Franco Cavalli, MD, FCRP

1
ESMO Conference Lugano 5-8 July 2007, Lugano
Highlights in Lymphoma Malignancies

• Franco Cavalli, MD, FCRP
• IOSI - ONCOLOGY INSTITUTE OF SOUTHERN SWITZERLAND

2

• LYMPHOMA CLASSIFICATIONS
• Rappaport Classification (USA, used until the
  70's)
• Lukes and Collins Classification (USA)
• BNLI classification (UK)
• Kiel classification (Europe, revised in 1988)
• NCI Working Formulation (1982)
• REAL - Revised European-American Lymphoma
  Classification (1994)
• WHO classification of haematopoietic and lymphoid
  tissues tumours (2001)

3
A new paradigm in the REAL and WHO
Classifications of NHLs

• a large number of distinct diseases associated
  with distinctive epidemiology, morphology,
  immunophenotype,
• genetic features, clinical features

4
Non-random Chromosomal Translocations of
NHLs ---------------------------------------------
--------------------------------------------------
----------------------------- NHL Chromosomal
Oncogene Mechanism of Oncogene histologic
type Alteration Involved Oncogene Activation
Function -------------------------------------
--------------------------------------------------
------------------------------------- Lymphoplasma
cytic t(914)(p13q32) PAX-5 Transcriptional
Regulator of deregulation B-cell
differentiation


Follicular t(1418)(q32q21) BCL-2
Transcriptional Negative regulator deregula
tion of apoptosis MALT t(1118)(q21q21)
API2/MALT1 Fusion protein NF-kB activation



t(114)(p22q32) BCL-10
Transcriptional NF-kB activation
deregulation t(1418)(q32q21)
MALT1 Transcriptional NF-kB activation
deregulation Mantle cell
t(1114)(q13q32) BCL-1 Transcriptional Regulato
r
deregulation
of cell cycle


B-DLCL der(3)(q27) BCL-6
Transcriptional Regulator of germinal
translocations
deregulation
center formation Burkitt's t(814)(q24q32) c-
MYC Transcriptional Regulation of
t(28)(p11q24) deregulation cell
differentiation t(822)(q24q11)
and apoptosis


T-cell anaplastic
t(25)(p23q35) NPM/ALK Fusion protein ALK is
a tyrosine kinase ------------------------------
--------------------------------------------------
--------------------------------------------
5
Toward a revised WHO CLASSIFICATION CLINICAL
ADVISORY COMMITTEE MEETING Airlie House,
Warrenton, VA, March 8-9, 2007
Provisional proposals

• No grading for follicular lymphomas (grade 1 to
  3a FL grade 3bDLBCL with FL component)
• Molecular and immunohistochemical definition of
  Burkitts lymphoma irrespective of morphology
• Provisional subtypes of DLBCL
• GCB
• ABC
• PMLBCL
• CD5
• cutaneous ? as in the WHO/EORTC

6
NHL outcome, by histology (IOSI database
1979-2006)
7
Estimates of annual changes in lymphoma incidence
in Europe (15-79 yrs olds)

• Country change 95 C.I.
• Denmark 2.7 0.8 to 4.5
• Finland 4.5 1.3 to 7.8
• France 2.8 -3.5 to 9.5
• Italy 6.9 3.3 to 10.5
• Netherlands 5.7 2.1 to 9.4
• Spain 8.0 2.2 to 14.3
• UK 3.5 1.6 to 5.4
• total NHL 4.2 3.1 to 5.3
• HODGKINS DISEASE, total 0.1 -1.9 to 2.1

8
NHL increasing incidence USA 1974-1988

• nodal cases increase 1.7 - 2.5 per year
• extranodal casea increase 3.0 - 6.9 per year

• sites with the greatest increase
• à skin
• à stomach
• à intestine
• à brain and eye

9
Primary Extranodal Lymphomas survival according
to site (all stages)
100 75 50 25 0
gastric MALToma
salivary glands
overall survival
all extranodal sites
intestinal
CNS
testis
0 5
10 years
modified from Cavalli, 1997
10
INTERNATIONAL EXTRANODAL LYMPHOMA STUDY GROUP
IELSG
http//www.ielsg.org
11
IELSG Testis Lymphoma Study (Zucca et
al. JCO 2003)
1.00
Overall Survival, n373 5-yr OS 48 10-yr OS 27
0.75
0.50
0.25
0.00
0
10
20
30
survival
12
IELSG 10 study of testis lymphoma R-CHOP IF-FR
i.t. MTX N49
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IELSG study of PCNSL

