hodgkin’s and non hodgkin’s lymphoma
TRANSCRIPT
Hodgkin’s andnon-Hodgkin’s Lymphoma
A/Prof Graham YoungSenior Staff Specialist
Institute of HaematologyRoyal Prince Alfred Hospital
Sydney
Tonight’s Talk
• What is Lymphoma?
• Do we know what causes it?
• Hodgkin’s Lymphoma
• Non-Hodgkin’s Lymphoma
• What’s New?
• Questions and discussion
• Resourses and Information
WHAT IS LYMPHOMA?
LYMPHOMA
is the term applied to a heterogeneous collection of diseases characterised by the presence of malignant lymphoid cells.
i.e.
Cancer of the Lymphatic System
LYMPHOMA
Traditionally 2 main Types of Lymphoma
Non-Hodgkin’s Lymphoma Hodgkin’s Lymphoma
6th Most Common Cancer Much less common
4.1% of cancers in Australia 0.5% of cancers
3500 new cases / year 400 new cases / year
Incidence increases with age Peak incidence in
Many different subtypes Adolescence and >50
What causes Lymphoma?
• In most cases we do not know• It is likely that several factors are important
e.g. Genetic predisposition
plus infection (bacteria or virus) plus chemicals plus ????
• But in some cases we know some risk factors
RISKFACTORS
Haemopoiesis
erythroid myeloid megakaryocytic
B lymphoid T lymphoid
AML
Lymphoma/
CLL
ALL
Types of lymphocytes (defined by surface antigens, in vitro function, types of illness when lacking)
B cells: humoral immunity
• antibody production
T cells: cellular immunity
• cytotoxicity against virus, fungus
• B cell help
Most lymphomas are of B cell type (80%)
B cell malignancies
Pre-B acute lympho-
blastic leukaemia
B cell lymphoma Chronic lympho-
cytic leukaemia
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
How does lymphoma present?
• Patient notices lumps in neck, under arms, in groin (lymphadenopathy)
• Lymphadenopathy noted during examination for other reason eg. check up
Abnormal blood findings unusual (cf. leukaemia)
Making the diagnosis
• Surgical node biopsy is essential at initial diagnosis
• Fine needle aspiration biopsy can be useful to
confirm disease where biopsy is difficult eg.
lung, liver or to document relapse but only after
diagnosis has been established by node biopsy
Making the diagnosis
nodular (follicular) diffuse
small cell large cell
Indolent Aggressive
Hodgkin’s Lymphoma - Staging
PET (Positron Emission Tomography) Scan
xxxxxx xxx
Hodgkin’s lymphoma (HL)
• Accounts for ~ 30% of all malignant lymphomas
• Composed of two different disease entities:Lymphocyte-predominant Hodgkin’s (LPHL), making up ~ 5% of cases and
Classical HL, representing ~ 95% of all HLs.
A common factor of both HL types is that neoplastic cells constitute only a small minority of the cells in the affected tissue, often corresponding to < 2% of the total tumour
Features of Classical Hodgkin Lymphoma
Fatal disease with 90% of untreated patients dying within 2 to 3 years
With chemotherapy, >80% of patients suffering from cHL are cured.
Pathogenesis of cHL is still largely unknown.
