Hodgkins and non-Hodgkins Lymphoma

A/Prof Graham Young

Senior Staff Specialist Institute of Haematology Royal Prince Alfred Hospital Sydney

Tonights Talk
What is Lymphoma? Do we know what causes it? Hodgkins Lymphoma Non-Hodgkins Lymphoma Whats 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-Hodgkins Lymphoma 6th Most Common Cancer 4.1% of cancers in Australia 3500 new cases / year Incidence increases with age Many different subtypes Hodgkins Lymphoma Much less common 0.5% of cancers 400 new cases / year Peak incidence in 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

RISK FACTORS

Haemopoiesis

AML

ALL

Lymphoma/ CLL

B lymphoid erythroid myeloid megakaryocytic

T lymphoid

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
Bone marrow Lymph node, lymph, blood, bone marrow Lymph node, lymph, blood, bone marrow Bone marrow

Progressive B lymphocyte maturation

Lymphoid stem cell

Maturing B cell many stages

Mature B cell

Plasma cell

Pre-B acute lymphoblastic leukaemia

B cell lymphoma

Chronic lymphocytic leukaemia

Multiple myeloma

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

Indolent

Aggressive

small cell

large cell

Hodgkins Lymphoma - Staging

PET (Positron Emission Tomography) Scan

xxxxxx

xxx

Hodgkins lymphoma (HL)

Accounts for ~ 30% of all malignant lymphomas Composed of two different disease entities: Lymphocyte-predominant Hodgkins (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

Hodgkins Lymphoma - Management

We have come a long way 1 2 3 Prognostic or Risk Factor allocation of treatment groups Staging (PET and CT) Intensive treatment strategies e.g. BEACOPP

Hodgkins Lymphoma - Progress

Hodgkins Lymphoma - Advanced Disease

< late 1960s

1966

Radiotherapy
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 MOPP salvage 20 % of MOPP failures 1990s 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 9 /l 9 Lymphopaenia <0.6 x10 /l or < 8 % total WCC

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 Vincristine Procarbazine Prednisone Doxorubicin Bleomycin Vinblastine Dacarbazine

Y Y Y Y Y Y Y Y

Y Y Y Y Y Y N etoposide N instead

BEACOPP-dose escalated + accelerated regimen+ RT vs COPP/ ABVD +RT (HD 9 Trial) 5th interim analysis
A B C COPP /ABVD Sd. BEACOPP esc BEACOPP p (A vs C) CR % 5y FFTF% 5y OS% IPFP 0-1 2,3 4-7 AML/ MDS 84 67 79 88 75 90 96 89 90 <0.0001 0.0014

91 81 57
1

91 90 85
4

95 90 77
9

NS NS <0.0099

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.

Hodgkins Lymphoma Management Algorithm

BIOPSY Tissue

STAGING CT/PET

PROGNOSTIC FACTORS

EARLY STAGE (Favourable)

EARLY STAGE (Unfavourable)

ADVANCED STAGE (Favourable)

ADVANCED STAGE (Unfavourable)

ABVD (3) + IFRT

ABVD (6) + IFRT

ABVD (6 8)

BEACOPP (6-8)

Second Malignant Neoplasms Among Long-Term Survivors of Hodgkins Disease: A Population-Based Evaluation Over 25 Years
Graa 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 digestive tract female breast (Obs = 377; O/E = 2.9) (Obs = 376; O/E = 1.7) (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;

Hodgkins 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-Hodgkins lymphoma (DLBCL) with a CHOP-like regimen with or without the anti-CD20 antibody MabThera early stopping after first interim analysis
M Pfreundschuh, L Trmper, D Ma, A sterborg, 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)

MInT: trial design

6 x CHOP-like CD20+ DLBCL 1860 years IPI 0,1 Stages IIIV, I with bulk
+ 3040 Gy (Bulk, E)

Randomisation

6 x CHOP-like + MabThera
+ 3040 Gy (Bulk, E)

Pfreundschuh M, et al., Proc Am Soc Clin Oncol 2004;23:556 (Abstract 6500)

MInT Interim Analysis: patient characteristics

Chemo n=165
Median age (years) Histology (%) DLBCL other Bulky disease (%) 48

R-Chemo n= 161
47

96
4 52

95
5 49

B-symptoms (%)
Extranodal involvement (%)

29
33

27
32

Pfreundschuh M, et al., Proc Am Soc Clin Oncol 2004;23:556 (Abstract 6500)

MInT Interim Analysis: patient characteristics

Chemo n=165
Ann Arbor stage (%) I II III IV ECOG performance status (%) 0,1 2,3 LDH >UNL (%) IPI age-adjusted (%) 0 1
19 55 12 15 99 1 29 43 57 45 55

