disordini linfoproliferativi (ii) classificazione linfomi staging system prognosi terapia
TRANSCRIPT
• 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
*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%)
NON-HODGKIN LYMPHOMAS:
FCL
non follicular low grade NHL
B-cell DLCL
T-cell NHL
Other lymphomas
30%
6%16%
28%
20%
INCIDENZA DEI VARI TIPI DI LINFOMA NON-HODGKIN
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
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
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 aPERSON'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 walkand do light work
2 Able to walk and capable of all self care, but unable tocarry out any work. Up and about more than 50% of wakinghours
3 Capable of only limited self care, confined to bed or chairmore than 50% of waking hours
4 Completely disabled. Cannot carry on any self care. Totallyconfined to bed or chair
Overall Survival in DLCL according to risk group defined by Age-Adjusted IPI
(PS, stage, LDH)
Risk group ScoreC RRate(%)
5-yrsurvival
(%)
Low 0 92 83
Low-intermediate 1 78 69
High-intermediate 2 57 46
High 3 46 32
• 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)
IIL prognostic system
Federico M et al., Blood 2000, 95: 783-789Prognosis 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
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
Prognosticclassification Factor
Factors with independent prognostic value
for survival in lymphomas of both
high and low grade histology
I P I(New Engl J Med 1993)
age >60performance statusserum LDH levelAnn Arbor stageextranodal involvement
aa I P I(New Engl J Med 1993)
Performance statusserum LDH levelAnn Arbor stage
I I L(Blood 2000)
Age (>60)Sex (male)ESR ()Serum LDH level ()Systemic symptomsextranodal involvement
13-gene predictor:
cured gene-espression signature
fatal/refractory gene-espression signature
13-gene outcomepredictor:
IPI-outcomepredictor:
13-gene predictor:
cured gene-espression signature
fatal/refractory gene-espression signature
Overall Survival of advanced-stage DLCLwith 3rd generation chemotherapy regimens
Overall Survival of FCL patients
Turin-group experience with the i-HDS scheme
Corradini P et al, Blood 1997 Jan 15;89:724-31
Tarella C et al, Leukemia 2000 Apr 14:740-7
a “high-dose” approach aimed to obtain maximal tumor cytoreduction and to exploit
the in vivo-purging effect operated bychemotherapy
VP-162 g/sqmAPO x 2 DHAP x 2
G - C S F
CTX7 g/sqm
PBPC/BMharvest
MIT
OX
+ L
-PA
M+
PB
PC
au
togr
aft
I-HDS SCHEME FOR HIGH-RISKFCL PATIENTS
G - C S F
MTX8 g/sqm
DEX 40
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
•A PROJECTED EFS AT 9 YEARS OF 62% AND A PROJECTED OS OF 78%
00 1 2 3 4 5 6 7 8 9
years
102030405060708090
100
% s
urv
ivin
g
Event-free survival
1 2 3 4 5 6 7 8 9 years
0102030405060708090
100
0
% s
urv
ivin
g
Overall survival
Gianni AM et al; NEJM 1997; 336: 1290-97“HDS vs MACOP-B in aggressive B-cell NHL“
MOUSE
CHIMERICAL HUMANIZED
HUMAN
DEVELOPMENT OF MONOCLONAL ANTIBODIES
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”
ANTIGEN NAME INDICAZIONI
CD20
CD25
CD52
CD22
STRUTTURA
Rituximab
BasiliximabDaclizumab
Campath 1H
Epratuzumab
Chimerico
Chimericoumanizzato
umanizzato
umanizzato
FCL,MCL,HCL, DLCL
Trapianto
LLC, Trapianto
FCL
Radiation-induced cytolysisEffector mechanisms
TARGET ANTIGENS: •NOT SHED•NOT INTERNALIZED ?
RADIOIMMUNOCONJUGATE
NB. Properties of each immunoconiugate depend on which isotope is chosen
hd-CY VP16 +CDDP
hd-Ara-C
PB
SC
au
tog
raft
ing
A P O PBSCharvest
G-CSFG-CSF
PBSCharvest
G-CSF
C-HDS + Rituximab schedule
RITUXIMAB
C-HDS + Rituximab in high-risk DLCL patients: a multicenter italian study
R- HDS
historical
82%
46-57%
71 % (3yr.)
CR OS
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
40
100
P<0.005
PCR negative
PCR positive
% s
urv
ivin
g
80
60
20
0
0 2 10 12
years4 6 8
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
week 20 6 10 14 24 28
Id/KLH
(0.5 mg + 0.5 mg)
GM-CSF
(150 µg/sqm)
VACCINATION SCHEDULE
• 15 MM in first remission after HDS and PBPC infusion;
Protein-based vaccine
tum
or
bu
rden
remission
threshold
timediagnosis relapse
remission phase
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
%
0
25
50
75
100
0 5 10
III-IV (n=259)
I-II (n=153)
Years after relapse
SURVIVAL byAnn Arbor stage at relapse
I . I . L .1999
p<0.0001