• 370 immunocompetent patients with PCNSL treated
  at 23 cancer centers from 5 countries
• CT followed by RT superior to RT alone
• Best CT HD MTX HD ARA-C?
• RT unnecessary in CR after HD MTX?
• Ferreri et al. Neurology 2002

14
PCNSL survival according to the IELSG prognostic
score
Subset of 75 cases treated with HD-MTX /- WBRT
105 cases with complete data about all the 5
prognostic variables
Ferreri et al. J Clin Oncol 2003
15
The MALT concept

• Native MALT normally present in certain
  extranodal sites (e.g., Peyers patches)

• Acquired MALTwhere lymphoid tissue is not a
  natural component (e.g., Sjögren, Hashimoto, H.
  pylori-gastritis)

• MALT Lymphoma first described in the
  stomach by Isaacson and Wright in 1983, but
  can arise from a wide variety of extranodal
  tissues (usually at acquired
  MALT sites)

16
MALT lymphoma(Extranodal Marginal Zone B-Cell
Lymphoma of MALT)

• HISTOLOGICAL FEATURES AND PHENOTYPE
• centrocyte-like cells (usually)
• lymphoepithelial lesions
• plasma cell differentiation
• scattered transformed blasts
• admixed non-neoplastic T-cell
• follicular colonisation
• sIg (usually IgM and IgD - )
• CD20, CD21, CD35 positive
• CD5, CD10, CD23 negative

http//www.ncl.ac.uk/pathology/teaching/
17
H. pylori and gastric MALT lymphoma
H. pylori strain-specific stimulation
Neutrophils activations with release of
genotoxic radicals
B
contact-dependent B-cell stimulation
by CD40-CD40L interaction
B
B
B
B
B
B
B
T
T
B
B
B
B
B
T
B
B
T
B
Geneticalterations
B
antigen selection, autoimmunity
T
B
B
B
mucosal T-cell proliferation
B-cell proliferation
H. pylori-dependent MALT lymphoma
Additional genetic damages
tumor progression
18
Different chromosomal translocations
affecting the same signalling pathway in MALT
lymphoma
common t(1118) CagA strains API2/MALT1 fusion
raret(114) BCL10 deregulation
at non-GI sites t(1418) MALT 1deregulation
more recentlydescribed t(314)
FOXP1overexpression
?
NF-kB activation
poorer outcome and higher risk of histological
transformation
Antibiotic-resistantgastric lymphoma
19
Clinical and biological features of the four main
recurrent translocations of MALT lymphomas
Bertoni Zucca , J. Clin. Invest. 200611622-26
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Response to antibiotics in stage I gastric
MALToma (H.pylori-positive )
Reference pts. staging CR time follow
relapses method rate to CR up (n)
() (mos.) (mos.) (n) Savio,
1996 12 CT 84 2-4 24 0 Pinotti,
1997 45 CT 67 3-18 23 2 Neubauer, 1997
50 CTEUS 80 1-9 15 5 Nobre Leitao, 1998 17
CTEUS 100 1-12 12 1 Steinbach,
1999 23 CTEUS 56 3-45 gt18 0 Montalban,
2001 19 CTEUS 95 2-19 37 0 Ruskone-Formestra
ux, 2001 24 CTEUS 79 2-18 23 2 LY03 interim
analysis, 2000 190 CT 62 3-24 27 15
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INTERNATIONAL EXTRANODAL LYMPHOMA STUDY
GROUP Ongoing IELSG-19 Study
Randomized trial of chlorambucil versus
chlorambucil plus rituximab in MALT lymphoma
Control arm
Chlorambucil weeks 1-6 // 9-10
// 13-14 // 17-18 // 21-22 (6 mg/m2
/d)
Study arm
Chlorambucil weeks 1-6 // 9-10
// 13-14 // 17-18 // 21-22 (6 mg/m2
/d) 1 8 15 22 42 56 70 84 98 112 126
140 154 Rituximab

