Transcript Hodgkin’s Disease and Non

Hodgkin’s Disease
and
Non-Hodgkin’s
Lymphoma
Harold M. Chung, MD
Associate Professor of Medicine
VCU Medical Center – MCV Hospitals
Bone Marrow Transplantation Program
November 8, 2011
Why Men Can’t Be Babysitters
Agenda

Discuss Hodgkin’s Disease

Discuss Non-Hodgkin’s Lymphoma

Classification Systems

Treatment Options
2008 Estimated US Cancer Cases*
Men
720,280
Women
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
4%
Non-Hodgkin
lymphoma
4%
Melanoma of skin
Kidney
3%
3%
Thyroid
Oral cavity
3%
3%
Ovary
Leukemia
3%
2%
Urinary bladder
Pancreas
2%
2%
Pancreas
18%
22%
All Other Sites
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
291,270
Women
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%
bile duct
4%
Leukemia
3%
Non-Hodgkin
lymphoma
3%
Uterine corpus
2%
Multiple myeloma
Brain/ONS
Esophagus
4%
Non-Hodgkin
lymphoma
3%
Urinary bladder
3%
2%
Kidney
3%
23%
All other sites
23%
ONS=Other nervous system.
Source: American Cancer Society, 2008.
All other sites
WHO/REAL Classification of Lymphoid Neoplasms
B-Cell Neoplasms
Precursor B-cell neoplasm
Precursor B-lymphoblastic leukemia/lymphoma
(precursor B-acute lymphoblastic leukemia)
Mature (peripheral) B-neoplasms
B-cell chronic lymphocytic leukemia / small lymphocytic
lymphoma
B-cell prolymphocytic leukemia
Lymphoplasmacytic lymphoma‡
Splenic marginal zone B-cell lymphoma
(+ villous lymphocytes)*
Hairy cell leukemia
Plasma cell myeloma/plasmacytoma
Extranodal marginal zone B-cell lymphoma of MALT type
Nodal marginal zone B-cell lymphoma
(+ monocytoid B cells)*
Follicular lymphoma
Mantle cell lymphoma
Diffuse large B-cell lymphoma
Mediastinal large B-cell lymphoma
Primary effusion lymphoma†
Burkitt’s lymphoma/Burkitt cell leukemia§
T and NK-Cell Neoplasms
Precursor T-cell neoplasm
Precursor T-lymphoblastic leukemia/lymphoma
(precursor T-acute lymphoblastic leukemia
‡
Formerly known as lymphoplasmacytoid lymphoma or immunocytoma
Entities formally grouped under the heading large granular lymphocyte
leukemia of T- and NK-cell types
* Provisional entities in the REAL classification
II
Mature (peripheral) T neoplasms
T-cell chronic lymphocytic leukemia / small
lymphocytic lymphoma
T-cell prolymphocytic leukemia
T-cell granular lymphocytic leukemiaII
Aggressive NK leukemia
Adult T-cell lymphoma/leukemia (HTLV-1+)
Extranodal NK/T-cell lymphoma, nasal type#
Enteropathy-like T-cell lymphoma**
Hepatosplenic γδ T-cell lymphoma*
Subcutaneous panniculitis-like T-cell lymphoma*
Mycosis fungoides/Sézary syndrome
Anaplastic large cell lymphoma, T/null cell,
primary cutaneous type
Peripheral T-cell lymphoma, not otherwise characterized
Angioimmunoblastic T-cell lymphoma
Anaplastic large cell lymphoma, T/null cell,
primary systemic type
Hodgkin’s Lymphoma (Hodgkin’s Disease)
Nodular lymphocyte predominance Hodgkin’s lymphoma
Classic Hodgkin’s lymphoma
Nodular sclerosis Hodgkin’s lymphoma (grades 1 and 2)
Lymphocyte-rich classic Hodgkin’s lymphoma
Mixed cellularity Hodgkin’s lymphoma
Lymphocyte depletion Hodgkin’s lymphoma
†
Not described in REAL classification
Includes the so-called Burkitt-like lymphomas
** Formerly known as intestinal T-cell lymphoma
# Formerly know as angiocentric lymphoma
§
Hematopoietic System
B cell malignancies
Lymph node,
lymph, blood,
bone marrow
Bone marrow
Lymph node,
lymph, blood,
bone marrow
Bone marrow
Progressive B lymphocyte maturation
Lymphoid stem cell
Pre-B acute lymphoblastic leukemia
Maturing B cell
many stages
B cell lymphoma
Mature B cell
Chronic lymphocytic leukemia
Plasma cell
Multiple myeloma
Boys Need Parents
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
Lymphocyte depleted. – high grade
Nodular lymphocyte-rich Hodgkin’s
1798-1866
Hodgkin’s Disease/Lymphoma
In the Beginning
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Bimodal age distribution
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first peak between 2nd - 3rd decade of life
second peak between 5th - 6th decade of life
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Male: Female 2:1 in kids, adults almost equal M:F
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Mixed cellularity (MC) Hodgkin’s Disease is more
common at younger ages
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More common in immune deficiency patients
Hodgkin’s Disease/Lymphoma
In the Beginning

