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Agenda
Discuss Hodgkins Disease
Discuss Non-Hodgkins Lymphoma
Classification Systems
Treatment Options
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2008 Estimated US Cancer Deaths*
ONS=Other nervous system.
Source: American Cancer Society, 2008.
Men
291,270
Women
273,56026% Lung & bronchus
15% Breast
10% Colon & rectum
6% Pancreas
6% Ovary
4% Leukemia
3% Non-Hodgkinlymphoma
3% Uterine corpus2% Multiple myeloma
2% Brain/ONS
23% All other sites
Lung & bronchus 31%
Colon & rectum 10%
Prostate 9%
Pancreas 6%
Leukemia 4%
Liver & intrahepatic 4%bile duct
Esophagus 4%
Non-Hodgkin 3%lymphoma
Urinary bladder 3%
Kidney 3%
All other sites 23%
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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 lymphocyticlymphoma
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 typeNodal 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
Burkitts lymphoma/Burkitt cell leukemia
T and NK-Cell Neoplasms
Precursor T-cell neoplasmPrecursor T-lymphoblastic leukemia/lymphoma
(precursor T-acute lymphoblastic leukemia
Formerly known as lymphoplasmacytoid lymphoma or immunocytomaII Entities formally grouped under the heading large granular lymphocyte
leukemia of T- and NK-cell types* Provisional entities in the REAL classification
Mature (peripheral) T neoplasms
T-cell chronic lymphocytic leukemia / smalllymphocytic lymphoma
T-cell prolymphocytic leukemiaT-cell granular lymphocytic leukemiaII
Aggressive NK leukemiaAdult T-cell lymphoma/leukemia (HTLV-1+)
Extranodal NK/T-cell lymphoma, nasal type#
Enteropathy-like T-cell lymphoma**
Hepatosplenic T-cell lymphoma*
Subcutaneous panniculitis-like T-cell lymphoma*
Mycosis fungoides/Szary 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
Hodgkins Lymphoma (Hodgkins Disease)
Nodular lymphocyte predominance Hodgkins lymphoma
Classic Hodgkins lymphoma
Nodular sclerosis Hodgkins lymphoma (grades 1 and 2)Lymphocyte-rich classic Hodgkins lymphoma
Mixed cellularity Hodgkins lymphoma
Lymphocyte depletion Hodgkins 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
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Hematopoietic System
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B cell malignancies
Pre-B acute lympho-
blastic leukemia
B cell lymphoma Chronic lympho-
cytic leukemia
Multiple myeloma
Progressive B lymphocyte maturation
Bone marrow
Lymph node,
lymph, blood,
bone marrow
Lymph node,
lymph, blood,
bone marrowBone marrow
Lymphoid stem cell Maturing B cell
many stages
Mature B cell Plasma cell
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Boys Need Parents
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Hodgkins Disease/Lymphoma
In the Beginning
1798-1866
First described in 1832 by Dr. Thomas Hodgkin
Neoplasm of B lymphocyteslarge pleomorphic prominentnucleolus in a halo - Hodgkin cells
Reed-Sternberg cellbinucleate Hodgkin cell with owl eyeappearance
Classification:Classical Hodgkins
Nodular sclerosislow gradeMixed cellularityLymphocyte rich classicalLymphocyte depleted.high grade
Nodular lymphocyte-rich Hodgkins
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Hodgkins Disease/Lymphoma
In the Beginning
Bimodal age distribution first peak between 2nd- 3rddecade of life
second peak between 5th - 6thdecade of life
Male: Female 2:1 in kids, adults almost equal M:F
Mixed cellularity (MC) Hodgkins Disease is morecommon at younger ages
More common in immune deficiency patients
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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 neoplasticcells constitute only a small minority of the cells inthe affected tissue, often corresponding to < 2% ofthe total tumor
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Fatal disease with 90% of untreated patients dyingwithin 2 to 3 years
With chemotherapy, >80% of patients suffering fromHD are cured.
Pathogenesis of HD is still largely unknown.
