmaceuticals
Ofirmev
November 2, 2010 FDA Approval

IV acetaminophen

$800/IV dose
Boys Need Parents
Non-Hodgkins Lymphoma

Deep Breath

Stand up

Stretch
 Histologic Classification of
Non-Hodgkins 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-Hodgkins Lymphoma
Rappaport Classification
Nodular (follicular) Diffuse

Indolent Aggressive

Small cell Large cell

Non-Hodgkins Lymphoma
Rappaport Classification

Small cell, follicular

Small cell, diffuse
Large cell, follicular
Large cell, diffuse
 Non-Hodgkins Lymphoma
Immunophenotyping
Immunohistochemistry
Immunofluorescence
Flow cytometry

Identification of CDs (cluster determinants)

CD5 = T cell type
CD20 = B cell type
Non-Hodgkins
Lymphoma
Cluster
Determinants
 Non-Hodgkins Lymphoma
Lukes-Collins & Kiel Classifications

Lukes-Collins System US
Kiel System Europe

Differentiation of B-cell and T-cell lymphomas

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

Goal was to clarify now a new system!

No consideration to B-cell or T-cell typing
Goal was to group lymphomas according to
aggressiveness (low, intermediate, high)
 Non-Hodgkins Lymphoma
Working Classification
Low Grade
Small Lymphocytic
Follicular small-cleaved cell
Follicular mixed small-cleaved and large cell
Intermediate Grade
Follicular large cell
Diffuse small cleaved cell
Diffuse mixed small and large cell
Diffuse large cell
High Grade
Large cell immunoblastic
Lymphoblastic
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-Hodgkins Lymphoma
REAL Classification
Revised European-American Lymphoma
Mid 1990s International Lymphoma
Study Group (informal group of hematopathologists)

Using immunophenotype, cytogenetics,

molecular diagnostics
Reclassified lymphomas by diagnostic
criteria and not by risk categories
 Frequency of NHL Subtypes in Adults

Mantle cell (6%)

Peripheral T-cell (6%)

Indolent (35%)
Other subtypes with a
frequency 2% (9%)

Composite
lymphomas (13%)

Diffuse large
Armitage et al. J Clin Oncol. 1998;16:27802795
B-cell (31%)
 Non-Hodgkins Lymphoma
WHO Classification
Bruce Cheson, MD and the NCI International
Working Group reported in January 1999
Adopted in 2001, Revised in 2008

Discredited the Working (non-REAL) Classification

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 T-cell lymphoma*
(+ villous lymphocytes)*
Subcutaneous panniculitis-like T-cell lymphoma*
Hairy cell leukemia
Mycosis fungoides/Szary 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 Hodgkins Lymphoma (Hodgkins Disease)
Primary effusion lymphoma Nodular lymphocyte predominance Hodgkins lymphoma
Burkitts lymphoma/Burkitt cell leukemia
Classic Hodgkins lymphoma
T and NK-Cell Neoplasms
Nodular sclerosis Hodgkins lymphoma (grades 1 and 2)
Precursor T-cell neoplasm
Precursor T-lymphoblastic leukemia/lymphoma Lymphocyte-rich classic Hodgkins lymphoma
(precursor T-acute lymphoblastic leukemia Mixed cellularity Hodgkins lymphoma
Lymphocyte depletion Hodgkins 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
Includes the so-called Burkitt-like lymphomas
* Provisional entities in the REAL classification
** Formerly known as intestinal T-cell lymphoma
# Formerly know as angiocentric lymphoma
Non-Hodgkins Lymphoma
Specific Types

Time For A Deep Breath

or an Excedrin
 Follicular Lymphoma
Mbr (major breakpoint region, 150 bp)

Bcl2 Chromosome 18

C Chromosome 14

JH

Double strand DNA break by RAG1/2

Translocation takes place in B cell precursors.