(375 mg/ m2 )
day
ielsg_at_ticino.com
22
INTERNATIONAL EXTRANODAL LYMPHOMA STUDY
GROUP IELSG-25 Study Design
Two parallel phase II trials of VELCADETM (1.3
mg/m2/d on d1, d4, d8, d11 q21days, up to 6
cycles) Simons Mini-Max design, a5 and
power80
A Relapsing/refractory MALT lymphoma at any
site, with 1 previous line of systemic
treatment (CT antiCD20) Target ORR of
interest 40 Expected sample size, max 33 pts
B Relapsing/refractory MALT lymphoma at any site,
with gt1 previous line of systemic treatment
(CT antiCD20) Target ORR of interest
30 Expected sample size, max 25 pts
ielsg_at_ticino.com
23
INTERNATIONAL EXTRANODAL LYMPHOMA STUDY GROUP
IELSG-9 study of primary mediastinal DLBCL
Plt0.0001 N426
CHOP 3rd generation HDS / ABMT CR after
CT 49 51 53 CR after CTRT 61 79 75 10-year
OS 44 71 77 Follow-up 52 mos 55 mos 36 mos
(Zinzani et al. Haematologica 2002)
24
Gene expression of PMBCL identifies a clinically
favorable subgroup of DLCL (a separate entity?)
related to Hodgkin Lymphoma
The PMBCL molecular profile is resembling that of
classical HL over one third of the genes that
were more highly expressed in PMBL than in other
DLCLs were also characteristically expressed in HL
A Rosenwald, et al.J Exp Med 2003 KJ Savage, et
al.Blood 2003
25
Diffuse Large B-Cell Lymphoma (DLBCL)

• The commonest type (30 of NHL) 
• Aggressive histology(most lymphoma cells are
  highly atypical large and irregular, with
  vesicular nuclei and prominent nucleoli
• Aggressive behavior(untreated, these NHL kill
  patients in 1-2 years)

26
WHO CLASSIFICATION (2001) DLBCL Variants and
subtypes

• Diffuse large B-cell lymphoma, NOS
• Germinal center B-cell type
• Activated B-cell type
• DLBCL associated with chronic inflammation
• EBV-positive DLBCL, NOS
• T cell/histiocyte rich large B-cell lymphoma
• Primary mediastinal (thymic) large B-cell
  lymphoma
• Primary DLBCL of the CNS
• Primary cutaneous DLBCL, leg type
• Intravascular large B-cell lymphoma
• ALK positive DLBCL
• Plasmablastic lymphoma
• Primary effusion lymphoma
• DLBCL associated with HHV8 multicentric
  Castleman Disease

27
DLBCL outcome, by IPI (IOSI database 1979-2006)
1.00
low risk
0.75
low-intermediate risk
cause-specific survival
0.50
intermediate-high risk
0.25
high risk
0.00
0
10
20
30
years from diagnosis
28
Prognosis of DLBCL (Barrans et al, Blood 2002)

• Combination of
• Germinal center phenotype (Bcl-6, CD10)
• Bcl-2 expression
• International Prognostic Index

Low Risk ? IPI low, IPI intermediate without
Bcl-2 expression but with GCB phenotype
High Risk ? IPI high, IPI intermediate with
Bcl-2 expression (regardless of phenotype)
29
Overall survival by treatment era
All Patients in British Columbia N294
Sehn, L. H. et al. J Clin Oncol 235027-5033 2005
30
Which chemotherapy regimen should be considered
the best treatment for DLCL?
CHOP is no longer the standard

• Randomised trials showed that either R-CHOP,
  CHOP-14, CHOEP, or ACVBP are better than CHOP in
  various clinical settings
• DA-EPOCH-R is being tested in a randomised study
  at NIH
• Specific therapeutic approach may be needed for
  each extranodal presentation

31
Who should receive myeloablative therapy for
DLBCL?

• ASCT in DLCL
• standard treatment at 1st relapse (in pts lt65
  yr)
• controversial benefit in upfront treatment of
  poor risk patients

32
Early Consolidation by Myeloablative
Radiochemotherapy followed by ASCT in 1st
Remission prolongs PFS in MCL
Randomized Trial of the European MCL Network
Progression Free Survival N122
Median PFS, 39 mos. (ASCT) vs. 17 mos (IFN)
Dreyling et al. Blood, prepublished online Dec.
9, 2004 DOI 10.1182/blood-2004-10-3883
33
Rituximab plus Hyper-CVAD alternating with
rituximab plus HD-MTX-Cytarabine in untreated
MCL Prolonged follow-up confirms high rates of
FFS and OS

• R-HyperCVAD/ R-HD-MTX-Cytarabine in MCL
• ORR after 6 cycles 98 (CR 87)
• CRPR 88 9 in pts 65 years 84 16
  in pts gt 65 years
• Significant hematologic toxicity
• Median f-up 3.3 years
• Median FFS not reached
• 3-yr FFS 78 in pts 65 years 46 in pts
  gt 65 years