HD nearly always arises and disseminates in lymphnodes
Hodgkins Disease/LymphomaIn the Beginning
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Hodgkins Disease/Lymphoma
Interest tidbits
Pel-Ebstein Fevers
Pain with alcohol consumption
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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 cavasyndrome
abdominal pain, bowel disturbances, ascites
bone pain
Hodgkins Disease/Lymphoma
Clinical Presentation
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SIGNS & SYMPTOMS % OF PATIENTS
Lymphadenopathy 90
Mediastinal mass 60
B symptoms 30Fever, weight loss, night sweats
Hepatosplenomegaly 25
Most commonly involved lymph nodes are thecervical and supraclavicular in 75%
Bone marrow is involved in 5% of patients
Hodgkins Disease/Lymphoma
Clinical Presentation
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CD 30 Immunostain
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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 noderegions on the same side of the diaphragm (IIE)
III Involvement of lymph node regions on both sides of the diaphragm (III) which may beaccompanied by involvement of the spleen (IIIS) or by localized involvement of anextralymphatic organ or site (IIIE) or both (IIISE)
IV Diffuse or disseminated involvement of one or more extra lymphatic organs or tissues withor without associated lymph node involvement
B symptoms: fever > 38C for three consecutive days, drenching night sweats or unexplained loss 10% or more ofweight the preceding 6 months
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Hodgkins Disease/Lymphoma
Treatment
Unfavorable prognostic factors:
- Stage IIIB, IV
- B symptoms
- Bulky disease
- High ESR >50
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Long term effects of treatment should betaken 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)
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Treatment
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Adolescent patients who have achievedmaximum growth can be treated as adultpatients
Chemotherapy alone protocols forlocalized disease has been used indeveloping countries with some success
Hodgkins Disease/Lymphoma
Treatment
Lobo-Sanahuja F: Medical and Pediatric Oncology 22(6);1994
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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
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Hodgkins Disease/Lymphoma
Treatment Progress
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Almost no MDS/AML (at 15 years 1.0%)
(Valagussa 86)
Oligospermia50% 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.
Hodgkins Disease/Lymphoma
Treatment
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Canellos, G. P. et al. J Clin Oncol; 22:1532-1533 2004
Cancer and Leukemia Group B 8251 and 8952:
Recurrent Hodgkin's Disease by Treatment
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Hodgkins Disease/Lymphoma Advanced Stage
ABVD vs MEC vs Stanford V
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Stanford, Hoppe et al
IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
IIIIIIIIIIIIIIIIIIIIIIIIIII
IIIIIIIIIIIIIIIIII III
IIII IIIIIII II
II II
III
I III I I II
IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIIIII IIIIIII III IIII III I I II
0
20
40
60
80
100
0 5 10 15 20 25 30 35
PROBABILITY
(%)
YEARS
I Observed Survival
I HD Survival
Expected Survival
Hodgkins Disease/Lymphoma
Actual Treatment Progress
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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
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SECOND TUMORS LONG-TERM SURVIVORS OF
HODGKINS DISEASE/LYMPHOMA
(PRIMARY RT OR COMBINED MODALITY)
# pts Actu ar ial Incidence Median Fol low-up
Princess Margaret 865 18% (20 years) 20 yearsHospital, 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 yearsRegistries and Seer
(JCO 20:3474, 2002)
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HODGKINS DISEASE/LYMPHOMA
SALVAGE REGIMENS
Regimen Patients CR/PR to ASCTDHAP 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)
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CALGB 50203 Treatment Plan
AVG:
Doxorubicin 25mg/m2IV d1, D15
Vinblastine 6mg/m2IV d1, d15
Gemcitabine 1,000mg/m2
IV d1, d15 800mg/m2if gr. 4 ANC/plt ct in 2.6 pts
Repeat every 28 days x 6 cycles
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HODGKINS DISEASE/LYMPHOMAAutologous 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]
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PROBABILITY OF SURVIVAL AFTER
AUTOTRANSPLANTS FOR RELAPSED
HODGKINS DISEASE/LYMPHOMA, 1996-2001
P
ROBABILITY,%
100
0
20
40
60
80
YEARS
P = 0.0001
0 1 2 3 4 65
CR1 (N =
226)
CR2+ (N =
733)
Never in r emis sio n (N = 823)
Relap se (N = 1,744)
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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
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HODGKINS DISEASE/LYMPHOMANon-Myeloablative Allotransplants
7 series (2004-2008)
Total Patients = 547 (1.55-year follow-up)
Relapse 43-64%
PFS 18-32%
OS 28-61%
Treatment-Related Mortality 5-24%
(The majority failed autotransplantation)
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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
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CTN 0701
Tandem Transplant
Modeled after myeloma data
High-risk Hodgkins Disease
University of NebraskaJulie Vose, MD
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Monoclonal Antibodies
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MDX-060- Anti-CD30 target
Anti-CD30 antibody
Medarex 2004Orphan Drug Status
Hodgkins Disease/Lymphoma
Anaplastic Large Cell NHL
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SGN-35 (Seattle Genetics)
A Younes et al, N Engl J Med 2010;363:1812-21.
