1. disordini linfoproliferativi (II)
classificazione linfomi
staging system
prognosi
terapia

2. 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

3. 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

4. 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%)

5. INCIDENZA DEI VARI TIPI DI LINFOMA NON-HODGKIN
28%
16% 6%
30%
20%
B-cell DLCL
FCL
T-cell NHL
non follicular low grade
NHL
Other lymphomas

6. 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

7. Hodgkin's Disease - Classification
Type Histologic Features Frequency Prognosis
Nodular sclerosis
Bands of fibrosis, Most frequent type, Good
Lacunar cells more common in women most are stage I-II
Mixed cellular
Composed of many Most frequent Fair
different cells in older persons, most are stage III
second most frequent overall
Lymphocyte predominance
Mostly B-cells and few Uncommon Good
Reed-Sternberg variant cells most are stage I or II
Lymphocyte depletion
Many Reed-Sternberg Uncommon Poor
cells and variants most are stage III or IV

8. CARATTERIZZAZIONE RISCHIO PROGNOSTICO:
biopsia linfonodale
biopsia osteo-midollare
tipizzazione immunofenotipica
tipizzazione molecolare
stadiazione della malattia

13. DEFINIZIONE RISCHIO PROGNOSTICO:
biopsia linfonodale
biopsia osteo-midollare
tipizzazione immunofenotipica
tipizzazione molecolare
stadiazione della malattia
fattori di rischio

14. 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)

18. Overall Survival in DLCL according
to risk group defined by Age-Adjusted IPI
(PS, stage, LDH)
C R
5-yr
Risk group
Score
Rate
survival
(%)
(%)
Low 92 83
Low-intermediate 1 78 69
High-intermediate 2 57 46
High 3 46 32

19. 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)

20. Federico M et al., Blood 2000, 95: 783-789
Prognosis of follicular lymphoma: a predictive model based on a retrospective analysis of 987 cases

21. 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

22. Hodgkin's Disease - Classification
Type Histologic Features Frequency Prognosis
Nodular sclerosis
Bands of fibrosis, Most frequent type, Good
Lacunar cells more common in women most are stage I-II
Mixed cellular
Composed of many Most frequent Fair
different cells in older persons, most are stage III
second most frequent overall
Lymphocyte predominance
Mostly B-cells and few Uncommon Good
Reed-Sternberg variant cells most are stage I or II
Lymphocyte depletion
Many Reed-Sternberg Uncommon Poor
cells and variants most are stage III or IV

23. Factors with independent prognostic value
for survival in lymphomas of both
high and low grade histology
Prognostic
classification
Factor
age >60
performance status
I P I
serum LDH level
(New Engl J Med 1993)
Ann Arbor stage
extranodal involvement
Performance status
aa I P I
serum LDH level
(New Engl J Med 1993)
Ann Arbor stage
Age (>60)
Sex (male)
I I L
ESR ()
(Blood 2000)
Serum LDH level ()
Systemic symptoms
extranodal involvement

27. 13-gene predictor: cured gene-espression signature
fatal/refractory gene-espression
signature

28. 13-gene outcome
predictor:
IPI-outcome
predictor:

29. 13-gene predictor: cured gene-espression signature
fatal/refractory gene-espression
signature

31. Overall Survival of advanced-stage DLCL with 3rd generation chemotherapy regimens

32. Overall Survival of FCL patients

34. 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

35. I-HDS SCHEME FOR HIGH-RISK FCL PATIENTS MITOX + L-PAM + PBPC autograft
VP-16 2 g/sqm
MTX 8 g/sqm
CTX 7 g/sqm
DHAP x 2
APO x 2
PBPC/BM harvest
MITOX + L-PAM + PBPC autograft
DEX 40
G - C S F
G - C S F

36. results of the Torino group experience
I-HDS REGIMEN IN FCL:
results of the Torino group experience
Leukemia 2000, 14:
CR RATE OF 79%
ACCEPTABLE RATE OF EARLY AND LATE TOXICITIES
A PROJECTED EFS AT 9 YEARS OF 62% AND A PROJECTED OS OF 78% 10 20 30 40 50 60 70 80 90
100
% surviving
100 90 80 70
% surviving 60 50 40 30
Event-free survival 20
Overall survival 10 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9
years
years

37. Gianni AM et al; NEJM 1997; 336: 1290-97 “HDS vs MACOP-B in aggressive B-cell NHL“

38. DEVELOPMENT OF MONOCLONAL ANTIBODIES
MOUSE
HUMAN
CHIMERICAL
HUMANIZED

39. UNLABELED CHIMERIC ANTIBODY
IMMUNOTOXIN
RADIOCONJUGATE

40. Meccanismo d’azione mAbs
effetto diretto
signaling  apoptosi
citossico (tossine o radiomarcati)
effetto indiretto
complemento
ADCC (NK, GN)
immunosensibilizzazione

41. Principali anticorpi monoclonali “unlabelled”
ANTIGEN
NAME
STRUTTURA
INDICAZIONI
CD20
CD25
CD52
CD22
Rituximab
Basiliximab
Daclizumab
Campath 1H
Epratuzumab
Chimerico
umanizzato
FCL,MCL,HCL, DLCL
Trapianto
LLC, Trapianto
FCL

42. Radiation-induced cytolysis
RADIOIMMUNOCONJUGATE
Effector mechanisms
Radiation-induced cytolysis
TARGET ANTIGENS:
NOT SHED
NOT INTERNALIZED ?
NB. Properties of each immunoconiugate depend on which isotope is chosen

43. RITUXIMAB C-HDS + Rituximab schedule hd-CY hd- Ara-C VP16 + CDDP
PBSC autografting
A P O
PBSC
harvest
PBSC
harvest
G-CSF
G-CSF
G-CSF
RITUXIMAB

44. C-HDS + Rituximab in high-risk DLCL patients: a multicenter italian studyCR OS
R- HDS
82%
71 % (3yr.)
historical
46-57%
32-46% (5yr.)

45. identification of residual disease
The role of 67Ga scanning or FDG-PET in discriminating between active or fibrotic residual masses is well established

46. 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

47. DFS comparison between PCR-positive and PCR-negative patients40
100
P<0.005
PCR negative
PCR positive
% surviving 80 60 20 2 10 12
years 4 6 8

48. 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

49. Bendandi et al., Nat Med 5: 1171-1177, 1999

50. Protein-based vaccine
week 2 6 10 14 24 28
Id/KLH
(0.5 mg mg)
GM-CSF
(150 µg/sqm)
VACCINATION SCHEDULE
15 MM in first remission after HDS and PBPC infusion;

52. tumor burden remission phase time diagnosis relapse remission
threshold
remission phase
time
diagnosis
relapse

53. Early detection of recurrent disease
1. The efficacy of “salvage treatment” is well known in both high and low-grade lymphomas

54. Early detection of recurrent disease
2. “salvage treatments” are more effective if the recurrent disease is not extensively spread

55. Ann Arbor stage at relapse
SURVIVAL by
Ann Arbor stage at relapse
100 75
p<0.0001 % 50
I-II (n=153) 25
III-IV (n=259) 5 10
I . I . L .
1999
Years after relapse