Bcl2 C t(14;18) translocation

Transformation takes place

during B cell activation in GC.

bcl2 E C C 3E

Unregulation of Bcl2 expression by IgH enhancers

 Bcl2 inhibits apoptosis
Pro-survival oncogene

mitochondrion
Bax, Bad

Pro-caspase-9
cytochrome c
Bcl-2, Bcl-XL
Apaf-1
dATP or ATP

Apaf-1 Caspase-9

Pro-caspase-3 Caspase-3

Apoptosis
 Over-expression of Bcl-2 may prevent the apoptosis
of germinal center B cells
Plasma cells

Germinal center Germinal center

activation

apoptosis
Memory cells

Germinal center Germinal center

IgH-Bcl2

activation

follicular lymphoma
Most follicular lymphoma Ig V regions contain
Apoptosis inhibited
somatic hypermutation.
 Non-Hodgkins Lymphoma
Follicular Lymphoma
Low-grade lymphoma
Grade 1 Small cell
Grade 2 Mixed cell

Grade 3 Large cell

Indolent in growth
Chemotherapy sensitive
Incurable
 Non-Hodgkins Lymphoma
Cutaneous T-Cell (Mycosis Fungoides)
Low-grade/Indolent lymphoma
Radiation therapy sensitive
Total Skin Electron Beam Therapy

Control disease for years

Peripheralization of lymphoma cells = Sezary Cell
Sezary Syndrome
 Non-Hodgkins Lymphoma
Diffuse Large Cell
Very Aggressive
Curable if chemo-sensitive upfront, not so
if chemo-refractory or relapses within 6
months

Most common of all lymphomas

Accounts for ~ 31% of all lymphomas
 Non-Hodgkins Lymphoma
Mantle Cell
Aggressive
Accounts for ~ 6% of all lymphomas
Incurable with standard-dose therapy
Stem cell transplant is offered often as
front-line consolidation treatment in
younger patients
Mantle Cell Lymphoma
Morphology

Classical Mantle Cell

Nodular pattern

Diffuse pattern Blastoid Variant

 Mantle Cell - Treatment

CHOP + Rituxan
40 patients (new diagnosis)
CR 48%, PR 48%

Molecular CR seen in 36% of

patients with PCR detectable
cyclin D1/IgH translocation
Median PFS 16.6 months, all
patients relapsed by 36
months
No significant difference in PFS
for patients having a clinical or
molecular CR

Howard, O et al., JCO, 20 (5):1288

 Non-Hodgkins Lymphoma
Marginal Zone
Indolent
Accounts for ~10% of
all lymphomas
Subcategories
MALT (H. pylori)
Nodal
Extra-Nodal
Splenic
Non-Hodgkins Lymphoma
Splenic Lymphoma
 Non-Hodgkins Lymphoma
Primary CNS Lymphoma
Aggressive with poor outcome
Accounts for ~ 1-2% of all lymphomas
Different chemotherapy treatments
Often requires radiation to the brain:
Brain dysfunction in younger patients
Dementia in older patients
 Non-Hodgkins Lymphoma
Anaplastic Large Cell Lymphoma
Aggressive
Accounts for ~ 2% of all lymphomas

ALCL ALK-1+ better prognosis, more

common in younger patients and children

ALCL ALK-1-negative : as bad as any other

T-cell lymphoma
 Treatment results of aggressive advanced
non-Hodgkins lymphomas using different
chemotherapy programs

1. First-generation: CHOP
- CR: 50-55%. Long-term survival: 35-50 %.

2. Second-generation: mBACOD, ProMACE-CytaBOM

- CR: 70-80%. Long-term survival: 50-60%.

3. Third-generation: MACOP-B
- CR: 84%. Long-term survival: 75%
 Non-Hodgkins Lymphoma
Intergroup 0067 Study

3-year survival Mortality

___%________________%___

CHOP 41 1
mBACOD 46 5
ProMACE-CytoBOM 46 3
MACOP-B 41 6

Southwest Oncology Group

 Non-Hodgkins Lymphoma
Treatment of Patients Age over 60

Program________________5-year survival %

CHOP 45
mBACOD 39
ProMACE-CytoBOM 41
MACOP-B 23
t
 Non-Hodgkins Lymphoma
Peripheral T-cell Lymphoma

