Hodgkin’S And Non Hodgkin’S Lymphoma

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


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


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


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


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


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


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


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)


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)


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)


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)


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.

Health & Medicine

Hodgkin’S And Non Hodgkin’S Lymphoma