Hodgkin’s Diseaseand
Non-Hodgkin’s Lymphoma
Harold M. Chung, MDAssociate Professor of Medicine
VCU Medical Center – MCV HospitalsBone Marrow Transplantation Program
November 8, 2011
Why Men Can’t Be Why Men Can’t Be BabysittersBabysitters
Agenda
Discuss Hodgkin’s Disease
Discuss Non-Hodgkin’s Lymphoma
Classification Systems
Treatment Options
2008 Estimated US Cancer Cases*
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society, 2008.
Men720,280
Women679,510
31% Breast
12% Lung & bronchus
11% Colon & rectum
6% Uterine corpus
4% Non-Hodgkin lymphoma
4% Melanoma of skin
3% Thyroid
3% Ovary
2% Urinary bladder
2% Pancreas
22% All Other Sites
Prostate 33%
Lung & bronchus 13%
Colon & rectum 10%
Urinary bladder 6%
Melanoma of skin 5%
Non-Hodgkin4% lymphoma
Kidney 3%
Oral cavity 3%
Leukemia 3%
Pancreas 2%
All Other Sites 18%
2008 Estimated US Cancer Deaths*
ONS=Other nervous system.Source: American Cancer Society, 2008.
Men291,270
Women273,560
26% Lung & bronchus
15% Breast
10% Colon & rectum
6% Pancreas
6% Ovary
4% Leukemia
3% Non-Hodgkin lymphoma
3% Uterine corpus
2% 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%
WHO/REAL Classification of Lymphoid NeoplasmsB-Cell Neoplasms
Precursor B-cell neoplasmPrecursor B-lymphoblastic leukemia/lymphoma
(precursor B-acute lymphoblastic leukemia)Mature (peripheral) B-neoplasmsB-cell chronic lymphocytic leukemia / small
lymphocytic lymphoma
B-cell prolymphocytic leukemiaLymphoplasmacytic lymphoma‡
Splenic marginal zone B-cell lymphoma (+ villous lymphocytes)*
Hairy cell leukemiaPlasma cell myeloma/plasmacytomaExtranodal marginal zone B-cell lymphoma of MALT
typeNodal marginal zone B-cell lymphoma
(+ monocytoid B cells)*Follicular lymphomaMantle cell lymphomaDiffuse large B-cell lymphoma
Mediastinal large B-cell lymphomaPrimary effusion lymphoma†
Burkitt’s lymphoma/Burkitt cell leukemia§
T and NK-Cell NeoplasmsPrecursor T-cell neoplasm
Precursor T-lymphoblastic leukemia/lymphoma(precursor T-acute lymphoblastic leukemia
‡ Formerly known as lymphoplasmacytoid lymphoma or immunocytoma II 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 neoplasmsT-cell chronic lymphocytic leukemia / small
lymphocytic lymphomaT-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 γδ T-cell lymphoma*Subcutaneous panniculitis-like T-cell lymphoma*Mycosis fungoides/Sézary syndromeAnaplastic large cell lymphoma, T/null cell,
primary cutaneous typePeripheral T-cell lymphoma, not otherwise
characterized Angioimmunoblastic T-cell lymphomaAnaplastic large cell lymphoma, T/null cell,
primary systemic typeHodgkin’s Lymphoma (Hodgkin’s Disease)
Nodular lymphocyte predominance Hodgkin’s lymphomaClassic Hodgkin’s lymphoma
Nodular sclerosis Hodgkin’s lymphoma (grades 1 and 2)Lymphocyte-rich classic Hodgkin’s lymphomaMixed cellularity Hodgkin’s lymphomaLymphocyte 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
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 cellmany stages
Mature B cell Plasma cell
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Hodgkin’s Disease/LymphomaIn the Beginning
1798-1866
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 gradeMixed cellularityLymphocyte rich classical Lymphocyte depleted. – high
grade
Nodular lymphocyte-rich Hodgkin’s
Hodgkin’s Disease/LymphomaIn the Beginning
Bimodal age distributionBimodal age distribution first peak between 2first peak between 2ndnd - 3 - 3rdrd decade of life decade of life second peak between 5second peak between 5th th - 6- 6thth decade of life decade of life
Male: Female 2:1 in kids, adults almost equal M:FMale: Female 2:1 in kids, adults almost equal M:F
Mixed cellularity (MC) Hodgkin’s Disease is more Mixed cellularity (MC) Hodgkin’s Disease is more common at younger agescommon at younger ages
More common in immune deficiency patientsMore common in immune deficiency patients
Hodgkin’s Disease/LymphomaIn the Beginning
Accounts for ~ 30% of all malignant lymphomasAccounts for ~ 30% of all malignant lymphomas
Composed of two different disease entities:Composed of two different disease entities:
Lymphocyte-predominant Hodgkin’s (LPHD), making upLymphocyte-predominant Hodgkin’s (LPHD), making up~ 5% of cases~ 5% of cases
Classical HD, representing ~ 95% of all HDs.Classical HD, representing ~ 95% of all HDs.