Aggressive
Accounts for ~ 7% of all lymphomas
Very poor prognosis, often associated with
extra-nodal presentation
Often requiring salvage treatment and
transplant
Burkitts Lymphoma
breakpoints

myc Chromosome 8

*** C IgH Chromosome 14, 80%

V(D)J E S
IgChromosome 2

Class switch recombination Igchromosome 22

Somatic hypermutation

3E
myc C C
S
t(8:14)

3E
myc C C
E S
 Non-Hodgkins Lymphoma
Burkitts NHL
Very Aggressive
Curable with standard-dose therapy but
requires very extensive chemotherapy
protocol
Translocation t(8,14)
Specific Hematopathology Finding
Starry, Starry Night
Burkitts Lymhoma
Starry, Starry Night
 Non-Hodgkins Lymphoma
Lymphoblastic NHL

Very aggressive
Treatment is with acute lymphocytic
leukemia regimen
Often requires high-dose therapy and
allogeneic transplantation for
relapsed/refractory disease
 Gamma Delta-T-cell NHL
Very, very aggressive
Very poor outcome with standard-dose
therapy
High-dose therapy and allogeneic
transplantation is standard-of-care in first
remission
CD57 protein positivity
 Double-Hit Lymphomas

Multiple gene expressions

MYC gene
t(14,18)

Triple-Hit
MYC gene
t(14,18)

BCL-6 gene
 Non-Hodgkins Lymphoma
Aggressive chemotherapy regimens

Dose-dense CHOP
CHOP-Bleo
CEOP-Bleo
DexaBEAM
HyperCVAD
BMT for Non-Hodgkins Lymphoma
Indications

1. Refractory disease
2. Relapse
3. High risk in CR
4. Lymphoblastic, Burkitts, and gamma
delta-t-cell lymphomas
 PROBABILITY OF SURVIVAL AFTER
AUTOTRANSPLANTS FOR FOLLICULAR
NON-HODGKIN LYMPHOMA
100

CR1 (N =
80 174)
CR2+ (N =
PROBABILITY, %

322)
60
Never in remission (N = 418)
Relapse (N = 791)
40

20

P = 0.0009
0
0 1 2 3 4 5 6
YEARS
 PROBABILITY OF SURVIVAL AFTER HLA-
IDENTICAL SIBLING MYELOABLATIVE
TRANSPLANTS FOR
FOLLICULAR NON-HODGKIN LYMPHOMA
100

Never in remission (N =
80 138)
PROBABILITY, %

CR1-3 (N =
79)
60

Relapse (N = 193)
40

20

P = NS
0
0 1 2 3 4 5 6
YEARS
 PROBABILITY OF SURVIVAL AFTER
AUTOTRANSPLANTS FOR
DIFFUSE LARGE CELL LYMPHOMA
100

80
PROBABILITY, %

CR1 (N =
438)
60
CR2+ (N =
651)
40
Relapse (N = 1,443)

20 Never in remission (N = 986)

P = 0.0001
0
0 1 2 3 4 5 6
YEARS
 PROBABILITY OF SURVIVAL AFTER HLA-
IDENTICAL SIBLING MYELOABLATIVE
TRANSPLANTS FOR
DIFFUSE LARGE CELL LYMPHOMA
100

80
PROBABILITY, %

60

40 Relapse (N = 144)

CR1-3 (N =
20 56)
Never in remission (N = 133)
P = NS
0
0 1 2 3 4 5 6
YEARS
Monoclonal Abs - Rituxan
Radioimmunotherapy with Y-90
Zevalin

Monoclonal Ibritumomab
antibody Murine monoclonal
antibody parent of
Rituximab

Tiuxetan
Conjugated to
antibody, forming strong
urea-type bond
Stable retention of Y-90
Chelator
Beta
Y-90 radionuclide radiation
 New Treatment Options
Velcade + Flavoperidol MCC Trial
Velcade + Darinaparsin
 Conclusion
Discussed Hodgkins Disease

Discussed Non-Hodgkins Lymphoma

Discussed Classification Systems

Discussed Treatment Options