Accounts for ~ 30% of all malignant lymphomas

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
Hodgkin’s 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
Hodgkin’s Disease/Lymphoma
Interest tidbits
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Pel-Ebstein Fevers
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Pain with alcohol consumption
Hodgkin’s Disease/Lymphoma
Clinical Presentation

Nontender lymph nodes enlargement (localized)
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systemic symptoms (B symptoms)
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neck and supraclavicular area
mediastinal adenopathy
other (abdominal, extranodal disease)
fever
night sweats
unexplained weight loss (10% per 6 months)
other symptoms
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fatigue, weakness, pruritus
cough , chest pain, shortness of breath, vena cava
syndrome
abdominal pain, bowel disturbances, ascites
bone pain
Hodgkin’s 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
Hodgkin’s 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 > 38ºC for three consecutive days, drenching night sweats or unexplained loss 10% or more of
weight the preceding 6 months
Hodgkin’s Disease/Lymphoma
Treatment

Unfavorable prognostic factors:
- Stage IIIB, IV
- B symptoms
- Bulky disease
- High ESR >50
Hodgkin’s 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)
Hodgkin’s Disease/Lymphoma
Treatment

Adolescent patients who have achieved
maximum growth can be treated as adult
patients
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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
Hodgkin’s Disease/Lymphoma
Treatment
With appropriate treatment about 85% of
patients with Hodgkin’s disease are curable
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I A,B
II A
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IIB; IIIA,B; IVA,B
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Radiation Therapy
Combination Chemo +
Radiotherapy
Combination Chemo
(+/- radiotherapy)
Hodgkin’s Disease/Lymphoma
Treatment

Radiation therapy (35-40 Gy) 80-90% RC
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Mantle field
Paraaortic field
Pelvic field
Combination chemotherapy
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ABVD
BEACOPP
80% RC
90% RC
Hodgkin’s Disease/Lymphoma
Treatment Progress
ABVD vs
MOPP vs
MOPP/ABVD
Failure-free survival
Canellos et al,
NEJM, 2002
Overall survival
Hodgkin’s 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
Hodgkin’s Disease/Lymphoma – Advanced Stage
ABVD vs MEC vs Stanford V
Hodgkin’s Disease/Lymphoma
Actual Treatment Progress
PROBABILITY (%)
100 IIIIIIIIIIIIIIII
IIIIIIIIIII
IIIIIIIIIIII
IIIII IIIIIII
IIIII IIIIIIII
IIIIII IIIIIIIIIIII
IIIIIIIII
IIIII
IIIIIIIIIIIIIIIIIIIIII
IIIIIII
IIIIIIIIIIIIIIIIIIIIIIIIIIII
IIIII
IIIIIIIIIIIIIIIIIIIIIIIIIII
IIIIIII
IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIII IIIII III IIII
IIIIII
IIIIIII
IIIIIIIIII
IIIIIIII
IIIIIIII
IIIIIII
IIIIIIIIII
IIIIIII
IIIIIIII
IIIIIII
IIIIIII
IIIIIIII
IIIIIIIIIII
IIIIIIIII
IIIIII
IIII
IIIIIII
IIIIIIII
IIIIIIIIII
IIIIIIIIII
IIIIII
IIII
IIII
II
IIIIII
IIIIIII
IIIIII
IIIIIIIII
IIII
III II
III IIIII II
I II
III
I
I
80
60
40
IIII III
Expected Survival
HD Survival
20
I
IIII III
Observed Survival
0
0
5
10
15
20
25
30
35
YEARS
Stanford, Hoppe et al
Causes of Death among 2733 Patients
with Hodgkin’s 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%
930
100.0%
Total
Stanford, Hoppe et al
SECOND TUMORS LONG-TERM SURVIVORS OF
HODGKIN’S DISEASE/LYMPHOMA
(PRIMARY RT OR COMBINED MODALITY)
# pts
Actuarial Incidence
Median Follow-up