cHL nearly always arises and disseminates in lymph nodes
Hodgkin’s Lymphoma - Management
“We have come a long way”
1 Prognostic or Risk Factor allocation of treatment groups
2 Staging (PET and CT)
3 Intensive treatment strategies
e.g. BEACOPP
Hodgkin’s Lymphoma - Progress
Hodgkin’s Lymphoma - Advanced Disease
• < late 1960’s Radiotherapy
• 1966 MOPP 50 % cure
Mechlorethamine,
Oncovin (Vincristine),
Procarbazine,
Prednisone
Background to current recommended First line therapy
• 1982 ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine)
partial non-cross resistance with MOPPsalvage 20 % of MOPP failures
• 1990’s 5 randomised trials:
alternating monthly cycles of MOPP/ABVD superior to MOPP
Prognostic Score for Advanced HD Hasenclever et al, NEJM 1998
7 independent prognostic factors• Albumin < 40g/l• Hb < 10.5g/dl• Male• > 45 y.o.• Ann Arbor stage IV• WCC > 15 x 10 /l• Lymphopaenia <0.6 x10 /l or < 8 % total WCC
9
9
BEACOPP Developed as COPP / ABVD variant by GHLSG with same
dosages (except vincristine and procarbazine) in a shorter 3 week cycle):
COPP / ABVD BEACOPP
Cyclophosphamide Y YVincristine Y YProcarbazine Y YPrednisone Y YDoxorubicin Y YBleomycin Y YVinblastine Y N etoposideDacarbazine Y N instead
BEACOPP-dose escalated + accelerated regimen+ RT vs COPP/ ABVD +RT
(HD 9 Trial) 5th interim analysisA B C
COPP /ABVD Sd. BEACOPP esc BEACOPP p (A vs C)
CR % 84 88 96
5y FFTF% 67 75 89 <0.0001
5y OS% 79 90 90 0.0014
IPFP0-1 91 91 95 NS2,3 81 90 90 NS4-7 57 85 77 <0.0099
AML/ MDS1 4 9
BEACOPP-dose escalated + accelerated regimen+ RT vs COPP/ ABVD +RT (HD 9 Trial) 5th interim analysis
Side effects from escalated BEACOPP
Acute haematological “manageable”
but
3 % mortality
100 % infertility in men and women (cyclophosphamide and procarbazine)
Premature menopause in most women > 25 y.o.
Hodgkin’s Lymphoma – Management Algorithm
BIOPSYTissue
STAGINGCT/PET
PROGNOSTIC FACTORS
EARLY STAGE(Favourable)
ADVANCED STAGE(Unfavourable)
ADVANCED STAGE(Favourable)
EARLY STAGE(Unfavourable)
ABVD (3) + IFRT ABVD (6) + IFRT ABVD (6 – 8) BEACOPP (6-8)
Second Malignant Neoplasms Among Long-Term Survivors of Hodgkin’s Disease: A Population-Based Evaluation Over 25 Years
Graça M. Dores, Catherine Metayer et al, JCO, 20, (2002): 3484-3494
Data from 32,591 HD patients (1,111 25-year survivors) reported to 16 population-based cancer registries in North America and Europe (1935 to 1994) were analyzed.
2153 second cancers [O/E] = 2.3; 95% [CI] = 2.2 to 2.4)including 1,726 solid tumors (O/E = 2.0; 95% CI, 1.9 to 2.0) reported
Cancers of the lung (Obs = 377; O/E = 2.9) digestive tract (Obs = 376; O/E = 1.7) female breast (Obs = 234; O/E = 2.0)
25 years after HD diagnosis, the risk of developing a solid tumor was 21.9%.