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Good Ideas
Cadence Pharmaceuticals
Ofirmev
November 2, 2010FDA Approval
IV acetaminophen
$800/IV dose
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Boys Need Parents
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Non-Hodgkins Lymphoma
Deep Breath
Stand up
Stretch
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Histologic Classification of
Non-Hodgkins Lymphomas
1. Rappaport - 1966
2. Lukes and Collins - 1974
3. Kiel - 1974
3. Dorfman - 19744. Bennet et al., - 1974
5. Lennert - 1974
6. WHO - 19767. Working Formulation - 1982
8. REAL - 1994
9. WHO - 1999
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Non-Hodgkins Lymphoma
Rappaport Classification
Nodular (follicular) Diffuse
Small cell Large cell
Indolent Aggressive
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Non-Hodgkins Lymphoma
Immunophenotyping
Immunohistochemistry
Immunofluorescence
Flow cytometry
Identification of CDs (cluster determinants)
CD5 = T cell type CD20 = B cell type
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Non-Hodgkins
LymphomaCluster
Determinants
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Non-Hodgkins Lymphoma
Lukes-Collins & Kiel Classifications
Lukes-Collins SystemUS
Kiel SystemEurope
Differentiation of B-cell and T-cell lymphomas
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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)
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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)
H d ki
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Hodgkin
LymphomaNon Hodgkin Lymphoma
Highly
Aggressive
AggressiveIndolent
B cell
Follicular
SLL/CLL
Marginal zone
LP (WM)
T/NK cell
Mycosis fungoides
Sezary syndrome
Primary cut ALCL
B cell
Pre-B
lymphoblastic
Burkitt
T/NK cell
Pre-T
lymphoblastic
B cell
DLBCL
FLg3 and tFL
Mantle cell
Primary effusion
T/NK cell
ALCL
Angioimmunoblastic
Subq panniculitis-like
Blastic NKExtnanodal NK/T
nasal
Enteropathy-type
Hepatosplenic
PTCL nos
Classical HL
(NS, MC, LR,LD)
Nodular
lymphocyte
Predominant
(NLPHL)
Multiple
Myeloma
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F f NHL S bt i Ad lt
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Indolent (35%)
Diffuse large
B-cell (31%)Armitage et al. J Clin Oncol. 1998;16:27802795
Mantle cell (6%)
Peripheral T-cell (6%)
Other subtypes with a
frequency 2% (9%)
Frequency of NHL Subtypes in Adults
Composite
lymphomas (13%)
Non Hodgkins Lymphoma
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Non-Hodgkins Lymphoma
WHO Classification
Bruce Cheson, MD and the NCI InternationalWorking 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
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Non Hodgkins Lymphoma
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Non-Hodgkins Lymphoma
Specific Types
Time For A Deep Breath
or an Excedrin
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Over-expression of Bcl-2 may prevent the apoptosis
of germinal center B cells
activation
Germinal center Germinal center
apoptosis
IgH-Bcl2
activation
Germinal center Germinal center
Plasma cells
Memory cells
follicular lymphoma
Apoptosis inhibitedMost follicular lymphoma Ig V regions containsomatic hypermutation.
Non Hodgkins Lymphoma
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Non-Hodgkin s Lymphoma
Follicular Lymphoma
Low-grade lymphoma
Grade 1Small cell
Grade 2Mixed cell
Grade 3Large cell
Indolent in growth
Chemotherapy sensitive
Incurable
Non Hodgkins Lymphoma
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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
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Non-Hodgkin s Lymphoma
Diffuse Large Cell
Very Aggressive
Curable if chemo-sensitive upfront, not soif chemo-refractory or relapses within 6
months
Most common of all lymphomas
Accounts for ~ 31% of all lymphomas
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Mantle Cell Lymphoma
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M tl C ll T t t
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Mantle Cell - Treatment
CHOP + Rituxan 40 patients (new diagnosis)
CR 48%, PR 48%
Molecular CR seen in 36% ofpatients with PCR detectablecyclin D1/IgH translocation
Median PFS 16.6 months, allpatients relapsed by 36months
No significant difference in PFSfor patients having a clinical ormolecular CR
Howard, O et al., JCO, 20 (5):1288
Non-Hodgkins Lymphoma
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Non-Hodgkin s Lymphoma
Marginal Zone
Indolent Accounts for ~10% of
all lymphomas
Subcategories MALT (H. pylori)
Nodal
Extra-Nodal
Splenic
Non-Hodgkins Lymphoma