A common factor of both HD types is that neoplastic A common factor of both HD types is that neoplastic cells constitute only a small minority of the cells in cells constitute only a small minority of the cells in the affected tissue, often corresponding to < 2% of the affected tissue, often corresponding to < 2% of the total tumorthe total tumor
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/LymphomaIn the Beginning
Hodgkin’s Disease/LymphomaInterest tidbits
Pel-Ebstein Fevers
Pain with alcohol consumption
Nontender lymph nodes enlargement (localized)Nontender lymph nodes enlargement (localized) neck and supraclavicular areaneck and supraclavicular area mediastinal adenopathymediastinal adenopathy other (abdominal, extranodal disease)other (abdominal, extranodal disease)
systemic symptoms (B symptoms)systemic symptoms (B symptoms) fever fever night sweatsnight sweats unexplained weight loss (10% per 6 months)unexplained weight loss (10% per 6 months)
other symptoms other symptoms fatigue, weakness, pruritusfatigue, weakness, pruritus cough , chest pain, shortness of breath, vena cava cough , chest pain, shortness of breath, vena cava
syndromesyndrome abdominal pain, bowel disturbances, ascitesabdominal pain, bowel disturbances, ascites bone painbone pain
Hodgkin’s Disease/LymphomaClinical 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
Hodgkin’s Disease/LymphomaClinical Presentation
Reed-Sternberg Cells
CD 30 Immunostain
Hodgkin’s Disease/LymphomaClinical 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/LymphomaTreatment
Unfavorable prognostic factors: Unfavorable prognostic factors: - Stage IIIB, IV- Stage IIIB, IV - B symptoms- B symptoms - Bulky disease- Bulky disease - High ESR >50- High ESR >50
Long term effects of treatment should be Long term effects of treatment should be taken into consideration:taken into consideration:
- Treatment-related second neoplasms - Treatment-related second neoplasms
(i.e. AML, NHL and breast cancer)(i.e. AML, NHL and breast cancer)
- Infertility- Infertility
- Growth consideration- Growth consideration
- Long-term organ dysfunction (i.e., - Long-term organ dysfunction (i.e., thyroid, heart, lung)thyroid, heart, lung)
Hodgkin’s Disease/LymphomaTreatment
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
Hodgkin’s Disease/LymphomaTreatment
Lobo-Sanahuja F: Medical and Pediatric Oncology 22(6);1994
With appropriate treatment about 85% of With appropriate treatment about 85% of patients with Hodgkin’s disease are curablepatients with Hodgkin’s disease are curable
I A,B I A,B Radiation TherapyRadiation Therapy II A II A Combination Chemo + Combination Chemo +
RadiotherapyRadiotherapy IIB; IIIA,B; IVA,B IIB; IIIA,B; IVA,B Combination Chemo Combination Chemo
(+/- radiotherapy)(+/- radiotherapy)
Hodgkin’s Disease/LymphomaTreatment
Radiation therapy (35-40 Gy) 80-90% RC Mantle field Paraaortic field Pelvic field
Combination chemotherapy ABVD 80% RC BEACOPP 90% RC
Hodgkin’s Disease/LymphomaTreatment
Hodgkin’s Disease/LymphomaTreatment Progress
ABVD vs MOPP vs
MOPP/ABVDFailure-free survival
Overall survival
Canellos et al, NEJM, 2002
Almost no MDS/AML (at 15 years 1.0%) Almost no MDS/AML (at 15 years 1.0%) (Valagussa ’86)(Valagussa ’86)
Oligospermia – 50% complete recoveryOligospermia – 50% complete recovery
Median FSH in normal range Median FSH in normal range (Viviani ’85)(Viviani ’85)
Bleomycin-related pulmonary toxicity ~1/3 Bleomycin-related pulmonary toxicity ~1/3 have reduced PFT but recover in 3 months; have reduced PFT but recover in 3 months; ~20% omit Bleomycin.~20% omit Bleomycin.