Increased risks for all solid tumors taken together were observed after therapy with either radiation alone (Obs = 632; O/E = 2.3; chemotherapy alone (Obs = 211; O/E = 1.7; combined-modality therapy (Obs = 149; O/E = 3.1;
Hodgkin’s Lymphoma - Fertility
• Sperm counts are often low before therapy• MOPP causes high incidence of infertility• ABVD rarely causes permanent infertility
and currently sperm cryopreservation is not recommended (Draft Lymphoma guidelines)
• BEACOPP / High dose CT less certain• If fertility recovers – sperm quality is good• No excess of congenital abnormalities with
prior chemotherapy
Types of lymphoma
• Indolent lymphoma– nodular or follicular
lymph node pattern
– slowly growing
– respond to treatment but incurable
– treatment can be observe only or start with mild and simple therapy
• Aggressive/highly aggressive lymphoma– diffuse lymph node
pattern
– grow rapidly
– some cured (30-40%)
– those not cured die within 1-2 years
– require aggressive initial chemotherapy to attempt cure
Randomised intergroup trial of first line treatment for patients 60 years with diffuse
large B-cell non-Hodgkin’s lymphoma (DLBCL) with a CHOP-like regimen with or without the
anti-CD20 antibody MabThera – early stoppingafter first interim analysis
M Pfreundschuh, L Trümper, D Ma, A Österborg, R Pettengell, M Trneny, L Shepherd, J Walewski,
P-L Zinzani, and M Loeffler for the MabThera International Trial (MInT) Group
Pfreundschuh M, et al., Proc Am Soc Clin Oncol 2004;23:556 (Abstract 6500)
CD20+ DLBCL18–60 years
IPI 0,1Stages II–IV,I with bulk
CD20+ DLBCL18–60 years
IPI 0,1Stages II–IV,I with bulk
6 x CHOP-like+ 30–40 Gy (Bulk, E)
6 x CHOP-like+ 30–40 Gy (Bulk, E)
6 x CHOP-like+ MabThera
+ 30–40 Gy (Bulk, E)
6 x CHOP-like+ MabThera
+ 30–40 Gy (Bulk, E)
RandomisationRandomisation
MInT: trial design
Pfreundschuh M, et al., Proc Am Soc Clin Oncol 2004;23:556 (Abstract 6500)
Median age (years) 48 47
Histology (%)
DLBCL 96 95
other 4 5
Bulky disease (%) 52 49
B-symptoms (%) 29 27
Extranodal involvement (%) 33 32
Chemo n=165
R-Chemo n= 161
MInT Interim Analysis: patient characteristics
Pfreundschuh M, et al., Proc Am Soc Clin Oncol 2004;23:556 (Abstract 6500)
Chemo n=165
R-Chemo n= 161
MInT Interim Analysis: patient characteristics
Ann Arbor stage (%) I 19 19 II 55 60 III 12 12 IV 15 9
ECOG performance status (%) 0,1 99 100 2,3 1 -
LDH >UNL (%) 29 34
IPI age-adjusted (%) 0 43 45 1 57 55
Pfreundschuh M, et al., Proc Am Soc Clin Oncol 2004;23:556 (Abstract 6500)
MInT: adverse events*
Per
cen
tag
e o
f p
atie
nts
5753
40 39
116 8 8
2 3
*Reported toxicity CTC Grades 3 and 4
Chemotherapy
MabThera + chemotherapy
60
50
40
30
20
10
0
Total
Haem
atoto
xici
ty
Gastro
inte
stin
al
Infe
ctio
ns
Nervo
us sy
stem
Pfreundschuh M, et al., Proc Am Soc Clin Oncol 2004;23:556 (Abstract 6500)
p<0.000005crit=0.00192*
81% MabThera + chemotherapy
58% Chemotherapy
MonthsMedian time of observation: 24 months
Pro
bab
ilit
y
*crit for updated interim analysis
MInT Interim Analysis: time to treatment failure
1.0
0.8
0.6
0.4
0.2
00 5 10 15 20 25 30 35 40 45 50
Pfreundschuh M, et al., Proc Am Soc Clin Oncol 2004;23:556 (Abstract 6500)
p=0.0026
95% MabThera + Chemotherapy
85% Chemotherapy
MonthsMedian time of observation: 24 months
Pro
bab
ilit
y
1.0
0.8
0.6
0.4
0.2
00 5 10 15 20 25 30 35 40 45 50
MInT Interim Analysis: overall survival
Pfreundschuh M, et al., Proc Am Soc Clin Oncol 2004;23:556 (Abstract 6500)
MInT: conclusions
MabThera plus CHOP or CHOP-like chemotherapy in young patients with low-risk DLBCL results in
– higher remission rates
– reduced progression rates
– prolonged time to treatment failure
– increased survival rates
– no additional toxicity
Pfreundschuh M, et al., Proc Am Soc Clin Oncol 2004;23:556 (Abstract 6500)
ANNUAL NUMBERS OF ANNUAL NUMBERS OF BLOOD AND MARROW TRANSPLANTS BLOOD AND MARROW TRANSPLANTS
WORLDWIDEWORLDWIDE1970-20021970-2002
NU
MB
ER
OF
TR
AN
SP
LA
NT
S
YEAR
1970 1975 1980 1985 1990 1995
Autologous
Allogeneic
20000
5,000
10,000
15,000
20,000
25,000
30,000
35,000
40,000
45,000
1
..