Princess Margaret
Hospital, Toronto
865
18% (20 years)
20 years

US Pediatric Series
(JCO 21:4386, 2003)
1380
26.3% (30 years)
17 years

Harvard/Joint Center
(Blood 100:1989, 2002)
1319
35% (25 years)
12 years

Netherlands
(JCO 18:481, 2000)
1253
27.7% (25 years)
14.1 years

NIH Survey of
Registries and Seer
(JCO 20:3474, 2002)
32,591
21.9% (25 years)
10 years
HODGKIN’S DISEASE/LYMPHOMA
SALVAGE REGIMENS
Regimen
DHAP
Patients
102
CR/PR to ASCT
87%
60%
(dexamethasone, ara-C, cisplatin)
Mini-BEAM
89
77%
82%
75%
75%
62%
88%
84%
86%
64%
--
(BCNU, etoposide, ara-C, melphalan; 2 series)
Dexa-BEAM
225
(above plus dexamethasone; 3 series)
GDP
34
(gemcitabine, dexamethasone, oxaloplatin)
ICE
65
(ifosfamide, carboplatin, etoposide)
GND
38
(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
HODGKIN’S 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
CR
89%
RFS (5 years) 88%
OS (5 years) 88%
80 (4 more cycles ABVD)
92%
94%
88%
[no difference]
PROBABILITY OF SURVIVAL AFTER
AUTOTRANSPLANTS FOR RELAPSED
HODGKIN’S DISEASE/LYMPHOMA, 1996-2001
100
CR1 (N =
226)
PROBABILITY, %
80
CR2+ (N =
733)
60
Never in remission (N = 823)
40
Relapse (N = 1,744)
20
P = 0.0001
0
0
1
2
3
YEARS
4
5
6
ALLOTRANSPLANTATION
HODGKIN’S DISEASE/LYMPHOMA
Patients
Median age
Event-free
Survival
Median F/U (mos.)
Overall Survival
Treatment Mortality
GVH Acute
Chronic
EBMTR
45
29
IBMTR
100
28
JOHNS HOPKINS
53
28
15%
31
25%
48%
15%
36
21%
61%
26%
60
30%
43%
63%
55%
35%
45%
45%
17%
HODGKIN’S DISEASE/LYMPHOMA
Non-Myeloablative Allotransplants
7 series (2004-2008)
Total Patients = 547 (1.5 – 5-year follow-up)
Relapse
PFS
OS
Treatment-Related Mortality
43-64%
18-32%
28-61%
5-24%
(The majority failed autotransplantation)
HODGKIN’S DISEASE/LYMPHOMA
Residual Masses By PET scan
5 series (2001-present)
Total Patients
204
Relapses
PET negative
after therapy
144
18 (12.5%)
PET positive
after therapy
60
35 (58.3%)
? 40% false positive rate
CTN 0701

Tandem Transplant
Modeled after myeloma data
 High-risk Hodgkin’s Disease
 University of Nebraska – Julie Vose, MD

Monoclonal Antibodies
MDX-060 - Anti-CD30 target
Anti-CD30 antibody
Medarex 2004 – Orphan Drug Status
Hodgkin’s 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-Hodgkin’s Lymphoma
Deep Breath…
Stand up…
Stretch…
Histologic Classification of
Non-Hodgkin’s Lymphomas
1. Rappaport
2. Lukes and Collins
3. Kiel
3. Dorfman
4. Bennet et al.,
5. Lennert
6. WHO
7. Working Formulation
8. REAL
9. WHO
-
1966
1974
1974
1974
1974
1974
1976
1982
1994
1999
Non-Hodgkin’s Lymphoma
Rappaport Classification
Nodular (follicular)
Diffuse
Indolent
Aggressive
Small cell
Large cell
Non-Hodgkin’s Lymphoma
Rappaport Classification



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Small cell, follicular
Small cell, diffuse
Large cell, follicular
Large cell, diffuse
Non-Hodgkin’s Lymphoma
Immunophenotyping

Immunohistochemistry
Immunofluorescence
Flow cytometry

Identification of CD’s (cluster determinants)


CD5 = T cell type
 CD20 = B cell type

Non-Hodgkin’s
Lymphoma
Cluster
Determinants
Non-Hodgkin’s Lymphoma
Lukes-Collins & Kiel Classifications

