• disordini linfoproliferativi (II)
• classificazione linfomi
• staging system
• prognosi
• terapia
B-Cell Neoplasms
I. Precursor B-cell neoplasm:
a. Precursor B-lymphoblastic leukemia/lymphoma
II. Mature (peripheral) B-cell neoplasms
a. B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma
b. B-cell prolymphocytic leukemia
c. Lymphoplasmacytic lymphoma
d. Splenic marginal zone B-cell lymphoma (+/- villous lymphocytes)
e. Hairy cell leuekmia
f. Plasma cell myeloma/plasmacytoma
g. Extranodal marginal zone B-cell lymphoma of mucosa-associated
lymphoid tissue type
h. Nodal marginal zone lymphoma (+/- monocytoid B-cells)
i. Follicle center lymphoma, follicular,
j. Mantle cell lymphoma
k. Diffuse large cell B-cell lymphoma
• Mediastinal large B-cell lymphoma
• Primary effusion lymphoma
l. Burkitt's lymphoma/Burkitt's cell leukemia
T-Cell and Natural Killer Cell Neoplasms
I. Precursor T cell neoplasm:
a. Precursor T-lymphoblastic lymphoma/leukemia
II. Mature (peripheral) T cell and NK-cell neoplasms
a. T cell prolymphocytic leukemia
b. T-cell granular lymphocytic leukemia
c. Aggressive NK-Cell leukemia
d. Adult T cell lymphoma/leukemia (HTLV1+)
e. Extranodal NK/T-cell lymphoma, nasal type
f. Enteropathy-type T-cell lymphoma
g. Hepatosplenic gamma-delta T-cell lymphoma
h. Subcutaneous panniculitis-like T-cell lymphoma
i. Mycosis fungoides/Sézary's syndrome
j. Anaplastic large cell lymphoma, T/null cell, primary cutaneous type
k. Peripheral T cell lymphoma, not otherwise characterized
l. Angioimmunoblastic T cell lymphoma
m. Anaplastic large cell lymphoma, T/null cell, primary systemic type
NON-HODGKIN LYMPHOMAS:
*1) non-Hodkin lymphomas are a diverse collection of approximately
*40 entities, with different immunopathologic and cytogenetic characteristics
*2) the most frequent entities are the:
*
- Follicle Centre lymphoma (FCL)
*
- Diffuse Large Cell lymphoma (DLCL)
*3) B-cell derived are by far more frequent compared to T-cell derived
*(90% vs. 10%)
INCIDENZA DEI VARI TIPI DI LINFOMA NON-HODGKIN
28%
6%
16%
30%
20%
FCL
B-cell DLCL
non follicular low grade
NHL
T-cell NHL
Other lymphomas
Hodgkin's lymphoma (Hodgkin's Disease)
a.Nodular lymphocyte predominance Hodgkin's lymphoma
b.Classical Hodgkin's lymphoma
• Nodular sclerosis Hodgkin's lymphoma
• Lymphocyte-rich classical Hodgkin's lymphoma
• Mixed cellularity Hodgkin's lymphoma
• Lymphocyte depletion Hodgkin's lymphoma
Hodgkin's Disease - Classification
Type
Histologic Features
Frequency
Prognosis
Bands of fibrosis,
Lacunar cells
Most frequent type,
more common in women
Good
most are stage I-II
Composed of many
different cells
Most frequent
in older persons,
second most frequent overall
Fair
most are stage III
Nodular sclerosis
Mixed cellular
Lymphocyte predominance
Mostly B-cells and few
Uncommon
Reed-Sternberg variant cells
Good
most are stage I or II
Lymphocyte depletion
Many Reed-Sternberg
cells and variants
Uncommon
Poor
most are stage III or IV
CARATTERIZZAZIONE RISCHIO PROGNOSTICO:
biopsia linfonodale
biopsia osteo-midollare
tipizzazione immunofenotipica
tipizzazione molecolare
stadiazione della malattia
DEFINIZIONE RISCHIO PROGNOSTICO:
biopsia linfonodale
biopsia osteo-midollare
tipizzazione immunofenotipica
tipizzazione molecolare
stadiazione della malattia
fattori di rischio
Fattori con valore prognostico sfavorevole indipendente:
 performance status > 2
 LDH > normale
 siti extranodali  2
 stadio III o IV
 età > 60 anni
No. di fattori presenti
Tipo di rischio prognostico
0-1 basso (L)
2
intermedio-basso (LI)
3
intermedio-alto (HI)
4-5 alto (H)
A World Health Organisation classification indicating a
PERSON's status relating to activity / disability.