Romaguera JE et al. ASH 2004, Abstract 128 -
34
Follicular Lymphoma

• Morphologya tumor of follicle center B-cells,
  composed of a mixture of centrocytes and
  centroblasts, with at least a partially
  follicular growth pattern
• - Grade 1 0-5 centroblasts per high-power
  field- Grade 2 6-15 centroblasts per
  high-power field- Grade 3 gt15 centroblasts per
  high-power field
• Immunophenotype CD19, CD20,CD22 sIg,
  CD10/-, CD5-, CD43-Bcl-2,nuclear Bcl-6
  expression
• Genetic features- (1418) with BCL-2/JH
  rearrangement- BCL-6 frequently
  mutated/rearranged

35
FLIPI Follicular Lymphoma International
Prognostic Index
Age ?60 yr vs. ? 60 yr Haemoglobin ?12g/dL
vs. ?12g/dL Serum LDH ?ULN vs. ?ULN Ann Arbor
Stage III vs. IIIIV No. of Nodal Sites
?4 vs. ?4
Risk Factors
Risk Group No. of 5-yr OS 10-yr OS RR
Factors GOOD 0-1 91 71
1.0 INTERMEDIATE 2 78 51 2.3 POOR
?3 53 36 4.3
36
SAKK 35/98 effect on event free survival of
FL Ghielmini et al, Blood 2004
37
SAKK 35/03 The ongoing SAKK study
SAKK Standard
R
RITUXIMAB375 mg/m² weekly x 4
SD,PR,CR
Prolonged
RITUXIMAB375 mg/m² every 2 month x 4 until
progression (max 5 yrs)
PD off study
38
Meta-Analysis of Chemo vs R-Chemo Overall
Survival of Follicular Lymphomas
Study Weight HR (95-CI)
HR (95-CI)
Forstpointner 2005 4.76 0.38 Herold 2005
15.13 0.45 Marcus 2005 19.55 0.70 Hiddemann
2005 35.04 0.60 Subtotal 74.48 0.57 (0.43 -
0.77) Total events
45 /525 77 /490 Heterogeneity (P
0.65), I² 0
0.2
0.5
1
2
Favors Chemo
Favors R Chemo
Schulz et al, ASH 2005
39
Myeloablative Therapy With Autologous Bone Marrow
Transplantation for FL at the Time of Second or
Subsequent Remission
Risk of AML/MDS
Long-Term Follow-Up of theSaint Bartholomew's /
Dana-Farber Study
Overall Survival
Remission Duration
Rohatiner, A. Z.S. et al. J Clin Oncol
252554-2559 2007
40
I-131 Tositumomab as initial therapy for
indolent NHL
n76 pts, 97 RR, 76 CR
Kaminski MS, N Engl J Med 2005
41
Are we changing the outcome of follicular
lymphomas?
Follicular lymphomas in the IOSI series, N 258
42
CLL and Survival multivariate analysis (n300)
Parameter Hazard Ratio
17p - 5.53 IgVH 5.27 Age 1.49 WBC 1.26 LDH 1.11

43
ZAP70

• Zeta-associated Protein 70 (ZAP-70) is a
  receptor associated Tk usually found in T/Nk
  cells, not in normal B-cells.
• gt 20 cells ZAP70 ? ? unmutated
• Tend to be stable over time

Kröber et al.JCO 2006 24969-975
44
B-cell lymphoma biology

• In many lymphomas, such as follicular lymphoma,
  mucosa-associated lymphoid tissue lymphomas and
  classical Hodgkins lymphoma, the tumor
  micro-environment seems to be important for the
  survival and/or proliferation of the lymphoma
  cell
• The recognition that the survival and/or
  proliferation of many B-cell lymphomas depends on
  their interaction with other cells in the
  microenvironment, as well as on expression of the
  B-cell-receptor and, sometimes, antigen
  activation, might lead to novel treatment options
  for B-cell lymphomas

R. Küppers, Nature Reviews Cancer 2005 5 251-162
45
10-ICML 10th INTERNATIONAL CONFERENCE ON
MALIGNANT LYMPHOMA Palazzo dei Congressi, Lugano,
Switzerland June 04-07, 2008
ORGANIZING COMMITTEE F. Cavalli (Bellinzona) M.
Gospodarowicz (Toronto) J.O. Armitage (Omaha)
O. Jackson (Lugano) M.F. Fey (Bern) P.
Johnson (Southampton) M. Ghielmini (Bellinzona)
E. Zucca (Bellinzona)