Hodgkin’s Disease/LymphomaTreatment
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
Hodgkin’s Disease/Lymphoma – Advanced StageABVD vs MEC vs Stanford V
Stanford, Hoppe et al
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IIII 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
PR
OB
AB
ILIT
Y
(%)
YEARS
I Observed Survival
I HD Survival
Expected Survival
Hodgkin’s Disease/LymphomaActual Treatment Progress
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%
Total 930 100.0%
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 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)
HODGKIN’S DISEASE/LYMPHOMASALVAGE 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)
CALGB 50203 Treatment Plan
AVGAVG::
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/LYMPHOMAAutologous Transplants as Primary Therapy
1996 - 2002: 7 uncontrolled trialsEvent-free survival 242/337 patients 72%Median follow-up 42-46 months (30-86 months)
2003: Prospective Randomized Trial (JCO 21:2320, 2003)
16383 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
HODGKIN’S DISEASE/LYMPHOMA, 1996-2001
PR
OB
AB
ILIT
Y,
%
100
0
20
40
60
80
YEARS
P = 0.0001
0 1 2 3 4 65
CR1 (N = 226)
CR2+ (N = 733)
Never in remission (N = 823)
Relapse (N = 1,744)
ALLOTRANSPLANTATIONHODGKIN’S 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%
HODGKIN’S DISEASE/LYMPHOMANon-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)
HODGKIN’S DISEASE/LYMPHOMAResidual 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 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 SGN-35 (Seattle Genetics)Genetics)
A Younes et al, N Engl J Med 2010;363:1812-21.A Younes et al, N Engl J Med 2010;363:1812-21.
Good IdeasGood Ideas
Cadence PharmaceuticalsCadence Pharmaceuticals OfirmevOfirmev November 2, 2010 – FDA ApprovalNovember 2, 2010 – FDA Approval IV acetaminophenIV acetaminophen $800/IV dose $800/IV dose
Boys Need ParentsBoys Need Parents
Non-Hodgkin’s Lymphoma
Deep Breath…
Stand up…
Stretch…
Histologic Classification of Non-Hodgkin’s Lymphomas
1. Rappaport - 19662. Lukes and Collins - 19743. Kiel - 19743. Dorfman - 19744. Bennet et al., - 19745. Lennert - 19746. WHO - 19767. Working Formulation - 19828. REAL - 19949. WHO - 1999
Non-Hodgkin’s LymphomaRappaport Classification
Nodular (follicular) Diffuse
Small cell Large cell
Indolent Aggressive
Non-Hodgkin’s LymphomaRappaport Classification
Small cell, follicular Small cell, diffuse Large cell, follicular Large cell, diffuse
Non-Hodgkin’s LymphomaImmunophenotyping
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 LymphomaLukes-Collins & Kiel Classifications
Lukes-Collins System – US Kiel System – Europe
Differentiation of B-cell and T-cell lymphomas
Non-Hodgkin’s LymphomaWorking Classification
Developed in 1980’s 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-Hodgkin’s LymphomaWorking 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)
HodgkinLymphoma
Non Hodgkin Lymphoma
HighlyAggressive
AggressiveIndolent
B cellFollicularSLL/CLL
Marginal zoneLP (WM)
T/NK cellMycosis fungoidesSezary syndromePrimary cut ALCL
B cellPre-B
lymphoblasticBurkitt
T/NK cellPre-T
lymphoblastic
B cellDLBCL
FLg3 and tFLMantle cell
Primary effusion
T/NK cellALCL
AngioimmunoblasticSubq panniculitis-like
Blastic NKExtnanodal NK/T
nasalEnteropathy-type
HepatosplenicPTCL nos
Classical HL(NS, MC, LR,
LD)
Nodular lymphocyte
Predominant(NLPHL)
MultipleMyeloma
Non-Hodgkin’s LymphomaREAL Classification
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
Indolent (35%)
Diffuse largeB-cell (31%)
