• 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