Lukes-Collins System – US
Kiel System – Europe

Differentiation of B-cell and T-cell lymphomas

Non-Hodgkin’s Lymphoma
Working Classification

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

Developed in 1980’s
NCI Investigators reviewed Rappaport, LukesCollins, 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-Hodgkin’s Lymphoma
Working Classification

Low Grade




Intermediate Grade





Small Lymphocytic
Follicular small-cleaved cell
Follicular mixed small-cleaved and large cell
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
Lymphoma
Classical HL
(NS, MC, LR,
LD)
Nodular
lymphocyte
Predominant
(NLPHL)
Multiple
Myeloma
Non Hodgkin Lymphoma
Indolent
Aggressive
Highly
Aggressive
B cell
Follicular
SLL/CLL
Marginal zone
LP (WM)
B cell
DLBCL
FLg3 and tFL
Mantle cell
Primary effusion
B cell
Pre-B
lymphoblastic
Burkitt
T/NK cell
Mycosis fungoides
Sezary syndrome
Primary cut ALCL
T/NK cell
ALCL
Angioimmunoblastic
Subq panniculitis-like
Blastic NK
Extnanodal NK/T
nasal
Enteropathy-type
Hepatosplenic
PTCL nos
T/NK cell
Pre-T
lymphoblastic
Non-Hodgkin’s Lymphoma
REAL Classification



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Revised European-American Lymphoma
Mid 1990’s – 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%)
Armitage et al. J Clin Oncol. 1998;16:2780–2795
Diffuse large
B-cell (31%)
Non-Hodgkin’s 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
Precursor B-cell neoplasm
Precursor B-lymphoblastic leukemia/lymphoma
(precursor B-acute lymphoblastic leukemia)
Mature (peripheral) B-neoplasms
B-cell chronic lymphocytic leukemia / small lymphocytic
lymphoma
B-cell prolymphocytic leukemia
Lymphoplasmacytic lymphoma‡
Splenic marginal zone B-cell lymphoma
(+ villous lymphocytes)*
Hairy cell leukemia
Plasma cell myeloma/plasmacytoma
Extranodal marginal zone B-cell lymphoma of MALT type
Nodal marginal zone B-cell lymphoma
(+ monocytoid B cells)*
Follicular lymphoma
Mantle cell lymphoma
Diffuse large B-cell lymphoma
Mediastinal large B-cell lymphoma
Primary effusion lymphoma†
Burkitt’s lymphoma/Burkitt cell leukemia§
T and NK-Cell Neoplasms
Precursor T-cell neoplasm
Precursor T-lymphoblastic leukemia/lymphoma
(precursor T-acute lymphoblastic leukemia
‡
Formerly known as lymphoplasmacytoid lymphoma or immunocytoma
Entities formally grouped under the heading large granular lymphocyte
leukemia of T- and NK-cell types
* Provisional entities in the REAL classification
II
Mature (peripheral) T neoplasms
T-cell chronic lymphocytic leukemia / small
lymphocytic lymphoma
T-cell prolymphocytic leukemia
T-cell granular lymphocytic leukemiaII
Aggressive NK leukemia
Adult T-cell lymphoma/leukemia (HTLV-1+)
Extranodal NK/T-cell lymphoma, nasal type#
Enteropathy-like T-cell lymphoma**
Hepatosplenic γδ T-cell lymphoma*
Subcutaneous panniculitis-like T-cell lymphoma*
Mycosis fungoides/Sézary syndrome
Anaplastic large cell lymphoma, T/null cell,
primary cutaneous type
Peripheral T-cell lymphoma, not otherwise characterized
Angioimmunoblastic T-cell lymphoma
Anaplastic large cell lymphoma, T/null cell,
primary systemic type
Hodgkin’s Lymphoma (Hodgkin’s Disease)
Nodular lymphocyte predominance Hodgkin’s lymphoma
Classic Hodgkin’s lymphoma
Nodular sclerosis Hodgkin’s lymphoma (grades 1 and 2)
Lymphocyte-rich classic Hodgkin’s lymphoma
Mixed cellularity Hodgkin’s lymphoma
Lymphocyte depletion Hodgkin’s lymphoma
†
Not described in 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
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
t(14;18) translocation
C
Transformation takes place
during B cell activation in GC.
bcl2
E
C
Unregulation of Bcl2 expression by IgH enhancers
C
3’E
Bcl2 inhibits apoptosis
Pro-survival oncogene
mitochondrion
Bax, Bad
Pro-caspase-9
cytochrome c
Bcl-2, Bcl-XL
Apaf-1
dATP or ATP
Caspase-9
Apaf-1
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
somatic hypermutation.
Apoptosis inhibited
Non-Hodgkin’s 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-Hodgkin’s 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-Hodgkin’s 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-Hodgkin’s 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-Hodgkin’s Lymphoma
Marginal Zone