Armitage et al. J Clin Oncol. 1998;16:2780–2795
Mantle cell (6%)
Peripheral T-cell (6%)
Other subtypes with a frequency 2% (9%)
Frequency of NHL Subtypes in Adults
Composite lymphomas (13%)
Non-Hodgkin’s LymphomaWHO 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 NeoplasmsB-Cell Neoplasms
Precursor B-cell neoplasmPrecursor B-lymphoblastic leukemia/lymphoma
(precursor B-acute lymphoblastic leukemia)Mature (peripheral) B-neoplasmsB-cell chronic lymphocytic leukemia / small
lymphocytic lymphoma
B-cell prolymphocytic leukemiaLymphoplasmacytic lymphoma‡
Splenic marginal zone B-cell lymphoma (+ villous lymphocytes)*
Hairy cell leukemiaPlasma cell myeloma/plasmacytomaExtranodal marginal zone B-cell lymphoma of MALT
typeNodal marginal zone B-cell lymphoma
(+ monocytoid B cells)*Follicular lymphomaMantle cell lymphomaDiffuse large B-cell lymphoma
Mediastinal large B-cell lymphomaPrimary effusion lymphoma†
Burkitt’s lymphoma/Burkitt cell leukemia§
T and NK-Cell NeoplasmsPrecursor T-cell neoplasm
Precursor T-lymphoblastic leukemia/lymphoma(precursor T-acute lymphoblastic leukemia
‡ Formerly known as lymphoplasmacytoid lymphoma or immunocytoma II 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 neoplasmsT-cell chronic lymphocytic leukemia / small
lymphocytic lymphomaT-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 γδ T-cell lymphoma*Subcutaneous panniculitis-like T-cell lymphoma*Mycosis fungoides/Sézary syndromeAnaplastic large cell lymphoma, T/null cell,
primary cutaneous typePeripheral T-cell lymphoma, not otherwise
characterized Angioimmunoblastic T-cell lymphomaAnaplastic large cell lymphoma, T/null cell,
primary systemic typeHodgkin’s Lymphoma (Hodgkin’s Disease)
Nodular lymphocyte predominance Hodgkin’s lymphomaClassic Hodgkin’s lymphoma
Nodular sclerosis Hodgkin’s lymphoma (grades 1 and 2)Lymphocyte-rich classic Hodgkin’s lymphomaMixed cellularity Hodgkin’s lymphomaLymphocyte 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 LymphomaSpecific Types
Time For A Deep Breath…
or an Excedrin
Follicular Lymphoma
Bcl2 Chromosome 18
Mbr (major breakpoint region, 150 bp)
JH
C
Double strand DNA break by RAG1/2
Chromosome 14
Bcl2 C t(14;18) translocation
bcl2 CE C 3’E
Unregulation of Bcl2 expression by IgH enhancers
Translocation takes place in B cell precursors.
Transformation takes placeduring B cell activation in GC.
Bcl2 inhibits apoptosis
cytochrome c
Apaf-1
dATP or ATP
mitochondrion
Apaf-1
Pro-caspase-9
Caspase-9
Pro-caspase-3 Caspase-3
Apoptosis
Bcl-2, Bcl-XL
Bax, Bad
Pro-survival oncogene
Over-expression of Bcl-2 may prevent the apoptosisof 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 contain somatic hypermutation.
Non-Hodgkin’s LymphomaFollicular 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 LymphomaCutaneous 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 LymphomaDiffuse 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 LymphomaMantle 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
Nodular pattern
Diffuse pattern
Classical Mantle Cell
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 LymphomaMarginal Zone
Indolent Accounts for ~10% of
all lymphomas Subcategories
MALT (H. pylori) Nodal Extra-Nodal Splenic
Non-Hodgkin’s LymphomaSplenic Lymphoma
Non-Hodgkin’s LymphomaPrimary 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 LymphomaAnaplastic 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: CHOP1. First-generation: CHOP
- CR: 50-55%. Long-term survival: 35-50 %.- CR: 50-55%. Long-term survival: 35-50 %.