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Non-Hodgkin s Lymphoma
Splenic Lymphoma
Non-Hodgkins Lymphoma
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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-Hodgkins Lymphoma
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Non-Hodgkin s Lymphoma
Anaplastic Large Cell Lymphoma
Aggressive
Accounts for ~ 2% of all lymphomas
ALCL ALK-1+ better prognosis, morecommon in younger patients and children
ALCL ALK-1-negative : as bad as any otherT-cell lymphoma
Treatment results of aggressive advanced
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Treatment results of aggressive advancednon-Hodgkins lymphomas using different
chemotherapy programs1. 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%
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Non-Hodgkins Lymphoma
Intergroup 0067 Study
3-year survival Mortality
___%________________%___
CHOP 41 1
mBACOD 46 5
ProMACE-CytoBOM 46 3MACOP-B 41 6
Southwest Oncology Group
Non Hodgkins Lymphoma
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Non-Hodgkins Lymphoma
Treatment of Patients Age over 60
Program________________5-year survival %
CHOP 45mBACOD 39
ProMACE-CytoBOM 41
MACOP-B 23
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t
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Non-Hodgkins Lymphoma
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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 andtransplant
Burkitts Lymphoma
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Burkitt s Lymphoma
myc Chromosome 8
SC
EChromosome 14, 80%IgH
Ig Chromosome 2
Ig chromosome 22
breakpoints
Class switch recombination
V(D)J
Somatic hypermutation
***
mycS
C C3E
myc C C3E
SE
t(8:14)
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Non-Hodgkins Lymphoma
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Non Hodgkin s Lymphoma
Lymphoblastic NHL
Very aggressive
Treatment is with acute lymphocyticleukemia regimen
Often requires high-dose therapy and
allogeneic transplantation forrelapsed/refractory disease
G D lt T ll NHL
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Gamma Delta-T-cell NHL
Very, very aggressive
Very poor outcome with standard-dosetherapy
High-dose therapy and allogeneictransplantation is standard-of-care in firstremission
CD57 protein positivity
D bl Hit L h
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Double-HitLymphomas
Multiple gene expressions MYC gene
t(14,18)
Triple-Hit
MYC gene
t(14,18)
BCL-6 gene
Non-Hodgkins Lymphoma
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g y p
Aggressive chemotherapy regimens
Dose-dense CHOP
CHOP-Bleo
CEOP-Bleo
DexaBEAM
HyperCVAD
BMT f N H d ki L h
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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
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PROBABILITY OF SURVIVAL AFTER
AUTOTRANSPLANTS FOR FOLLICULAR
NON-HODGKIN LYMPHOMA
PROBABILITY,%
100
0
20
40
60
80
YEARS
P = 0.0009
0 1 2 3 4 65
CR1 (N =
174)CR2+ (N =
322)
Never in rem iss ion (N = 418)
Relaps e (N = 791)
PROBABILITY OF SURVIVAL AFTER HLA-
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IDENTICAL SIBLING MYELOABLATIVE
TRANSPLANTS FOR
FOLLICULAR NON-HODGKIN LYMPHOMA
PROBABILITY,%
100
0
20
40
60
80
YEARS
P = NS
0 1 2 3 4 65
CR1-3 (N =
79)
Never in remissio n (N =
138)
Relaps e (N = 193)
PROBABILITY OF SURVIVAL AFTER
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PROBABILITY OF SURVIVAL AFTER
AUTOTRANSPLANTS FOR
DIFFUSE LARGE CELL LYMPHOMA
PROBABILITY,%
100
0
20
40
60
80
YEARS
P = 0.0001
0 1 2 3 4 65
CR1 (N =
438)
CR2+ (N =
651)
Relaps e (N = 1,443)
Never in rem iss ion (N = 986)
PROBABILITY OF SURVIVAL AFTER HLA-
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IDENTICAL SIBLING MYELOABLATIVE
TRANSPLANTS FOR
DIFFUSE LARGE CELL LYMPHOMA
PROBABILITY,%
100
0
20
40
60
80
YEARS
P = NS
0 1 2 3 4 65
CR1-3 (N =
56)
Relaps e (N = 144)
Never in rem iss ion (N = 133)
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Radioimmunotherapy with Y-90
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py
Zevalin
Ibritumomab Murine monoclonal
antibody parent of
Rituximab
Tiuxetan Conjugated to
antibody, forming strong
urea-type bond
Stable retention of Y-90
Y-90 radionuclideBetaradiation
Chelator
Monoclonalantibody
New Treatment Options
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New Treatment Options
Velcade + FlavoperidolMCC Trial
Velcade + Darinaparsin
Conclusion
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Conclusion
Discussed Hodgkins Disease
Discussed Non-Hodgkins Lymphoma
Discussed Classification Systems
Discussed Treatment Options
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