0 Able to carry out all normal activity without restriction
1 Restricted in physically strenuous activity, but able to walk
and do light work
2 Able to walk and capable of all self care, but unable to
carry out any work. Up and about more than 50% of waking
hours
3 Capable of only limited self care, confined to bed or chair
more than 50% of waking hours
4 Completely disabled. Cannot carry on any self care. Totally
confined to bed or chair
Tab 4 – Correlazioni tra gruppi di rischio definiti dall'IPI e possibilità di remissione completa,
sopravvivenza libera da ricadute di malattia e sopravvivenza globale nei linfomi aggressivi
Rischio
prognostico
secondo IPI
Basso
Intermedio-basso
Intermedio-alto
Alto
No. Fattori
sfavorevoli
presenti
0-1
2
3
4-5
% Remissione
Completa
87
67
55
44
% sopravvivenza a
%
5 anni senza
sopravvivenza
ricadute di malattia globale a 5 anni
70
73
50
51
49
43
40
26
Overall Survival in DLCL according
to risk group defined by Age-Adjusted IPI
(PS, stage, LDH)
Score
CR
Rate
(%)
5-yr
survival
(%)
Low
0
92
83
Low-intermediate
1
78
69
High-intermediate
2
57
46
High
3
46
32
Risk group
IIL prognostic system
• Age (< vs. > 60 vs)
• Sex (F vs M)
• Extranodal sites (0-1 vs  2)
• Serum LDH (normal vs elevated)
• B symptoms (absent vs present)
• ESR (less than 30 vs at least 30)
Federico M et al., Blood 2000, 95: 783-789
Prognosis of follicular lymphoma: a predictive model based on a retrospective analysis of 987 cases
Hodgkin's lymphoma (Hodgkin's Disease)
a.Nodular lymphocyte predominance Hodgkin's lymphoma
b.Classical Hodgkin's lymphoma
• Nodular sclerosis Hodgkin's lymphoma
• Lymphocyte-rich classical Hodgkin's lymphoma
• Mixed cellularity Hodgkin's lymphoma
• Lymphocyte depletion Hodgkin's lymphoma
Hodgkin's Disease - Classification
Type
Histologic Features
Frequency
Prognosis
Bands of fibrosis,
Lacunar cells
Most frequent type,
more common in women
Good
most are stage I-II
Composed of many
different cells
Most frequent
in older persons,
second most frequent overall
Fair
most are stage III
Nodular sclerosis
Mixed cellular
Lymphocyte predominance
Mostly B-cells and few
Uncommon
Reed-Sternberg variant cells
Good
most are stage I or II
Lymphocyte depletion
Many Reed-Sternberg
cells and variants
Uncommon
Poor
most are stage III or IV
Factors with independent prognostic value
for survival in lymphomas of both
high and low grade histology
Prognostic
classification
IPI
(New Engl J Med 1993)
aa I P I
(New Engl J Med 1993)
IIL
(Blood 2000)
Factor
age >60
performance status
serum LDH level
Ann Arbor stage
extranodal involvement
Performance status
serum LDH level
Ann Arbor stage
Age (>60)
Sex (male)
ESR ()
Serum LDH level ()
Systemic symptoms
extranodal involvement
13-gene predictor:
cured gene-espression
signature
fatal/refractory gene-espression
signature
13-gene outcome
predictor:
IPI-outcome
predictor:
13-gene predictor:
cured gene-espression
signature
fatal/refractory gene-espression
signature
Overall Survival of advanced-stage DLCL
with 3rd generation chemotherapy regimens
Overall Survival of FCL patients
Turin-group experience
with the i-HDS scheme
a “high-dose” approach aimed to obtain
maximal tumor cytoreduction and to exploit
the in vivo-purging effect operated by
chemotherapy