..
. ........... ... ......
.
..... . .............
................
......... .........................
.. ........ ................ ...........................
... ................. .......... .. ....
.. ...........
......
.... ...
.....
.........
.
..
......
..
.
..
. . ..
. ..... ..
................. ..................
. ..................... .... ............ .........
.............
.
.
.
.
.. ...
. .. .
.
.
..
.. . ..
..
... ..
. ... ....
2
LOCATION OF CENTERS PARTICIPATING LOCATION OF CENTERS PARTICIPATING IN THE IBMTR / ABMTRIN THE IBMTR / ABMTR
20032003
INDICATIONS FOR BLOOD AND MARROW INDICATIONS FOR BLOOD AND MARROW TRANSPLANTATION IN NORTH AMERICATRANSPLANTATION IN NORTH AMERICA
20022002
TR
AN
SP
LA
NT
S
4,500
0
500
1,000
1,500
2,000
Allogeneic (Total N = 7,200)Autologous (Total N = 10,500)
2,500
3,000
4,000
3,500
BreastCancer
NHLMultipleMyeloma
AML ALL CMLMDS / Other
Leukemia
CLL OtherCancerNeuroblastoma
HodgkinDisease
Non-MalignantDisease
7
PROBABILITY OF SURVIVAL AFTER PROBABILITY OF SURVIVAL AFTER AUTOTRANSPLANTS FOR HODGKIN DISEASE, 1996-AUTOTRANSPLANTS FOR HODGKIN DISEASE, 1996-
20012001
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)
33
PROBABILITY OF SURVIVAL AFTER PROBABILITY OF SURVIVAL AFTER AUTOTRANSPLANTS FOR FOLLICULAR NON-AUTOTRANSPLANTS FOR FOLLICULAR NON-
HODGKIN LYMPHOMA, 1996-2001HODGKIN LYMPHOMA, 1996-2001
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)
34
PROBABILITY OF SURVIVAL AFTER HLA-IDENTICAL PROBABILITY OF SURVIVAL AFTER HLA-IDENTICAL SIBLING MYELOABLATIVE TRANSPLANTS FOR SIBLING MYELOABLATIVE TRANSPLANTS FOR
FOLLICULAR NON-HODGKIN LYMPHOMA, 1996-2001FOLLICULAR NON-HODGKIN LYMPHOMA, 1996-2001
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)
35
PROBABILITY OF SURVIVAL AFTER PROBABILITY OF SURVIVAL AFTER AUTOTRANSPLANTS FOR DIFFUSE LARGE CELL AUTOTRANSPLANTS FOR DIFFUSE LARGE CELL
LYMPHOMA, 1996-2001LYMPHOMA, 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 = 438)
CR2+ (N = 651)
Relapse (N = 1,443)
Never in remission (N = 986)
36
PROBABILITY OF SURVIVAL AFTER HLA-IDENTICAL PROBABILITY OF SURVIVAL AFTER HLA-IDENTICAL SIBLING MYELOABLATIVE TRANSPLANTS FOR SIBLING MYELOABLATIVE TRANSPLANTS FOR DIFFUSE LARGE CELL LYMPHOMA, 1996-2001DIFFUSE LARGE CELL LYMPHOMA, 1996-2001
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)
37
TAKE HOME MESSAGES
• 1 Lymphoma is the term applied to a collection of diseases characterised by a malignant proliferation of lymphoid cells.
• 2 Optimal management relies on accurate histological classification and anatomical and biological staging.
• 3 Many patients can be cured of their lymphoma.