2. Second-generation: mBACOD, ProMACE-CytaBOM2. Second-generation: mBACOD, ProMACE-CytaBOM
- CR: 70-80%. Long-term survival: 50-60%.- CR: 70-80%. Long-term survival: 50-60%.
3. Third-generation: MACOP-B3. Third-generation: MACOP-B
- CR: 84%. Long-term survival: 75%- CR: 84%. Long-term survival: 75%
Non-Hodgkin’s LymphomaIntergroup 0067 Study
3-year survival Mortality3-year survival Mortality
______%_%_______________________________%%______
CHOPCHOP 4141 1 1
mBACODmBACOD 4646 5 5
ProMACE-CytoBOM ProMACE-CytoBOM 4646 3 3
MACOP-BMACOP-B 4141 6 6
Southwest Oncology Group
Non-Hodgkin’s LymphomaTreatment of Patients Age over 60
Program_Program_______________________________5-year survival %5-year survival %
CHOPCHOP 45 45
mBACODmBACOD 39 39
ProMACE-CytoBOMProMACE-CytoBOM 41 41
MACOP-BMACOP-B 23 23
tt
Non-Hodgkin’s LymphomaPeripheral 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
myc Chromosome 8
SC
EChromosome 14, 80%IgH
IgChromosome 2
Igchromosome 22
breakpoints
Class switch recombination
V(D)J
Somatic hypermutation
***
mycS
C C3’E
myc C C3’E
SE
t(8:14)
Non-Hodgkin’s LymphomaBurkitt’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 LymhomaStarry, Starry Night
Non-Hodgkin’s LymphomaLymphoblastic 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-HitDouble-Hit LymphomasLymphomas
Multiple gene expressions MYC gene t(14,18)
Triple-Hit MYC gene t(14,18) BCL-6 gene
Non-Hodgkin’s LymphomaAggressive 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
PR
OB
AB
ILIT
Y,
%
100
0
20
40
60
80
YEARS
P = 0.0009
0 1 2 3 4 65
CR1 (N = 174)
CR2+ (N = 322)
Never in remission (N = 418)
Relapse (N = 791)
PROBABILITY OF SURVIVAL AFTER HLA-IDENTICAL SIBLING MYELOABLATIVE
TRANSPLANTS FOR FOLLICULAR NON-HODGKIN LYMPHOMA
PR
OB
AB
ILIT
Y,
%
100
0
20
40
60
80
YEARS
P = NS
0 1 2 3 4 65
CR1-3 (N = 79)
Never in remission (N = 138)
Relapse (N = 193)
PROBABILITY OF SURVIVAL AFTER AUTOTRANSPLANTS FOR
DIFFUSE LARGE CELL LYMPHOMA
PR
OB
AB
ILIT
Y,
%
100
0
20
40
60
80
YEARS
P = 0.0001
0 1 2 3 4 65
CR1 (N = 438)
CR2+ (N = 651)
Relapse (N = 1,443)
Never in remission (N = 986)
PROBABILITY OF SURVIVAL AFTER HLA-IDENTICAL SIBLING MYELOABLATIVE
TRANSPLANTS FOR DIFFUSE LARGE CELL LYMPHOMA
PR
OB
AB
ILIT
Y,
%
100
0
20
40
60
80
YEARS
P = NS
0 1 2 3 4 65
CR1-3 (N = 56)
Relapse (N = 144)
Never in remission (N = 133)
Monoclonal Abs - Rituxan
Radioimmunotherapy with Y-90 Zevalin
IbritumomabIbritumomab Murine monoclonal Murine monoclonal
antibody parent of antibody parent of RituximabRituximab
TiuxetanTiuxetan Conjugated to Conjugated to
antibody, forming antibody, forming strong urea-type strong urea-type bondbond
Stable retention of Y-Stable retention of Y-9090
Y-90 radionuclideY-90 radionuclideBeta Beta radiationradiation
ChelatorChelator
Monoclonal Monoclonal antibodyantibody
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
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