Corradini P et al, Blood 1997 Jan 15;89:724-31
Tarella C et al, Leukemia 2000 Apr 14:740-7
APO x 2
VP-16
DHAP x 2 2 g/sqm
MTX
8 g/sqm
CTX
7 g/sqm
DEX
40
G-CSF
G-CSF
PBPC/BM
harvest
MITOX + L-PAM
+ PBPC autograft
I-HDS SCHEME FOR HIGH-RISK
FCL PATIENTS
I-HDS REGIMEN IN FCL:
results of the Torino group experience
Leukemia 2000, 14: 740-747
•CR RATE OF 79%
•ACCEPTABLE RATE OF EARLY AND LATE TOXICITIES
100
90
80
70
60
50
40
30
20
10
0
% surviving
% surviving
•A PROJECTED EFS AT 9 YEARS OF 62% AND A PROJECTED OS
OF 78%
Event-free survival
0
1
2
3
4
5
years
6
7
8
9
100
90
80
70
60
50
40
30
20
10
0
Overall survival
0
1
2
3
4
5
years
6
7
8
9
Gianni AM et al; NEJM 1997; 336: 1290-97
“HDS vs MACOP-B in aggressive B-cell NHL“
DEVELOPMENT OF MONOCLONAL
ANTIBODIES
HUMAN
MOUSE
CHIMERICAL
HUMANIZED
UNLABELED CHIMERIC
ANTIBODY
IMMUNOTOXIN
RADIOCONJUGATE
Meccanismo d’azione mAbs
• effetto diretto
• signaling  apoptosi
• citossico (tossine o radiomarcati)
• effetto indiretto
• complemento
• ADCC (NK, GN)
• immunosensibilizzazione
Principali anticorpi monoclonali “unlabelled”
STRUTTURA
INDICAZIONI
ANTIGEN
NAME
CD20
Rituximab
Chimerico
FCL,MCL,HCL, DLCL
CD25
Basiliximab
Daclizumab
Chimerico
umanizzato
Trapianto
CD52
Campath 1H
umanizzato
LLC, Trapianto
CD22
Epratuzumab umanizzato
FCL
RADIOIMMUNOCONJUGATE
Effector mechanisms
Radiation-induced cytolysis
TARGET ANTIGENS:
•NOT SHED
•NOT INTERNALIZED ?
NB. Properties of each immunoconiugate depend on which isotope is
chosen
hdAra-C
hd-CY
A P O
VP16 +
CDDP
PBSC
harvest
G-CSF
PBSC
harvest
G-CSF
RITUXIMAB
G-CSF
PBSC autografting
C-HDS + Rituximab schedule
C-HDS + Rituximab in high-risk DLCL patients: a
multicenter italian study
R- HDS
historical
CR
OS
82%
71 % (3yr.)
46-57%
32-46% (5yr.)
identification of residual disease
The role of 67Ga scanning or FDG-PET
in discriminating between active or fibrotic
residual masses is well established
identification of residual disease
The value of molecular biology techniques (PCR)
in evaluating the minimal residual disease in patients
with Bone Marrow involvement at presentation
DFS comparison between PCR-positive
and PCR-negative patients
100
PCR negative
% surviving
80
60
40
PCR positive
P<0.005
20
0
0
2
4
6
years
8
10
12
IMMUNOTERAPIA NEI DISORDINI LINFOPROLIFERATIVI
• percentuale di guarigione ancora insufficiente
• crescita abbastanza lenta
• markers tumore-specifici o lineage-specifici
• chemioterapia efficace ma non eradicante
• monitoraggio della malattia minima residua (MMR)
• MMR spesso MDR+
• immunosensibilita’ della MMR
• modelli animali disponibili
Bendandi et al., Nat Med 5: 1171-1177, 1999
Protein-based vaccine
VACCINATION SCHEDULE
week
0
2
6
10
14
24
28
Id/KLH
(0.5 mg + 0.5 mg)
GM-CSF
(150 µg/sqm)
• 15 MM in first remission after HDS and PBPC infusion;
tumor burden
remission
threshold
diagnosis
time
remission phase
relapse
Early detection of recurrent disease
1.
The efficacy of “salvage treatment” is well known in
both high and low-grade lymphomas
Early detection of recurrent disease
2.
“salvage treatments” are more effective if the
recurrent disease is not extensively spread
SURVIVAL by
Ann Arbor stage at relapse
100
75
%
p<0.0001
50
I-II (n=153)
25
III-IV (n=259)
0
I.I.L.
1999
0
5
10
Years after relapse