R-Chemo n= 161
19 60 12 9 100 34

Pfreundschuh M, et al., Proc Am Soc Clin Oncol 2004;23:556 (Abstract 6500)

MInT: adverse events*

60 Percentage of patients 50 Chemotherapy
57 53

40
30 20 10 0

40 39

MabThera + chemotherapy

11

8
2

*Reported

toxicity CTC Grades 3 and 4

Pfreundschuh M, et al., Proc Am Soc Clin Oncol 2004;23:556 (Abstract 6500)

MInT Interim Analysis: time to treatment failure

1.0 81% MabThera + chemotherapy 0.8 Probability 0.6 0.4 0.2 0 p<0.000005 crit=0.00192* 58% Chemotherapy

25 30 35 40 Months Median time of observation: 24 months

10

15

20

45

50

*crit for updated interim analysis Pfreundschuh M, et al., Proc Am Soc Clin Oncol 2004;23:556 (Abstract 6500)

MInT Interim Analysis: overall survival

1.0 0.8 Probability 0.6 0.4 0.2 p=0.0026 0 85% Chemotherapy 95% MabThera + Chemotherapy

25 30 35 40 Months Median time of observation: 24 months

10

15

20

45

50

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 BLOOD AND MARROW TRANSPLANTS WORLDWIDE 1970-2002

45,000 NUMBER OF TRANSPLANTS 40,000 35,000 30,000 25,000 20,000 15,000 10,000 5,000 0
1970 1975 1980 1985 1990 1995 2000

Autologous

Allogeneic

YEAR

LOCATION OF CENTERS PARTICIPATING IN THE IBMTR / ABMTR 2003

.. . . ... .................. .. .. ........... .. . ...... . . .. .... . . . .. .. . ...

..

. . . .... .. . . . ...... . . . ..

... . ... .......... . . . . ... .. . ... ..... . ..... ............. ........... ... ... .. . . ... .. . .. . . . .. . . . . . .... . .... . . . .
2

INDICATIONS FOR BLOOD AND MARROW TRANSPLANTATION IN NORTH AMERICA 2002

4,500 4,000 3,500
Allogeneic (Total N = 7,200) Autologous (Total N = 10,500)

TRANSPLANTS

3,000 2,500 2,000 1,500 1,000 500 0

Multiple NHL Myeloma AML Hodgkin ALL MDS / CML CLL Breast Other NonDisease Other Cancer Cancer Malignant Neuroblastoma Leukemia Disease

PROBABILITY OF SURVIVAL AFTER AUTOTRANSPLANTS FOR HODGKIN DISEASE, 19962001

100
CR1 (N = 226) CR2+ (N = 733)

80

PROBABILITY, %

60
Never in remission (N = 823)

40
Relapse (N = 1,744)

20
P = 0.0001

0 0 1 2 3 4 5 6

YEARS

33

PROBABILITY OF SURVIVAL AFTER AUTOTRANSPLANTS FOR FOLLICULAR NONHODGKIN LYMPHOMA, 1996-2001

100
CR1 (N = 174)

80

PROBABILITY, %

CR2+ (N = 322)

60
Never in remission (N = 418)
Relapse (N = 791)

40

20
P = 0.0009

0 0 1 2 3 4 5 6

YEARS

34

PROBABILITY OF SURVIVAL AFTER HLA-IDENTICAL SIBLING MYELOABLATIVE TRANSPLANTS FOR FOLLICULAR NON-HODGKIN LYMPHOMA, 1996-2001
100
Never in remission (N = 138)

80

PROBABILITY, %

CR1-3 (N = 79)

60
Relapse (N = 193)

40

20
P = NS

0 0 1 2 3 4 5 6

YEARS

35

PROBABILITY OF SURVIVAL AFTER AUTOTRANSPLANTS FOR DIFFUSE LARGE CELL LYMPHOMA, 1996-2001
100

80

PROBABILITY, %

60

CR1 (N = 438) CR2+ (N = 651)

40
Relapse (N = 1,443)

20
P = 0.0001

Never in remission (N = 986)

0 0 1 2 3 4 5 6

YEARS

36

PROBABILITY OF SURVIVAL AFTER HLA-IDENTICAL SIBLING MYELOABLATIVE TRANSPLANTS FOR DIFFUSE LARGE CELL LYMPHOMA, 1996-2001
100

80

PROBABILITY, %

60

40

Relapse (N = 144) CR1-3 (N = 56) Never in remission (N = 133) P = NS

20

0 0 1 2 3 4 5 6

YEARS

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.