Indolent
Accounts for ~10% of
all lymphomas
Subcategories




MALT (H. pylori)
Nodal
Extra-Nodal
Splenic
Non-Hodgkin’s Lymphoma
Splenic Lymphoma
Non-Hodgkin’s 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-Hodgkin’s 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-Hodgkin’s 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-Hodgkin’s Lymphoma
Intergroup 0067 Study
3-year survival
Mortality
___%________________%___
CHOP
mBACOD
ProMACE-CytoBOM
MACOP-B
41
46
46
41
1
5
3
6
Southwest Oncology Group
Non-Hodgkin’s Lymphoma
Treatment of Patients Age over 60
Program________________5-year survival %
CHOP
mBACOD
ProMACE-CytoBOM
MACOP-B
45
39
41
23
t
Non-Hodgkin’s 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
Burkitt’s Lymphoma
breakpoints
Chromosome 8
myc
C
***
V(D)J
IgH Chromosome 14, 80%
S
E
IgChromosome 2
Igchromosome 22
Class switch recombination
Somatic hypermutation
3’E
C
myc
C
S
t(8:14)
3’E
C
myc
E
S
C
Non-Hodgkin’s Lymphoma
Burkitt’s NHL




Very Aggressive
Curable with standard-dose therapy but
requires very extensive chemotherapy
protocol
Translocation t(8,14)
Specific Hematopathology Finding

Starry, Starry Night
Burkitt’s Lymhoma
Starry, Starry Night
Non-Hodgkin’s 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-Hodgkin’s Lymphoma
Aggressive chemotherapy regimens





Dose-dense CHOP
CHOP-Bleo
CEOP-Bleo
DexaBEAM
HyperCVAD
BMT for Non-Hodgkin’s Lymphoma
Indications
1. Refractory disease
2. Relapse
3. High risk in CR
4. Lymphoblastic, Burkitt’s, and gamma
delta-t-cell lymphomas
PROBABILITY OF SURVIVAL AFTER
AUTOTRANSPLANTS FOR FOLLICULAR
NON-HODGKIN LYMPHOMA
100
CR1 (N =
174)
PROBABILITY, %
80
CR2+ (N =
322)
60
Never in remission (N = 418)
Relapse (N = 791)
40
20
P = 0.0009
0
0
1
2
3
YEARS
4
5
6
PROBABILITY OF SURVIVAL AFTER HLAIDENTICAL SIBLING MYELOABLATIVE
TRANSPLANTS FOR
FOLLICULAR NON-HODGKIN LYMPHOMA
100
Never in remission (N =
138)
PROBABILITY, %
80
CR1-3 (N =
79)
60
Relapse (N = 193)
40
20
P = NS
0
0
1
2
3
YEARS
4
5
6
PROBABILITY OF SURVIVAL AFTER
AUTOTRANSPLANTS FOR
DIFFUSE LARGE CELL LYMPHOMA
100
PROBABILITY, %
80
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
YEARS
4
5
6
PROBABILITY OF SURVIVAL AFTER HLAIDENTICAL SIBLING MYELOABLATIVE
TRANSPLANTS FOR
DIFFUSE LARGE CELL LYMPHOMA
100
PROBABILITY, %
80
60
40
Relapse (N = 144)
CR1-3 (N =
56)
Never in remission (N = 133)
20
P = NS
0
0
1
2
3
YEARS
4
5
6
Monoclonal Abs - Rituxan
Radioimmunotherapy with Y-90
Zevalin
Monoclonal
antibody
 Ibritumomab

Murine monoclonal
antibody parent of
Rituximab
 Tiuxetan


Conjugated to
antibody, forming strong
urea-type bond
Stable retention of Y-90
Chelator
Y-90 radionuclide
Beta
radiation
New Treatment Options


Velcade + Flavoperidol – MCC Trial
Velcade + Darinaparsin
Conclusion

Discussed Hodgkin’s Disease

Discussed Non-Hodgkin’s Lymphoma

Discussed Classification Systems

Discussed Treatment Options